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<p><strong>The dark side of stress (learned helplessness)</strong> </p>
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Acetylcholine is the "neurotransmitter" of cholinergic nerves, including the parasympathetic system.
Cholinesterase (or acetylcholinesterase) is an enzyme that destroys acetylcholine, limiting the action of the
cholinergic nerves. Attaching a phosphate group to the cholinesterase enzyme inactivates it, prolonging and
intensifying the action of cholinergic stimulation.
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The autonomic nervous system has traditionally been divided into the sympathetic-adrenergic system, and the
parasympathetic-cholinergic system, with approximately opposing functions, intensifying energy expenditure and
limiting energy expenditure, respectively. The hormonal system and the behavioral system interact with these
systems, and each is capable of disrupting the others. Disruptive factors in the environment have increased in
recent decades.
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Living is development; the choices we make create our individuality. If genetically identical mice grow up in a
large and varied environment, small differences in their experience will affect cell growth in their brains,
leading to large differences in their exploratory behavior as they age (Freund, et al., 2013). Geneticists used
to say that "genes determine our limits," but this experiment shows that an environment can provide both
limitations and opportunities for expanding the inherited potential. If our environment restricts our choices,
our becoming human is thwarted, the way rats' potentials weren't discovered when they were kept in the standard
little laboratory boxes. An opportunity to be complexly involved in a complex environment lets us become more of
what we are, more humanly differentiated. A series of experiments that started at the University of California
in 1960 found that rats that lived in larger spaces with various things to explore were better at learning and
solving problems than rats that were raised in the standard little laboratory cages (Krech, et al., 1960).
Studying their brains, they found that the enzyme cholinesterase, which destroys the neurotransmitter,
acetylcholine, was increased. They later found that the offspring of these rats were better learners than their
parents, and their brains contained more cholinesterase. Their brains were also larger, with a considerable
thickening of the cortex, which is considered to be the part mainly responsible for complex behavior, learning
and intelligence. These processes aren't limited to childhood. For example, London taxi drivers who learn all
the streets in the city develop a larger hippocampus, an area of the brain involved with memory. The 1960s
research into environmental enrichment coincided with political changes in the US, but it went against the
dominant scientific ideas of the time. Starting in 1945, the US government had begun a series of projects to
develop techniques of behavior modification or mind control, using drugs, isolation, deprivation, and torture.
In the 1950s, psychiatry often used lobotomies (about 80,000, before they were generally discontinued in the
1980s) and electroconvulsive "therapy," and university psychologists tortured animals, often as part of
developing techniques for controlling behavior. The CIA officially phased out their MKultra program in 1967, but
that was the year that Martin Seligman, at the University of Pennsylvania, popularized the idea of "learned
helplessness." He found that when an animal was unable to escape from torture, even for a very short time, it
would often fail to even try to escape the next time it was tortured. Seligman's lectures have been attended by
psychologists who worked at Guantanamo, and he recently received a no-bid Pentagon grant of $31,000,000, to
develop a program of "comprehensive soldier fitness," to train marines to avoid learned helplessness. Curt
Richter already in 1957 had described the "hopelessness" phenomenon in rats (“a reaction of hopelessness is
shown by some wild rats very soon after being grasped in the hand and prevented from moving. They seem literally
to give up,”) and even how to cure their hopelessness, by allowing them to have an experience of escaping once
(Richter, 1957, 1958). Rats which would normally be able to keep swimming in a tank for two or three days,
would often give up and drown in just a few minutes, after having an experience of "inescapable stress." Richter
made the important discovery that the hearts of the hopeless rats slowed down before they died, remaining
relaxed and filled with blood, revealing the dominant activity of the vagal nerve, secreting acetylcholine. The
sympathetic nervous system (secreting noradrenaline) accelerates the heart, and is usually activated in stress,
in the "fight or flight" reaction, but this radically different (parasympathetic) nervous activity hadn't
previously been seen to occur in stressful situations. The parasympathetic, cholinergic, nervous system had been
thought of as inactive during stress, and activated to regulate processes of digestion, sleep, and repair.
Besides the cholinergic nerves of the parasympathetic system, many nerves of the central nervous system also
secrete acetylcholine, which activates smooth muscles, skeletal muscles, glands, and other nerves, and also has
some inhibitory effects. The parasympathetic nerves also secrete the enzyme, cholinesterase, which destroys
acetylcholine. However, many other types of cell (red blood cells, fibroblasts, sympathetic nerves, marrow
cells), maybe all cells, can secrete cholinesterase. Because cholinergic nerves have been opposed to the
sympathetic, adrenergic, nerves, there has been a tendency to neglect their nerve exciting roles, when looking
at causes of excitotoxicity, or the stress-induced loss of brain cells. Excessive cholinergic stimulation,
however, can contribute to excitotoxic cell death, for example when it's combined with high cortisol and/or
hypoglycemia. Drugs that block the stimulating effects of acetylcholine (the anticholinergics) as well as
chemicals that mimic the effects of acetylcholine, such as the organophosphate insecticides, can impair the
ability to think and learn. This suggested to some people that age-related dementia was the result of the
deterioration of the cholinergic nerves in the brain. Drugs to increase the stimulating effects of acetylcholine
in the brain (by inactivating cholinesterase) were promoted as treatment for Alzheimer's disease. Although
herbal inhibitors were well known, profitable new drugs, starting with Tacrine, were put into use. It was soon
evident that Tacrine was causing serious liver damage, but wasn't slowing the rate of mental deterioration. As
the failure of the cholinergic drug Tacrine was becoming commonly known, another drug, amantadine (later, the
similar memantine) was proposed for combined treatment. In the 1950s, the anticholinergic drug atropine was
proposed a few times for treating dementia, and amantadine, which was also considered anticholinergic, was
proposed for some mental conditions, including Creutzfeldt-Jacob Disease (Sanders and Dunn, 1973). It must have
seemed odd to propose that an anticholinergic drug be used to treat a condition that was being so profitably
treated with a pro-cholinergic drug, but memantine came to be classified as an anti-excitatory "NMDA blocker,"
to protect the remaining cholinergic nerves, so that both drugs could logically be prescribed simultaneously.
The added drug seems to have a small beneficial effect, but there has been no suggestion that this could be the
result of its previously-known anticholinergic effects. Over the years, some people have suspected that
Alzheimer's disease might be caused partly by a lack of purpose and stimulation in their life, and have found
that meaningful, interesting activity could improve their mental functioning. Because the idea of a "genetically
determined hard-wired" brain is no longer taught so dogmatically, there is increasing interest in this therapy
for all kinds of brain impairment. The analogy to the Berkeley enrichment experience is clear, so the
association of increasing cholinesterase activity with improving brain function should be of interest. The
after-effect of poisoning by nerve gas or insecticide has been compared to the dementia of old age. The
anticholinergic drugs are generally recognized for protecting against those toxins. Traumatic brain injury, even
with improvement in the short term, often starts a long-term degenerative process, greatly increasing the
likelihood of dementia at a later age. A cholinergic excitotoxic process is known to be involved in the
traumatic degeneration of nerves (Lyeth and Hayes, 1992), and the use of anticholinergic drugs has been
recommended for many years to treat traumatic brain injuries (e.g., Ward, 1950: Ruge, 1954; Hayes, et al.,
1986). In 1976 there was an experiment (Rosellini, et al.) that made an important link between the enrichment
experiments and the learned helplessness experiments. The control animals in the enrichment experiments were
singly housed, while the others shared a larger enclosure. In the later experiment, it was found that the rats
"who were reared in isolation died suddenly when placed in a stressful swimming situation," while the
group-housed animals were resistant, effective swimmers. Enrichment and deprivation have very clear biological
meaning, and one is the negation of the other. The increase of cholinesterase, the enzyme that destroys
acetylcholine, during enrichment, serves to inactivate cholinergic processes. If deprivation does its harm by
increasing the activity of the cholinergic system, we should expect that a cholinergic drug might substitute for
inescapable stress, as a cause of learned helplessness, and that an anticholinergic drug could cure learned
helplessness. Those tests have been done: "Treatment with the anticholinesterase, physostigmine, successfully
mimicked the effects of inescapable shock." "The centrally acting anticholinergic scopolamine hydrobromide
antagonized the effects of physostigmine, and when administered prior to escape testing antagonized the
disruptive effects of previously administered inescapable shock." (Anisman, et al., 1981.) This kind of
experiment would suggest that the anticholinesterase drugs still being used for Alzheimer's disease treatment
aren't biologically helpful. In an earlier newsletter I discussed the changes of growth hormone, and its
antagonist somatostatin, in association with dementia: Growth hormone increases, somatostatin decreases. The
cholinergic nerves are a major factor in shifting those hormones in the direction of dementia, and the
anticholinergic drugs tend to increase the ratio of somatostatin to growth hormone. Somatostatin and
cholinesterase have been found to co-exist in single nerve cells (Delfs, et al., 1984). Estrogen, which was
promoted so intensively as prevention or treatment for Alzheimer's disease, was finally shown to contribute to
its development. One of the characteristic effects of estrogen is to increase the level of growth hormone in the
blood. This is just one of many ways that estrogen is associated with cholinergic activation. During pregnancy,
it's important for the uterus not to contract. Cholinergic stimulation causes it to contract; too much estrogen
activates that system, and causes miscarriage if it's excessive. An important function of progesterone is to
keep the uterus relaxed during pregnancy. In the uterus, and in many other systems, progesterone increases the
activity of cholinesterase, removing the acetylcholine which, under the influence of estrogen, would cause the
uterus to contract. Progesterone is being used to treat brain injuries, very successfully. It protects against
inflammation, and in an early study, compared to placebo, lowered mortality by more than half. It's instructive
to consider its anticholinergic role in the uterus, in relation to its brain protective effects. When the brain
is poisoned by an organophosphate insecticide, which lowers the activity of cholinesterase, seizures are likely
to occur, and treatment with progesterone can prevent those seizures, reversing the inhibition of the enzyme
(and increasing the activity of cholinesterase in rats that weren't poisoned) (Joshi, et al., 2010). Similar
effects of progesterone on cholinesterase occur in menstrually cycling women (Fairbrother, et al., 1989),
implying that this is a general function of progesterone, not just something to protect pregnancy. Estrogen,
with similar generality, decreases the activity of cholinesterase. DHEA, like progesterone, increases the
activity of cholinesterase, and is brain protective (Aly, et al., 2011). Brain trauma consistently leads to
decreased activity of this enzyme (Östberg, et al., 2011; Donat, et al., 2007), causing the acetylcholine
produced in the brain to accumulate, with many interesting consequences. In 1997, a group (Pike, et al.) created
brain injuries in rats to test the idea that a cholinesterase inhibitor would improve their recovery and ability
to move through a maze. They found instead that it reduced the cognitive ability of both the injured and normal
rats. An anticholinergic drug, selegeline (deprenyl) that is used to treat Parkinson's disease and, informally,
as a mood altering antiaging drug, was found by a different group (Zhu, et al., 2000) to improve cognitive
recovery from brain injuries. One of acetylcholine's important functions, in the brain as elsewhere, is the
relaxation of blood vessels, and this is done by activating the synthesis of NO, nitric oxide. (Without NO,
acetylcholine constricts blood vessels; Librizzi, et al., 2000.) The basic control of blood flow in the brain is
the result of the relaxation of the wall of blood vessels in the presence of carbon dioxide, which is produced
in proportion to the rate at which oxygen and glucose are being metabolically combined by active cells. In the
inability of cells to produce CO2 at a normal rate, nitric oxide synthesis in blood vessels can cause them to
dilate. The mechanism of relaxation by NO is very different, however, involving the inhibition of mitochondrial
energy production (Barron, et al., 2001). Situations that favor the production and retention of a larger amount
of carbon dioxide in the tissues are likely to reduce the basic "tone" of the parasympathetic nervous system, as
there is less need for additional vasodilation. Nitric oxide can diffuse away from the blood vessels, affecting
the energy metabolism of nerve cells (Steinert, et al., 2010). Normally, astrocytes protect nerve cells from
nitric oxide (Chen, et al., 2001), but that function can be altered, for example by bacterial endotoxin absorbed
from the intestine (Solà, et al., 2002) or by amyloid-beta (Tran, 2001), causing them to produce nitric oxide
themselves. Nitric oxide is increasingly seen as an important factor in nerve degeneration (Doherty, 2011).
Nitric oxide activates processes (Obukuro, et al., 2013) that can lead to cell death. Inhibiting the production
of nitric oxide protects against various kinds of dementia (Sharma & Sharma, 2013; Sharma & Singh,
2013). Brain trauma causes a large increase in nitric oxide formation, and blocking its synthesis improves
recovery (Hüttemann, et al., 2008; Gahm, et al., 2006). Organophosphates increase nitric oxide formation, and
the protective anticholinergic drugs such as atropine reduce it (Chang, et al., 2001; Kim, et al., 1997).
Stress, including fear (Campos, et al., 2013) and isolation (Zlatković & Filipović, 2013) can activate the
formation of nitric oxide, and various mediators of inflammation also activate it. The nitric oxide in a
person's exhaled breath can be used to diagnose some diseases, and it probably also reflects the level of their
emotional well-being. The increase of cholinesterase by enriched living serves to protect tissues against an
accumulation of acetylcholine. The activation of nitric oxide synthesis by acetylcholine tends to block energy
production, and to activate autolytic or catabolic processes, which are probably involved in the development of
a thinner cerebral cortex in isolated or stressed animals. Breaking down acetylcholine rapidly, the tissue
renewal processes are able to predominate in the enriched animals. Environmental conditions that are favorable
for respiratory energy production are protective against learned helplessness and neurodegeneration, and other
biological problems that involve the same mechanisms. Adaptation to high altitude, which stimulates the
formation of new mitochondria and increased thyroid (T3) activity, has been used for many years to treat
neurological problems, and the effect has been demonstrated in animal experiments (Manukhina, et al., 2010).
Bright light can reverse the cholinergic effects of inescapable stress (Flemmer, et al., 1990). During the
development of learned helplessness, the T3 level in the blood decreases (Helmreich, et al., 2006), and removal
of the thyroid gland creates the "escape deficit," while supplementing with thyroid hormone before exposing the
animal to inescapable shock prevents its development (Levine, et al., 1990). After learned helplessness has been
created in rats, supplementing with T3 reverses it (Massol, et al., 1987, 1988). Hypothyroidism and excess
cholinergic tone have many similarities, including increased formation of nitric oxide, so that similar
symptoms, such as muscle inflammation, can be produced by cholinesterase inhibitors such as Tacrine, by
increased nitric oxide, or by simple hypothyroidism (Jeyarasasingam, et al., 2000; Franco, et al., 2006).
Insecticide exposure has been suspected to be a factor in the increased incidence of Alzheimer's disease
(Zaganas, et al., 2013), but it could be contributing to many other problems, involving inflammation, edema, and
degeneration. Another important source of organophosphate poisoning is the air used to pressurize airliners,
which can be contaminated with organophosphate fumes coming from the engine used to compress it. Possibly the
most toxic component of our environment is the way the society has been designed, to eliminate meaningful
choices for most people. In the experiment of Freund, et al., some mice became more exploratory because of the
choices they made, while others' lives became more routinized and limited. Our culture reinforces routinized
living. In the absence of opportunities to vary the way you work and live to accord with new knowledge that you
gain, the nutritional, hormonal and physical factors have special importance. Supplements of thyroid and
progesterone are proven to be generally protective against the cholinergic threats, but there are many other
factors that can be adjusted according to particular needs. Niacinamide, like progesterone, inhibits the
production of nitric oxide, and also like progesterone, it improves recovery from brain injury (Hoane, et al.,
2008). In genetically altered mice with an Alzheimer's trait, niacinamide corrects the defect (Green, et al.,
2008). Drugs such as atropine and antihistamines can be used in crisis situations. Bright light, without excess
ultraviolet, should be available every day. The cholinergic system is much more than a part of the nervous
system, and is involved in cell metabolism and tissue renewal. Most people can benefit from reducing intake of
phosphate, iron, and polyunsaturated fats (which can inhibit cholinesterase; Willis, et al., 2009), and from
choosing foods that reduce production and absorption of endotoxin. And, obviously, drugs that are intended to
increase the effects of nitric oxide (asparagine, zildenafil/Viagra, minoxidil/Rogaine) and acetylcholine
(bethanechol, benzpyrinium, etc.) should be avoided.
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complex I inactivation due to translocated neuronal nitric-oxide synthase. </strong>Franco MC, Antico
Arciuch VG, Peralta JG, Galli S, Levisman D, López LM, Romorini L, Poderoso JJ, Carreras MC. Laboratory of
Oxygen Metabolism, University Hospital, Facultad de Medicina, University of Buenos Aires, 1120-Buenos Aires,
Argentina. Although transcriptional effects of thyroid hormones have substantial influence on oxidative
metabolism,<span><strong> how thyroid sets basal metabolic rate remains obscure.</strong></span>
<span><strong>Compartmental localization of nitric-oxide synthases is important for nitric</strong></span>
<span><strong>oxide signaling. We therefore examined liver neuronal nitric-oxide synthase-alpha</strong></span>
<span><strong>(nNOS) subcellular distribution as a putative mechanism for thyroid effects on</strong></span>
<span><strong>rat metabolic rate. At low 3,3',5-triiodo-L-thyronine levels, nNOS mRNA increased</strong></span>
<span><strong>by 3-fold, protein</strong></span> expression by one-fold, and nNOS was selectively
translocated to mitochondria without changes in other isoforms. In contrast, under thyroid hormone
administration, mRNA level did not change and nNOS remained predominantly localized in cytosol. In
hypothyroidism, nNOS translocation resulted in enhanced mitochondrial nitric-oxide synthase activity with
low O2 uptake. In this context, NO utilization increased active O2 species and peroxynitrite yields and
tyrosine nitration of complex I proteins that reduced complex activity. Hypothyroidism was also associated
to high phospho-p38 mitogen-activated protein kinase and decreased phospho-extracellular signal-regulated kinase
1/2 and cyclin D1 levels.
<span><strong>Similarly to thyroid hormones, but without changing thyroid status, nitric-oxide </strong
></span>
<span><strong>synthase inhibitor N(omega)-nitro-L-arginine methyl ester increased basal</strong></span>
<span><strong>metabolic rate, prevented mitochondrial nitration and complex I derangement, and </strong
></span>
<span><strong>turned mitogen-activated protein kinase signaling and cyclin D1 expression back</strong></span>
<span><strong>to control pattern. We surmise that nNOS spatial confinement in mitochondria is a</strong></span>
<span><strong>significant downstream effector of thyroid hormone and hypothyroid phenotype.</strong></span>
Toxicology. 2013 May 10;307:3-11.<strong> Linking pesticide exposure and dementia: what is the
evidence? </strong>Zaganas I, Kapetanaki S, Mastorodemos V, Kanavouras K, Colosio C, Wilks MF,
Tsatsakis AM. J Pharmacol Exp Ther. 2000 Oct;295(1):314-20.<strong> Nitric oxide is involved in
acetylcholinesterase inhibitor-induced myopathy in rats. </strong>Jeyarasasingam G, Yeluashvili M, Quik
M. Neuroreport. 2000 Apr 27;11(6):1173-6.<strong> Tacrine, a reversible acetylcholinesterase inhibitor,
induces myopathy.</strong> Jeyarasasingam G, Yeluashvili M, Quik M. Biochem Biophys Res Commun. 2002
Jan 11;290(1):97-104. NO synthesis, unlike respiration, influences intracellular oxygen tension. Coste J, Vial
JC, Faury G, Deronzier A, Usson Y, Robert-Nicoud M, Verdetti J. We have developed a new phosphorescent probe,
PdTCPPNa(4), whose luminescence properties are affected by local variations of intracellular oxygen tension
(PO(2)). Spectrofluorometric measurements on living human umbilical venous endothelial cells loaded with this
molecule show that a decrease in extracellular oxygen tension induces a decrease of PO(2), illustrating the
phenomenon of oxygen diffusion and validating the use of this probe in living cells. Moreover, KCN- or
2,4-dinitrophenol-induced modifications of respiration do not lead to detectable PO(2) variations, probably
because O(2) diffusion is sufficient to allow oxygen supply. On the contrary,<strong> activation by
acetylcholine or endothelial nitric oxide synthase (eNOS), which produces NO while consuming oxygen, induces
a significant decrease in PO(2), whose amplitude is dependent on the acetylcholine dose, i.e., the eNOS
activity level. </strong>Hence, activated cytosolic enzymes could consume high levels of oxygen which
cannot be supplied by diffusion, leading to PO(2) decrease. Other cell physiology mechanisms leading to PO(2)
variations can now be studied in living cells with this probe. Science. 1984 Jan 6;223(4631):61-3. <strong
>Coexistence of acetylcholinesterase and somatostatin-immunoreactivity in neurons cultured from rat
cerebrum.</strong> Delfs JR, Zhu CH, Dichter MA. Genes Nutr. 2009 December; 4(4): 309–314.<strong
> Dietary polyunsaturated fatty acids improve cholinergic transmission in the aged brain</strong
> Willis LM, Shukitt-Hale B, Joseph JA. Toxicology. 2013 May 10;307:3-11. Linking pesticide exposure and
dementia: what is the evidence? Zaganas I, Kapetanaki S, Mastorodemos V, Kanavouras K, Colosio C, Wilks MF,
Tsatsakis AM. s sufficient for oxidative phosphorylation (references in ref. 1). These findings indicate that,
in execution of these tasks, the involved brain tissue switches to aerobic glycolysis. Acta Neurochir Suppl.
1997;70:130-3. Topical application of insulin like growth factor-1 reduces edema and upregulation of neuronal
nitric oxide synthase following trauma to the rat spinal cord. Sharma HS, Nyberg F, Gordh T, Alm P, Westman J.
Toxicol Appl Pharmacol. 2013 Aug 3. pii: S0041-008X(13)00326-8. <strong>Arsenic toxicity induced
endothelial dysfunction and dementia: Pharmacological interdiction by histone deacetylase and inducible
nitric oxide synthase inhibitors.</strong> Sharma B, Sharma PM. 2. Pharmacol Biochem Behav. 2013
Feb;103(4):821-30. <strong> Pharmacological inhibition of inducible nitric oxide synthase (iNOS) and
nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, convalesce behavior and biochemistry of
hypertension induced vascular dementia in rats. </strong>Sharma B, Singh N. CNS and CVS Research Lab.,
Pharmacology Division, Department of Pharmaceutical Sciences and Drug Research, Faculty of Medicine, Punjabi
University, Patiala 147002, Punjab, India. <a href="mailto:bhupeshresearch@gmail.com" target="_blank"
>bhupeshresearch@gmail.com</a>
Cognitive disorders are likely to increase over the coming years (5-10). Vascular dementia (VaD) has
heterogeneous pathology and is a challenge for clinicians. Current Alzheimer's disease drugs have had limited
clinical efficacy in treating VaD and none have been approved by major regulatory authorities specifically
for this disease. Role of iNOS and NADPH-oxidase has been reported in various pathological conditions but
there role in hypertension (Hypt) induced VaD is still unclear. This research work investigates the salutiferous
effect of aminoguanidine (AG), an iNOS inhibitor and 4'-hydroxy-3'-methoxyacetophenone (HMAP), a NADPH oxidase
inhibitor in Hypt induced VaD in rats. Deoxycorticosterone acetate-salt (DOCA-S) hypertension has been used for
development of VaD in rats. Morris water-maze was used for testing learning and memory. Vascular system
assessment was done by testing endothelial function. Mean arterial blood pressure (MABP), oxidative stress
[aortic superoxide anion, serum and brain thiobarbituric acid reactive species (TBARS) and brain
glutathione (GSH)], nitric oxide levels (serum nitrite/nitrate) and cholinergic activity (brain acetyl
cholinesterase activity-AChE) were also measured. DOCA-S treated rats have shown increased MABP with impairment
of endothelial function, learning and memory, reduction in serum nitrite/nitrate & brain GSH levels
along with increase in serum & brain TBARS, and brain AChE activity. AG as well as HMAP significantly
convalesce Hypt induced impairment of learning, memory, endothelial function, and alterations in various
biochemical parameters. It may be concluded that AG, an iNOS inhibitor and HMAP, a NADPH-oxidase inhibitor
may be considered as potential agents for the management of Hypt induced VaD. Copyright © 2012 Elsevier
Inc. All rights reserved. [Curr Pharm Des. 2010;16(25):2837-50. Nitric oxide: target for therapeutic strategies
in Alzheimer's disease. Fernandez AP, Pozo-Rodrigalvarez A, Serrano J, Martinez-Murillo R. "<strong>data
implicating nitric oxide (NO) in the progression of the disease. The three isoforms of the NO-synthesizing
enzyme (NOS) operate as central mediators of amyloid beta-peptide (Aβ) action, giving rise to elevated
levels of NO that contributes to the maintenance, self-perpetuation and progression of the disease.</strong
> "] J Neuropathol Exp Neurol. 2007 Apr;66(4):272-83. Nitric oxide synthase 3-mediated neurodegeneration
after intracerebral gene delivery. de la Monte SM, Jhaveri A, Maron BA, Wands JR. "<strong>increased nitric
oxide synthase 3 (NOS3) expression correlates with apoptosis in cortical neurons and colocalizes with
amyloid precursor protein (APP)-amyloid beta (Abeta) deposits in the brain."</strong>
Neuroscience. 2000;101(2):283-7. <strong>Nitric oxide synthase inhibitors unmask acetylcholine-mediated
constriction of cerebral vessels in the in vitro isolated guinea-pig brain.</strong> Librizzi L, Folco
G, de Curtis M. Pharmacology. 2000 Feb;60(2):82-9. Choline is a full agonist in inducing activation of neuronal
nitric oxide synthase via the muscarinic M1 receptor. Carriere JL, El-Fakahany EE. Glia. 2003 Jan
15;41(2):207-11. Alzheimer's disease is associated with a selective increase in alpha7 nicotinic acetylcholine
receptor immunoreactivity in astrocytes. Teaktong T, Graham A, Court J, Perry R, Jaros E, Johnson M, Hall R,
Perry E. 16. Neuroscientist. 2010 Aug;16(4):435-52.
<strong>Nitric oxide signaling in brain function, dysfunction, and dementia.</strong>
Steinert JR, Chernova T, Forsythe ID. Neurotoxicity at the Synaptic Interface, MRC Toxicology Unit, University
of Leicester, Leicester, UK. Nitric oxide (NO) is an important signaling molecule that is widely used in the
nervous system. With recognition of its roles in synaptic plasticity (long-term potentiation, LTP; long-term
depression, LTD) and elucidation of calcium-dependent, NMDAR-mediated activation of neuronal nitric oxide
synthase (nNOS), numerous molecular and pharmacological tools have been used to explore the physiology and
pathological consequences for nitrergic signaling. In this review, the authors summarize the current
understanding of this subtle signaling pathway, discuss the evidence for nitrergic modulation of ion
channels and homeostatic modulation of intrinsic excitability, and speculate about the pathological consequences
of spillover between different nitrergic compartments in contributing to aberrant signaling in neurodegenerative
disorders. Accumulating evidence points to various ion channels and particularly voltage-gated potassium
channels as signaling targets, whereby NO mediates activity-dependent control of intrinsic neuronal
excitability; such changes could underlie broader mechanisms of synaptic plasticity across neuronal networks. In
addition, <strong>the inability to constrain NO diffusion suggests that spillover from</strong>
<strong>endothelium (eNOS) and/or immune compartments (iNOS) into the nervous system</strong>
<strong>provides potential pathological sources of NO and where control failure in these </strong>
<strong>other systems could have broader neurological implications. </strong>Abnormal NO signaling could
therefore contribute to a variety of neurodegenerative pathologies such as stroke/excitotoxicity,
Alzheimer's disease, multiple sclerosis, and Parkinson's disease. Neurosci Bull. 2011 Dec;27(6):366-82. Nitric
oxide in neurodegeneration: potential benefits of non-steroidal anti-inflammatories. Doherty GH.18.
Neuroscience. 2010 Dec 15;171(3):859-68. Low energy laser light (632.8 nm) suppresses amyloid-β peptide-induced
oxidative and inflammatory responses in astrocytes. Yang X, Askarova S, Sheng W, Chen JK, Sun AY, Sun GY, Yao G,
Lee JC. Neurosci Behav Physiol. 2010 Sep;40(7):737-43. <strong>Prevention of neurodegenerative damage to
the brain in rats in experimental Alzheimer's disease by adaptation to hypoxia.</strong> Manukhina EB,
Goryacheva AV, Barskov IV, Viktorov IV, Guseva AA, Pshennikova MG, Khomenko IP, Mashina SY, Pokidyshev DA,
Malyshev IY. Physiol Behav. 1990 Jul;48(1):165-7.
<strong>Thyroparathyroidectomy produces a progressive escape deficit in rats.</strong>
Levine JD, Strauss LR, Muenz LR, Dratman MB, Stewart KT, Adler NT. Department of Anatomy, University of
Pennsylvania, Philadelphia. Abnormal thyroid status and affective disorders have been associated in the human
clinical literature. It has recently been shown <strong>that pretreatment with thyroid</strong>
<strong>hormone can prevent escape deficits produced by inescapable shock in an animal</strong>
<strong>analogue of depression.</strong> In this report we provide evidence that <strong
>hypothyroid</strong>
<strong>status can produce an escape deficit in rats.</strong> While sham-operated rats improved their
performance on a simple escape task over three days of testing, thyroparathyroidectomized rats showed a
pronounced decrease in their responses. Markov transition analysis was used to obtain conditional probabilities
of escaping given a prior escape or failure to escape for the two groups. This analysis shows that the structure
of the data set may be similar for the two groups. These results suggest that if intact rats learn to escape,
then hypothyroid rats may learn not to escape. 1. Pharmacol Biochem Behav. 1990 Aug;36(4):775-8.
<strong>Bright light blocks the capacity of inescapable swim stress to supersensitize a</strong>
<strong>central muscarinic mechanism.</strong>
Flemmer DD, Dilsaver SC, Peck JA. Department of Psychiatry, Ohio State University. Clinical and basic
researchers have proposed that muscarinic cholinergic mechanisms mediate some effects of chronic stress. Chronic
inescapable (forced) swim stress depletes brain biogenic amines and is used to produce learned helplessness in
rats. Behavioral and biochemical characteristics of animals in the state of learned helplessness lead some
investigators to believe this condition provides a useful animal model of depression. <strong>Inescapable
swim stress</strong>
<strong>also produces supersensitivity to the hypothermic effect of the muscarinic</strong>
<strong>agonist oxotremorine in the rat. </strong>The authors previously demonstrated that bright
light potently induces subsensitivity of a central muscarinic mechanism involved in the regulation of core
temperature under a variety of circumstances. They now report using a repeated measures design that
inescapable swim stress of five days duration produces supersensitivity to oxotremorine (increase in thermic
response of 405%). This <strong>supersensitivity is reversed within five days by treatment
with</strong>
<strong>bright light, despite continuation of daily swim stress. Daily inescapable swim</strong>
<strong>stress was continued beyond cessation of treatment with bright light. </strong>Five days later,
supersensitivity to the hypothermic effect of oxotremorine was once again evident. Pharmacol Biochem
Behav. 1986 Aug;25(2):415-21. Neurochemical and behavioral consequences of mild, uncontrollable shock:
effects of PCPA. Edwards E, Johnson J, Anderson D, Turano P, Henn FA. The present experiments
examined the role of the serotonergic system in the behavioral deficit produced by uncontrollable shock.
In Experiment 1: Establishment of model, the behavioral potential of the Sprague-Dawley rat was
defined. When exposed to mild uncontrollable stress such as a 0.8 mA electric footshock, a significant
percentage of rats developed a shock escape deficit which was evident when subsequently placed in a shock
escape paradigm. Serotonin depletion was produced by chronic treatment with p-chlorophenylalanine.
Biogenic amine levels and 5-HT levels were monitored in various brain areas using HPLC. Following
chronic treatment with PCPA, the shock escape capability of the Sprague-Dawley rat was
assessed. <strong>The severe depletion of 5-HT in various brain </strong>
<strong>regions was highly correlated with a dramatic improvement in the shock escape </strong>
<strong>scores. Thus, the detrimental effects of exposure to a mild course of inescapable </strong>
<strong>shock can be prevented by chronic treatment with PCPA</strong>. These experiments implicate the
serotonergic system as a possible mediator of the "learned helplessness" phenomenon. Biol
Psychiatry. 1985 Sep;20(9):1023-5. Triiodothyronine-induced reversal of learned helplessness in
rats. Martin P, Brochet D, Soubrie P, Simon P. Pharmacol Biochem Behav. 1982 Nov;17(5):877-83.
Evidence for a serotonergic mechanism of the learned helplessness phenomenon. Brown L, Rosellini RA,
Samuels OB, Riley EP. The present experiments examined the role of the serotonergic system in the
learned helplessness phenomenon. In Experiment 1, a 200 mg/kg dose of 1-tryptophan injected 30 min prior
to testing disrupted acquisition of Fixed Ratio 2 shuttle escape behavior. In Experiment 2, a 100 mg/kg
dose of 5-HTP produced interference with the acquisition of the escape response. Furthermore, this
interference was prevented by treatment with the serotonergic antagonist methysergide. In Experiment 3,
animals were pretreated with a subeffective dose of 1-tryptophan in combination with subeffective exposure
to inescapable shock. These animals showed a deficit in the acquisition of FR-2 shuttle escape. In
Experiment 4, combined exposure to a subeffective dose of 5-HTP and inescapable shock (40 trials) resulted
in an acquisition deficit. This deficit was reversed by methysergide. Experiment 5 showed that the
detrimental effects of exposure to prolonged (80 trials) of inescapable shock can be prevented by
treatment with methysergide. These studies implicate the serotonergic system as a possible mediator
of the learned helplessness phenomenon. 45. Med Hypotheses. 2004;63(2):308-21. Brain cholinesterases: II.
The molecular and cellular basis of Alzheimer's disease. Shen ZX. 2436 Rhode Island Avenue #3, Golden valley, MN
55427-5011, USA.
<a href="mailto:zhengxshen@yahoo.com" target="_blank">zhengxshen@yahoo.com</a>
Currently available evidence demonstrates that cholinesterases (ChEs), owing to their powerful enzymatic and
non-catalytic actions, unusually strong electrostatics, and <strong>exceptionally ubiquitous presence and
redundancy in their</strong>
<strong>capacity as the connector, the organizer and the safeguard of the brain, </strong>play fundamental
role(s) in the well-being of cells, tissues, animal and human lives, while they present themselves
adequately in quality and quantity. The widespread intracellular and extracellular membrane networks of
ChEs in the brain are also subject to various insults, such as aging, gene anomalies, environmental hazards,
head trauma, excessive oxidative stress, imbalances and/or deficits of organic constituents. The loss and the
alteration of ChEs on the outer surface membranous network may initiate the formation of extracellular senile
plaques and induce an outside-in cascade of Alzheimer's disease (AD). The alteration in ChEs on the
intracellular compartments membranous network may give rise to the development of intracellular neurofibrillary
tangles and induce an inside-out cascade of AD. The abnormal patterns of glycosylation and configuration changes
in ChEs may be reflecting their impaired metabolism at the molecular and cellular level and causing the
enzymatic and pharmacodynamical modifications and neurotoxicity detected in brain tissue and/or CSF of patients
with AD and in specimens in laboratory experiments. The inflammatory reactions mainly arising from
ChEs-containing neuroglial cells may facilitate the pathophysiologic process of AD. It is proposed that brain
ChEs may serve as a central point rallying various hypotheses regarding the etio-pathogenesis of AD. 3.
Neurology. 2011 Mar 22;76(12):1046-50. doi: 10.1212/WNL.0b013e318211c1c4. Cholinergic dysfunction after
traumatic brain injury: preliminary findings from a PET study. Östberg A, Virta J, Rinne JO, Oikonen V, Luoto P,
Någren K, Arponen E, Tenovuo O. Department of Neurology, University of Turku and Turku University Central
Hospital, Turku, Finland. OBJECTIVE: There is evidence that the cholinergic system is frequently involved in the
cognitive consequences of traumatic brain injury (TBI). We studied whether the brain cholinergic function is
altered after TBI in vivo using PET. METHODS: Cholinergic function was assessed with
[methyl-(11)C]N-methylpiperidyl-4-acetate, which reflects the acetylcholinesterase (AChE) activity, in 17
subjects more than 1 year after a TBI and in 12 healthy controls. All subjects had been without any centrally
acting drugs for at least 4 weeks. RESULTS: The AChE activity was significantly lower in subjects with TBI
compared
<hr />
0.004). CONCLUSIONS: Patients with chronic cognitive symptoms after TBI show widely lowered AChE activity across
the neocortex. © 2011 by AAN Enterprises, Inc. 9. Brain Inj. 2007 Sep;21(10):1031-7. Alterations of
acetylcholinesterase activity after traumatic brain injury in rats. Donat CK, Schuhmann MU, Voigt C, Nieber K,
Schliebs R, Brust P. Institute of Interdisciplinary Isotope Research, Permoserstasse 15, 04318 Leipzig,
Germany. <a href="mailto:donat@iif-leipzig.de" target="_blank">donat@iif-leipzig.de</a>
OBJECTIVE: The cholinergic system is highly vulnerable to traumatic brain injury (TBI). However, limited
information is available to what extent the degrading enzyme acetylcholinesterase (AChE) is involved. The
present study addresses this question. METHOD: Thirty-six anaesthetized Sprague-Dawley rats were subjected
to sham operation or to TBI using controlled cortical impact (CCI). The AChE activity was histochemically
determined in frozen brain slices at 2, 24 and 72 hours after TBI. RESULTS: High enzyme activity was observed in
regions rich in cholinergic innervation such as the olfactory tubercle, basal forebrain, putamen and superior
colliculi.<strong> Low activity was found in the cortex, cerebellum and particularly in</strong>
<strong>the white matter. A decrease of AchE activity (20-35%) was found in the</strong>
<strong>hippocampus and hypothalamus already at 2 hours after TBI. </strong>An increase of approximately
30% was found in the basal forebrain at 2 and 24 hours. No changes occurred at 72 hours. CONCLUSION: The
findings are consistent with impairment of the cholinergic neurotransmission after TBI and suggest the
involvement of the AChE in short-term regulatory mechanisms. 35. Res Commun Chem Pathol Pharmacol. 1990
Jun;68(3):391-4. Increase of muscarinic receptor following kainic acid lesions of the nucleus basalis
magnocellularis in rat brain: an autoradiographic study. Katayama S, Kito S, Yamamura Y. Third Department of
Internal Medicine, Hiroshima University School of Medicine, Japan. We observed changes in cholinergic markers in
rat brain seven days after lesioning the nucleus basalis magnocellularis (nbm) with kainic acid. In
histochemical preparations stained for acetylcholinesterase (AChE), <strong>there was a</strong>
<strong>marked loss of large AChE reactive neurons within and beneath the nbm on the</strong>
<strong>injected side, and the AChE positive fibers were greatly decreased particularly</strong>
<strong>in the IV-VI layers of the frontal and parietal cortices ipsilateral to the</strong>
kainate lesion. Using in vitro receptor autoradiography, we found a significant increase (about 25%) in 3H-QNB
binding sites in the I-IV layers of the ipsilateral frontal and parietal cortices (p 0.05, Student's
t-test). <strong>The area</strong>
<strong>with decreased AChE activity </strong>and increased density in 3H-QNB binding sites corresponded to
the innervation of the cholinergic system arising from the nbm. The increase of density in 3H-QNB binding sites
was considered to reflect the postsynaptic denervation supersensitivity. 36. Hum Exp Toxicol. 1992
Nov;11(6):517-23. Long-term study of brain lesions following soman, in comparison to DFP and metrazol poisoning.
Kadar T, Cohen G, Sahar R, Alkalai D, Shapira S. Department of Pharmacology, Israel Institute for Biological
Research, Ness-Ziona, Israel. The long-term histopathological effects of acute lethal (95 micrograms kg-1)
and sublethal (56 micrograms kg-1) doses of soman were studied in rats and were compared to lesions caused
by equipotent doses of either another cholinesterase (ChE) inhibitor, DFP (1.8 mg kg-1), or a
non-organophosphorus convulsant, metrazol (100 mg kg-1). Severe toxic signs were noted following one LD50 dose
administration of all the compounds, yet only soman induced brain lesions. Moreover, even when administered at a
sublethal dose (0.5 LD50), soman induced some histological changes without any clinical signs of intoxication.
Soman-induced brain lesions were assessed quantitatively using a computerized image analyser. The analysis was
carried out for up to 3 months following administration, and a dynamic pattern of pathology was shown. The
cortical thickness and area of CA1 and CA3 cells declined significantly as early as 1 week post-exposure. No
pathological findings were detected following DFP and metrazol administration. It is therefore suggested
that brain lesions are not common for all ChE inhibitors and that convulsions per se are not the only factor
leading to brain damage following the administration of soman. The degenerative process (found also with the
sublethal dose of soman) might be due to a secondary effect, unrelated to soman's clinical toxicity, but leading
to long-term brain injuries. 42. J Neurotrauma. 1997 Dec;14(12):897-905.<strong> Effect of
tetrahydroaminoacridine, a cholinesterase inhibitor, on cognitive performance following experimental brain
injury. </strong>Pike BR, Hamm RJ, Temple MD, Buck DL, Lyeth BG. Department of Psychology, Virginia
Commonwealth University, Medical College of Virginia, Richmond 23284-2018, USA. An emerging literature exists in
support of deficits in cholinergic neurotransmission days to weeks following experimental traumatic brain injury
(TBI). In addition, novel cholinomimetic therapeutics have been demonstrated to improve cognitive outcome
following TBI in rats. We examined the effects of repeated postinjury administration of a cholinesterase
inhibitor, tetrahydroaminoacridine (THA), on cognitive performance following experimental TBI. Rats were either
injured at a moderate level of central fluid percussion TBI (2.1+/-0.1 atm) or were surgically prepared but not
delivered a fluid pulse (sham injury). Beginning 24 h after TBI or sham injury, rats were injected (IP) daily
for 15 days with an equal volume (1.0 ml/kg) of either 0.0, 1.0, 3.0, or 9.0
<hr />
respectively). Cognitive performance was assessed on Days 11-15 after injury in a Morris water maze
(MWM). <span><strong>Analysis of maze latencies over days indicated that</strong></span>
<span><strong>chronic administration of THA produced a dose-related impairment in MWM</strong></span>
<span><strong>performance in both the injured and sham groups, with the 9.0 mg/kg dose</strong></span>
<span><strong>producing the largest deficit. T</strong></span>he 1.0 and 3.0 mg/kg doses of THA impaired MWM
performance without affecting swimming speeds. Thus, the results of this investigation do not support the use of
THA as a cholinomimetic therapeutic for the treatment of cognitive deficits following TBI. 43. Toxicol Lett.
1998 Dec 28;102-103:527-33. Chronic effects of low level exposure to anticholinesterases--a mechanistic review.
Ray DE. Medical Research Council Toxicology Unit, Leicester, UK. <a
href="mailto:der2@le.ac.uk"
target="_blank"
>der2@le.ac.uk</a>
High dose exposure to anticholinesterases which results in symptomatic poisoning can have lasting
consequences due to the trauma of intoxication, excitotoxicity, secondary hypoxic damage, and (for some
agents) a delayed onset polyneuropathy (OPIDN). The potential effects of low level exposure are less well
defined. The most reliable data comes from controlled clinical trials with specific agents. A single dose
of sarin or repeated doses of metrifonate or mevinphos, have produced only transient adverse effects at doses
causing substantial acetylcholinesterase inhibition. Other data comes from epidemiological surveys. These
have often used more sensitive indices than the clinical studies, but are less reliable due to the
difficulty of defining exposure and matching control and exposed populations. Subtle, mainly cognitive,
differences between exposed and non-exposed populations are sometimes seen. Low level exposure can cause a
reversible down-regulation of cholinergic systems, and a range of non-cholinesterase effects that are
structure-specific, and do not always parallel acute toxicity. Novel protein targets sensitive to low level
exposure to some organophosphates are known to exist in the brain, but their functional significance is not yet
understood. 44. Exp Neurol. 2000 Nov;166(1):136-52. Postinjury administration of L-deprenyl improves cognitive
function and enhances neuroplasticity after traumatic brain injury. Zhu J, Hamm RJ, Reeves TM, Povlishock
JT, Phillips LL. Department of Anatomy, Medical College of Virginia, Richmond, Virginia 23298-0709, USA. The rat
model of combined central fluid percussion traumatic brain injury (TBI) and bilateral entorhinal cortical lesion
(BEC) produces profound, persistent cognitive deficits, sequelae associated with human TBI. In contrast to
percussive TBI alone, this combined injury induces maladaptive hippocampal plasticity. Recent reports suggest a
potential role for dopamine in CNS plasticity after trauma. We have examined the effect of the dopamine enhancer
l-deprenyl on cognitive function and neuroplasticity following TBI. Rats received fluid percussion TBI, BEC
alone, or combined TBI + BEC lesion and were treated once daily for 7 days with l-deprenyl, beginning 24 h after
TBI alone and 15 min after BEC or TBI + BEC. Postinjury motor assessment showed no effect of l-deprenyl
treatment. Cognitive performance was assessed on days 11-15 postinjury and brains from the same cases examined
for dopamine beta-hydroxylase immunoreactivity (DBH-IR) and acetylcholinesterase (AChE) histochemistry.
Significant cognitive improvement relative to untreated injured cases was observed in both TBI groups following
l-deprenyl treatment; however, no drug effects were seen with BEC alone. l-Deprenyl attenuated injury-induced
loss in DBH-IR over CA1 and CA3 after TBI alone. However, after combined TBI + BEC, l-deprenyl was only
effective in protecting CA1 DBH-IR. AChE histostaining in CA3 was significantly elevated with l-deprenyl
in both injury models. <strong>After TBI + BEC, l-deprenyl also increased AChE</strong>
<strong>in the dentate molecular layer relative to untreated injured cases. These results</strong>
<strong>suggest that dopaminergic/noradrenergic enhancement facilitates cognitive</strong>
recovery after brain injury and that noradrenergic fiber integrity is correlated with enhanced synaptic
plasticity in the injured hippocampus. Copyright 2000 Academic Press. J Neurotrauma. 1992 May;9 Suppl
2:S463-74. <strong>Cholinergic and opioid mediation of traumatic brain injury.</strong> Lyeth BG,
Hayes RL. Psychosom Med. 1976 Jan-Feb;38(1):55-8.<strong> Sudden death in the laboratory rat. </strong
>Rosellini RA, Binik YM, Seligman MP. Vulnerability to sudden death was produced in laboratory rats by
manipulating their developmental history. Rats who were reared in isolation died suddenly when placed in a
stressful swimming situation. Handling of these singly-housed rats from 25 to 100 days of age potentiated the
phenomenon. However, animals who were group housed did not die even when they had been previously handled.
J Neurol Neurosurg Psychiatry. 1973 Aug;36(4):581-4. Creutzfeldt-Jakob disease treated with amantidine. A report
of two cases. Sanders WL, Dunn TL. The treatment of two cases of Creutzfeldt-Jakob disease with amantidine is
described. The first case made a remarkable initial improvement which was sustained for two months, but then
deteriorated and died. Histological examination of the brain showed changes consistent with early
Creutzfeldt-Jakob disease. The second case which was clinically one of Creutzfeldt-Jakob disease has now been
followed for 30 months since the start of treatment and appears to be cured. It is considered that amantidine
has a definite effect in this disease and it is suggested that its mode of action, though unknown, is more
likely to be metabolic than antiviral. Free PMC Article Arch Int Pharmacodyn Ther. 1986 Mar;280(1):136-44.
Effect of stress and glucocorticoids on the gastrointestinal cholinergic enzymes. Oriaku ET, Soliman KF.
(Glucocorticoids lower AChE) Cardiovasc Res. 1990 Apr;24(4):335-9. Sympathectomy alters acetylcholinesterase
expression in adult rat heart. Nyquist Battie C, Moran N. Harris LW, Garry VF, Jr, Moore RD. Biosynthesis
of cholinesterase in rabbit bone marrow cells in culture. Biochem Pharmacol. 1974 Aug;23(15):2155–2163.
Heller M, Hanahan DJ. Human erythrocyte membrane bound enzyme acetylcholinesterase. Biochim
Biophys Acta. 1972 Jan 17;255(1):251–272. J Cell Biol. 1976 June 1; 69(3): 638–646. Bartos EM. Properties
of growth-related acetylcholinesterase in a cell line of fibroblastic origin Behav Brain Res 2000
Jul;112(1-2):33-41 Impaired escape performance and enhanced conditioned fear in rats following exposure to an
uncontrollable stressor are mediated by glutamate and nitric oxide in the dorsal raphe nucleus. Grahn RE,
Watkins LR, Maier SF. Department of Psychology, Connecticut College, Box 5275, 270 Mohegan Avenue, 06320-4196,
New London, CT 06320-4196, USA. <a href="mailto:regra@conncoll.edu" target="_blank">regra@conncoll.edu</a>
Exposure to uncontrollable aversive events produces a variety of behavioral consequences that do not occur if
the aversive event is controllable. Accumulating evidence suggests that exaggerated excitation of serotonin
(5-HT) neurons in the dorsal raphe nucleus (DRN) is sufficient to cause these same behaviors, such as poor
shuttlebox escape performance and enhanced conditioned fear that occur 24 h after exposure to inescapable
tailshock (IS). The aim of the present studies was to explore the possibility that N-methyl-D-aspartate (NMDA)
receptor activation and nitric oxide (NO) formation within the DRN might be involved in mediating the behavioral
consequences of IS. To this end, either the NMDA receptor antagonist 2-amino-5-phosphonovaleric acid (APV) or
the nitric oxide synthase inhibitor Nw-nitro-L-arginine methyl ester (L-NAME), was microinjected into the DRN
before IS or before testing 24 h later. Blocking NMDA receptors with APV in the DRN during IS prevented the
usual impact of IS on escape responding and conditioned fear. However, injection of APV at the time of testing
only reduced these effects. The DRN was shown to be the critical site mediating blockade of these behavioral
changes since injection of APV lateral to the DRN did not alter the behavioral consequences of IS. Conversely,
L-NAME was most effective in reversing the effects of IS when administered at the time of testing. These results
suggest that there is glutamatergic input to the DRN at the time of IS that produces long-lasting changes in DRN
sensitivity. This plasticity in the DRN is discussed as a possible mechanism by which IS leads to changes in
escape performance and conditioned fear responding. and prolonged depression causes shrinkage of this area. The
high cortisol associated with depression is undoubtedly one of the factors causing brain shrinkage during
stress. Cushing's disease, in which the adrenal glands produce far too much cortisol, causes shrinkage of the
brain, and when the disease is cured by normalizing the level of cortisol, the brain size is restored. There are
two very different kinds of stress reaction. The best known "fight or flight reaction" could be called more
accurately "struggle to adapt." Another, less discussed kind, might appear to be a "give up and die or get
depressed" reaction, but it involves many processes that are protective and adaptive in certain circumstances.
tone and heart rate; drown easily. The role of acetylcholine, (Anisman, et al., 1981). A situation of
extreme restraint causes very rapid damage to the tissues, with bleeding ulcers of the stomach and intestine,
shrinking of the thymus gland, and, if the animal survives for a while, atrophy of the brain. (Doi, et al.,
1991; Gatón, et al., 1993) LH, somatotropin, GH, Ach. caffeine progest Behav Brain Res. 2012 Mar
17;228(2):294-8. doi: 10.1016/j.bbr.2011.11.036. Epub 2011 Dec 8. Parental enrichment and offspring development:
modifications to brain, behavior and the epigenome. Mychasiuk R, Zahir S, Schmold N, Ilnytskyy S, Kovalchuk O,
Gibb R. University of Lethbridge, Canadian Centre for Behavioural Neuroscience, Canada.
<a href="mailto:r.mychasiuk@uleth.ca" target="_blank">r.mychasiuk@uleth.ca</a>
4. Biomed Pharmacother. 2012 Jun;66(4):249-55. doi: 10.1016/j.biopha.2011.11.005. Epub 2011 Dec 21.
Cholinesterase activities and biochemical determinations in patients with prostate cancer: influence of Gleason
score, treatment and bone metastasis. Battisti V, Bagatini MD, Maders LD, Chiesa J, Santos KF, Gonçalves JF,
Abdalla FH, Battisti IE, Schetinger MR, Morsch VM. Departamento de Química, Centro de Ciências Naturais e
Exatas, Universidade Federal de Santa Maria, Campus Universitário, 97105-900 Santa Maria, RS, Brazil.
<a href="mailto:battistivanessa@gmail.com" target="_blank">battistivanessa@gmail.com</a>
Prostate cancer (PCa) is the sixth most common type of cancer worldwide. Cholinesterase is well known as having
non-cholinergic functions such as cellular proliferation and differentiation, suggesting a possible influence of
cholinesterase in tumorogenesis. Thus, the aim of this study was to investigate the whole blood
acetylcholinesterase (AChE) and plasma butyrylcholinesterase (BChE) activities and some biochemical parameters
in PCa patients. This study was performed in 66 PCa patients and 40 control subjects. AChE and BChE activities
were determined in PCa patients and the influence of the Gleason score; bone metastasis and treatment in the
enzyme activities were also verified. Furthermore, we also analyzed possible biochemical alterations in these
patients.
<strong>AChE and BChE activities decreased in PCa patients in relation to the control</strong>
<strong>group and various biochemical changes were observed in these patients. Moreover, </strong>
<strong>Gleason score, metastasis and treatment influenced cholinesterase activities and </strong>
<strong>biochemical determinations. Our results suggest that cholinesterases activities</strong>
<strong>and biochemical parameters are altered in PCa. These facts support the idea that </strong>
<strong>t</strong>he drop in the cholinesterase activity and the consequent increased amount of acetylcholine
could lead to a cholinergic overstimulation and increase the cell proliferation in PCa. Copyright © 2011
Elsevier Masson SAS. All rights reserved. 4. Biomed Pharmacother. 2012 Jun;66(4):249-55. doi:
10.1016/j.biopha.2011.11.005. Epub 2011 Dec 21. Cholinesterase activities and biochemical determinations in
patients with prostate cancer: influence of Gleason score, treatment and bone metastasis. Battisti V, Bagatini
MD, Maders LD, Chiesa J, Santos KF, Gonçalves JF, Abdalla FH, Battisti IE, Schetinger MR, Morsch VM.
Departamento de Química, Centro de Ciências Naturais e Exatas, Universidade Federal de Santa Maria, Campus
Universitário, 97105-900 Santa Maria, RS, Brazil.
<a href="mailto:battistivanessa@gmail.com" target="_blank">battistivanessa@gmail.com</a>
Prostate cancer (PCa) is the sixth most common type of cancer worldwide. Cholinesterase is well known as having
non-cholinergic functions such as cellular proliferation and differentiation, suggesting a possible influence of
cholinesterase in tumorogenesis. Thus, the aim of this study was to investigate the whole blood
acetylcholinesterase (AChE) and plasma butyrylcholinesterase (BChE) activities and some biochemical parameters
in PCa patients. This study was performed in 66 PCa patients and 40 control subjects. AChE and BChE activities
were determined in PCa patients and the influence of the Gleason score; bone metastasis and treatment in the
enzyme activities were also verified. Furthermore, we also analyzed possible biochemical alterations in these
patients. AChE and BChE activities decreased in PCa patients in relation to the control group and various
biochemical changes were observed in these patients. Moreover, Gleason score, metastasis and treatment
influenced cholinesterase activities and biochemical determinations. Our results suggest that
cholinesterases activities and biochemical parameters are altered in PCa. These facts support the idea
that the drop in the cholinesterase activity and the consequent increased amount of acetylcholine could
lead to a cholinergic overstimulation and increase the cell proliferation in PCa. Copyright © 2011 Elsevier
Masson SAS. All rights reserved. 1. Zhongguo Ying Yong Sheng Li Xue Za Zhi. 2012 May;28(3):253-4, 262.
[Progesterone exerts neuroprotective effect on hypoxic-ischemic encephalopathy-induced brain damage via
inhibition expression of inducible nitric oxide synthase and nitric oxide production]. [Article in Chinese] Wang
XY, Li XJ, Li DL, Wang CR, Guo XP.
<a href="mailto:wxyinwxyin@163.com" target="_blank">wxyinwxyin@163.com</a>
2. Mol Reprod Dev. 2012 Oct;79(10):689-96. doi: 10.1002/mrd.22075. Epub 2012 Sep 11. Roles of cytokines and
progesterone in the regulation of the nitric oxide generating system in bovine luteal endothelial cells.
Yoshioka S, Acosta TJ, Okuda K. Laboratory of Reproductive Physiology, Graduate School of Natural Science and
Technology, Okayama University, Okayama, Japan. Nitric oxide (NO) produced by luteal endothelial cells (LECs)
plays important roles in regulating corpus luteum (CL) function, yet the local mechanism regulating NO
generation in bovine CL remains unclear. The purpose of the present study was to elucidate if tumor necrosis
factor-α (TNF), interferon γ (IFNG), and/or progesterone (P4) play roles in regulating NO generating system in
LECs. Cultured bovine LECs obtained from the CL at the mid-luteal stage (Days 8-12 of the cycle) were treated
for 24 hr with TNF (2.9 nM), IFNG (2.5 nM), or P4 (0.032-32 µM). NO production was increased by TNF and IFNG,
but decreased by P4 (P < 0.05). TNF and IFNG stimulated the relative steady-state amounts of inducible nitric
oxide synthase (iNOS) mRNA and iNOS protein expression (P < 0.05), whereas P4 inhibited relative steady-state
amounts of iNOS mRNA and iNOS protein expression (P < 0.05). In contrast, endothelial nitric oxide synthase
(eNOS) expression was not affected by any treatment. TNF and IFNG stimulated NOS activity (P < 0.05) and
1400W, a specific inhibitor of iNOS, reduced NO production stimulated by TNF and IFNG in LECs
(P < 0.05)<strong>. Onapristone,</strong>
<strong>a specific P4 receptor antagonist, blocked the inhibitory effect of P4 on NO</strong>
production in LECs (P < 0.05). The overall findings suggest that TNF and IFNG accelerate luteolysis by
increasing NO production via stimulation of iNOS expression and NOS activity in bovine LECs. P4, on the other
hand, may act in maintaining CL function by suppressing iNOS expression in bovine LECs. Mol. Reprod. Dev. 79:
689-696, 2012. © 2012 Wiley Periodicals, Inc. Copyright © 2012 Wiley Periodicals, Inc. 3. J Neurochem. 2012
Jul;122(1):185-95. doi: 10.1111/j.1471-4159.2012.07753.x. Progesterone prevents mitochondrial dysfunction in the
spinal cord of wobbler mice. Deniselle MC, Carreras MC, Garay L, Gargiulo-Monachelli G, Meyer M, Poderoso
JJ, De Nicola AF. Laboratory of Neuroendocrine Biochemistry, Instituto de Biologia y Medicina
Experimental-CONICET, Buenos Aires, Argentina. In the Wobbler mouse, a mutation of the Vps54 protein increases
oxidative stress in spinal motoneurons, associated to toxic levels of nitric oxide and hyperactivity of
nitric oxide synthase (NOS). Progesterone neuroprotection has been reported for several CNS diseases, including
the Wobbler mouse neurodegeneration. In the present study, we analyzed progesterone effects on
mitochondrial-associated parameters of symptomatic Wobbler mice. The activities of mitochondrial respiratory
chain complexes I, II-III and IV and protein levels of mitochondrial and cytosolic NOS were determined in
cervical and lumbar cords from control, Wobbler and Wobbler mice receiving a progesterone implant for 18 days.
We found a significant reduction of complex I and II-III activities in mitochondria and increased protein levels
of mitochondrial, but not cytosolic nNOS, in the cervical cord of Wobbler mice. <strong>Progesterone
treatment prevented the </strong>
<strong>reduction of complex I in the cervical region and the increased level of</strong>
<strong>mitochondrial nNOS.</strong> Wobbler motoneurons also showed accumulation of amyloid precursor
protein immunoreactivity and decreased activity and immunostaining of MnSOD. Progesterone treatment avoided
these abnormalities. Therefore, administration of progesterone to clinically afflicted Wobblers (i) prevented
the abnormal increase of mitochondrial nNOS and normalized respiratory complex I; (ii) decreased amyloid
precursor protein accumulation, a sign of axonal degeneration, and (iii) increased superoxide dismutation. Thus,
progesterone neuroprotection decreases mitochondriopathy of Wobbler mouse cervical spinal cord. © 2012 The
Authors. Journal of Neurochemistry © 2012 International Society for Neurochemistry. Comp Biochem Physiol C. 1993
Sep;106(1):125-9.<strong> The role of the neurotransmitters acetylcholine and noradrenaline in the
pathogenesis of stress ulcers. </strong>Gatón J, Fernández de la Gándara F, Velasco A. People with
Cloninger's "harm avoidance" personality trait, which is closely associated with serotonin (Hansenne, et al.,
1999), are more likely to develop dementia (Clément, et al., 2010). These observations are consistent with the
stress-susceptibility of people with high serotonin exposure, and to the effects of cortisol on nerves and
glucose-derived energy production. Jpn J Surg. 1991 Jan;21(1):43-9.
<strong>Participation of the parasympathetic nervous system in the development of</strong>
<strong>activity-stress ulcers.</strong>
Doi K, Iwahashi K, Tsunekawa K.17. J Auton Nerv Syst. 1987 Oct;20(3):265-8. Adrenergic modulation of gastric
stress pathology in rats: a cholinergic link. Ray A, Sullivan RM, Henke PG. Department of Psychology, St.
Francis Xavier University, Antigonish, Nova Scotia, Canada. The effects of some adrenergic drugs were evaluated
on cold restraint-induced gastric ulcers in rats. The beta-adrenergic antagonist, (+/-)-propranolol (1 and
10 mg/kg), as well as the beta-agonist, isoproterenol (0.05 and 0.5 mg/kg) potentiated the gastric pathology. On
the other hand, the alpha-agonist, clonidine (0.5 mg/kg) attenuated and the alpha-antagonist, yohimbine (1
mg/kg) aggravated stress ulcer development. The anticholinergic agent, atropine methylnitrate (1 mg/kg), reduced
both the frequency and severity of stress ulcers and also antagonized the potentiating effects of
(+/-)-propranolol, isoproterenol and yohimbine. The results suggest a cholinergic role in the adrenergic
modulation of gastric stress pathology. Psychopharmacology (Berl). 1981;74(1):81-7.
<strong>Cholinergic influences on escape deficits produced by uncontrollable stress.</strong>
Anisman H, Glazier SJ, Sklar LS. A series of experiments assessed the potential role of acetylcholine (ACh) in
the escape interference produced by inescapable shock. <strong>Treatment with the</strong>
<strong>anticholinesterase, physostigmine, successfully mimicked the effects of</strong>
<strong>inescapable shock. </strong>That is, the drug disrupted performance when escape was prevented for 6
s on any given trial, thereby necessitating sustained active responding. When escape was possible upon shock
onset, the drug treatment did not influence performance. <strong>The centrally acting anticholinergic
scopolamine</strong>
<strong>hydrobromide antagonized the effects of physostigmine, and when administered</strong>
<strong>prior to escape testing antagonized the disruptive effects of previously</strong>
<strong>administered inescapable shock.</strong> In contrast, the peripherally acting agent scopolamine
methylbromide did not influence the effects of these treatments, suggesting that the effects of physostigmine
and inescapable shock involved central ACh changes. Scopolamine hydrobromide administered prior to inescapable
shock did not prevent the escape interference from subsequently appearing, but this effect could not be
attributed to state dependence. It was argued that the interference of escape following uncontrollable stress
was due to non-associative motor deficits. Alterations of the escape deficits by scopolamine were due to
elimination of the motor disruption. Curr Opin Oncol. 2005 Jan;17(1):55-60. DNA methylation and cancer therapy:
new developments and expectations. Esteller M. Cancer Epigenetics Laboratory, Spanish National Cancer Centre
(CNIO) Madrid, Spain. <a href="mailto:mesteller@cnio.es" target="_blank">mesteller@cnio.es</a>
PURPOSE OF REVIEW: In addition to having genetic causes, cancer can also be considered an epigenetic disease.
The main epigenetic modification is DNA methylation, and patterns of aberrant DNA methylation are now recognized
to be a common hallmark of human tumors. One of the most characteristic features is the inactivation of
tumor-suppressor genes by CpG-island hypermethylation of the CpG islands located in their promoter
regions. These sites, among others, are the targets of DNA-demethylating agents, the promising chemotherapeutic
drugs that are the focus of this article. RECENT FINDINGS: Four exciting aspects have recently arisen at the
forefront of the advancements in this field: first, the development of new compounds with DNA-demethylating
capacity that are less toxic (for example, procaine) and may be administered orally (for example,
zebularine); Science. 2013 May 10;340(6133):756-9.
<strong>Emergence of individuality in genetically identical mice.</strong>
Freund J, Brandmaier AM, Lewejohann L, Kirste I, Kritzler M, Krüger A, Sachser N, Lindenberger U, Kempermann G.
CRTD-DFG Research Center for Regenerative Therapies Dresden, Technische Universität Dresden, Dresden, Germany.
Comment in Science. 2013 May 10;340(6133):695-6. Brain plasticity as a neurobiological reflection
of individuality is difficult to capture in animal models. Inspired by behavioral-genetic investigations of
human monozygotic twins reared together, we obtained dense longitudinal activity data on 40 inbred mice
living in one large enriched environment. The exploratory activity of the mice diverged over time, resulting in
increasing individual differences with advancing age. Individual differences in cumulative roaming entropy,
indicating the active coverage of territory, correlated positively with individual differences in adult
hippocampal neurogenesis. Our results show that factors unfolding or emerging during development contribute to
individual differences in structural brain plasticity and behavior. The paradigm introduced here serves as
an animal model for identifying mechanisms of plasticity underlying nonshared environmental contributions to
individual differences in behavior. Neurobiol Aging. 1995 Jul-Aug;16(4):523-30. Delayed onset of Alzheimer's
disease with nonsteroidal anti-inflammatory and histamine H2 blocking drugs. Breitner JC, Welsh KA, Helms MJ,
Gaskell PC, Gau BA, Roses AD, Pericak-Vance MA, Saunders AM. If each opportunity we have to choose expands
our curiosity, we go beyond our inheritance to become something unique but also universal, that is, more
fully human. J Neurobiol. 1976 Jan;7(1):75-85. Effects of environment on morphology of rat cerebral cortex and
hippocampus. Diamond MC, Ingham CA, Johnson RE, Bennett EL, Rosenzweig MR. … strains of rats. KRECH D,
ROSENZWEIG MR, BENNETT EL.… 19. Pharmacol Biochem Behav. 1986 Sep;25(3):521-6. Cholinergic function and memory:
extensive inhibition of choline acetyltransferase fails to impair radial maze performance in rats. Wenk G,
Sweeney J, Hughey D, Carson J, Olton D. The present study investigated the effects of a potent inhibitor of
choline acetyltransferase (ChAT), BW813U, on the choice accuracy of rats in the radial arm maze. BW813U (100
mg/kg, IP) produced a rapid (within 1 hour) and substantial decrease in ChAT activity throughout the brain,
ranging from 66% (hippocampus) to 80% (caudate nucleus) that lasted up to 5 days. <strong>A single
injection (50 mg/kg, IP)</strong>
<strong>into rats with lesions (using ibotenic acid) in the nucleus basalis</strong>
<strong>magnocellularis and medial septal area, decreased ChAT activity by 75% and 60% in</strong>
<strong>the cortex and hippocampus, respectively. Lesioned and unlesioned rats were</strong>
<strong>trained on the radial arm maze until they reached a criterion level of</strong>
<strong>performance. </strong>Each rat then received an injection of BW813U (50 or 100 mg/kg, IP). Choice
accuracy was not impaired at any time following the injection. The lack of effect on performance may be due to 2
possible factors: The radial maze retention paradigm chosen may not be sufficiently difficult, or the decrease
in acetylcholine production was not sufficient to affect behavior. Compensation by non-cholinergic neural
systems might account for the insensitivity of the rats to significant cholinergic depletion. Psychol Aging.
1988 Dec;3(4):399-406. Genotype-environment interaction in personality development: identical twins reared
apart. Bergeman CS, Plomin R, McClearn GE, Pedersen NL, Friberg LT. Center for Developmental and Health
Genetics, Pennsylvania State University, University Park 16802. The focus of this study is to identify specific
genotype-environment (GE) interactions as they contribute to individual differences in personality in later
life. In behavioral genetics, GE interaction refers to the possibility that individuals of different genotypes
may respond differently to specific environments. A sample of 99 pairs of identical twins reared apart, whose
average age is 59 years, has been studied as part of the Swedish Adoption/Twin Study of Aging (SATSA).
Hierarchical multiple regression was used to detect interactions between personality and environmental measures
after the main effects of genotype and environment were removed. Analyses yield evidence for 11 significant
interactions that provide the first evidence for GE interaction in human development using specific
environmental measures. Thus, in addition to the main-effect contributions of heredity and environment, GE
interactions contribute to individual differences in personality as measured in the second half of the life
course.
<span>Wikipedia:</span>
<strong>Excitability and inhibition</strong>
<span>[<a
href="http://en.wikipedia.org/w/index.php?title=Acetylcholine&action=edit&section=8"
target="_blank"
><span>edit source</span></a> | <a
href="http://en.wikipedia.org/w/index.php?title=Acetylcholine&veaction=edit&section=8"
target="_blank"
><span>edit</span><span>beta</span></a>]</span>
<p>
Acetylcholine also has other effects on neurons. One effect is to cause a slow <a
href="http://en.wikipedia.org/wiki/Depolarization"
target="_blank"
><span>depolarization</span></a>
<span><sup>[</sup><a href="http://en.wikipedia.org/wiki/Wikipedia:Citation_needed" target="_blank"><span><em
>citation needed</em></span></a><sup>]</sup></span> by blocking a tonically active K<span
>+</span>
<span></span> current, which increases neuronal excitability. Alternatively, acetylcholine can activate
non-specific cation conductances to directly excite neurons.<a
href="http://en.wikipedia.org/wiki/Acetylcholine#cite_note-Haj-Dahmane-10"
target="_blank"
><span>[10]</span></a> An effect upon postsynaptic <a
href="http://en.wikipedia.org/wiki/Muscarinic_acetylcholine_receptor_M4"
target="_blank"
><span>M4-muscarinic ACh receptors</span></a> is to open <a
href="http://en.wikipedia.org/wiki/Inward-rectifier_potassium_ion_channel"
target="_blank"
><span>inward-rectifier potassium ion channel</span></a> (K<span><sub>ir</sub></span>) and cause
inhibition.<a href="http://en.wikipedia.org/wiki/Acetylcholine#cite_note-Eggermann-11" target="_blank"><span
>[11]</span></a> The influence of acetylcholine on specific neuron types can be dependent upon the
duration of cholinergic stimulation. For instance, transient exposure to acetylcholine (up to several
seconds) can inhibit cortical pyramidal neurons via M1 type muscarinic receptors that are linked to Gq-type
G-protein alpha subunits. <strong>M1 receptor activation can induce calcium-release from intracellular
stores, which then activate a calcium-activated potassium conductance which inhibits </strong
>pyramidal neuron firing.<a
href="http://en.wikipedia.org/wiki/Acetylcholine#cite_note-Gulledge1-12"
target="_blank"
><span>[12]</span></a> <strong>On the other hand, tonic M1 receptor activation is strongly
excitatory. </strong>Thus, ACh acting at one type of receptor can have multiple effects on the same
postsynaptic neuron, depending on the duration of receptor activation.<a
href="http://en.wikipedia.org/wiki/Acetylcholine#cite_note-Gulledge2-13"
target="_blank"
><span>[13]</span></a> Recent experiments in behaving animals have demonstrated that cortical neurons
indeed experience both transient and persistent changes in local acetylcholine levels during cue-detection
behaviors.<a href="http://en.wikipedia.org/wiki/Acetylcholine#cite_note-Sarter1-14" target="_blank"><span
>[14]</span></a>
</p>
<p>
In the cerebral cortex, tonic ACh inhibits layer 4 <a
href="http://en.wikipedia.org/wiki/Medium_spiny_neuron"
target="_blank"
><span>medium spiny neurons</span></a>, the main targets of thalamocortical inputs while exciting<a
href="http://en.wikipedia.org/wiki/Pyramidal_cell"
target="_blank"
><span>pyramidal cells</span></a> in layers 2/3 and layer 5.<a
href="http://en.wikipedia.org/wiki/Acetylcholine#cite_note-Eggermann-11"
target="_blank"
><span>[11]</span></a> This filters out weak sensory inputs in layer 4 and amplifies inputs that reach
the layers 2/3 and layer L5 excitatory microcircuits. As a result, these layer-specific effects of ACh might
function to improve the signal noise ratio of cortical processing.<a
href="http://en.wikipedia.org/wiki/Acetylcholine#cite_note-Eggermann-11"
target="_blank"
><span>[11]</span></a> At the same time, acetylcholine acts through nicotinic receptors to excite
certain groups of inhibitory interneurons in the cortex, which further dampen down cortical activity.<a
href="http://en.wikipedia.org/wiki/Acetylcholine#cite_note-Gulledge3-15"
target="_blank"
><span>[15]</span></a>
</p>
<p>
<strong>Role in decision making</strong>
<span>[<a
href="http://en.wikipedia.org/w/index.php?title=Acetylcholine&action=edit&section=9"
target="_blank"
><span>edit source</span></a> | <a
href="http://en.wikipedia.org/w/index.php?title=Acetylcholine&veaction=edit&section=9"
target="_blank"
><span>edit</span><span>beta</span></a>]</span>
</p>
<p>
One well-supported function of acetylcholine (ACh) in cortex is increased responsiveness to sensory stimuli,
a form of <a href="http://en.wikipedia.org/wiki/Attention" target="_blank"><span>attention</span></a
>.<a
href="http://en.wikipedia.org/w/index.php?title=Phasic&action=edit&redlink=1"
target="_blank"
><span>Phasic</span></a> increases of ACh during visual,<a
href="http://en.wikipedia.org/wiki/Acetylcholine#cite_note-16"
target="_blank"
><span>[16]</span></a> auditory <a
href="http://en.wikipedia.org/wiki/Acetylcholine#cite_note-17"
target="_blank"
><span>[17]</span></a> and somatosensory <a
href="http://en.wikipedia.org/wiki/Acetylcholine#cite_note-18"
target="_blank"
><span>[18]</span></a> stimulus presentations have been found to increase the firing rate of neurons in
the corresponding primary sensory cortices. When cholinergic neurons in the basal forebrain are lesioned,
animals' ability to detect visual signals was robustly and persistently impaired.<a
href="http://en.wikipedia.org/wiki/Acetylcholine#cite_note-19"
target="_blank"
><span>[19]</span></a> In that same study, animals' ability to correctly reject non-target trials was
not impaired, further supporting the interpretation that phasic ACh facilitates responsiveness to stimuli.
Looking at ACh's effect on thalamocortical connections, a known pathway of sensory information, in vitro
application of cholinergic <a href="http://en.wikipedia.org/wiki/Agonist" target="_blank"><span
>agonist</span></a> <a href="http://en.wikipedia.org/wiki/Carbachol" target="_blank"><span
>carbachol</span></a> to mouse auditory cortex enhanced thalamocortical activity.<a
href="http://en.wikipedia.org/wiki/Acetylcholine#cite_note-Hsieh-20"
target="_blank"
><span>[20]</span></a> In addition, Gil et al. (1997) applied a different cholinergic agonist, <a
href="http://en.wikipedia.org/wiki/Nicotine"
target="_blank"
><span>nicotine</span></a>, and found that activity was enhanced at thalamocortical synapses.<a
href="http://en.wikipedia.org/wiki/Acetylcholine#cite_note-Gil-21"
target="_blank"
><span>[21]</span></a>This finding provides further evidence for a facilitative role of ACh in transmission
of sensory information from the thalamus to selective regions of cortex.
</p>
<p>
An additional suggested function of ACh in cortex is suppression of intracortical information transmission.
Gil et al. (1997) applied the cholinergic agonist <a
href="http://en.wikipedia.org/wiki/Muscarine"
target="_blank"
><span>muscarine</span></a> to neocortical layers and found that <a
href="http://en.wikipedia.org/wiki/Excitatory_post-synaptic_potentials"
target="_blank"
><span>excitatory post-synaptic potentials</span></a> between intracortical synapses were depressed.<a
href="http://en.wikipedia.org/wiki/Acetylcholine#cite_note-Gil-21"
target="_blank"
><span>[21]</span></a> In vitro application of cholinergic agonist carbachol to mouse auditory cortex
suppressed intracortical activity as well.<a
href="http://en.wikipedia.org/wiki/Acetylcholine#cite_note-Hsieh-20"
target="_blank"
><span>[20]</span></a> Optical recording with a voltage-sensitive dye in rat visual cortical slices
demonstrated significant suppression in intracortical spread of excitement in the presence of ACh.<a
href="http://en.wikipedia.org/wiki/Acetylcholine#cite_note-22"
target="_blank"
><span>[22]</span></a>
</p>
<p>
Some forms of learning and plasticity in cortex appear dependent on the presence of acetylcholine. Bear et
al. (1986) found that the typical synaptic remapping in <a
href="http://en.wikipedia.org/wiki/Striate_cortex"
target="_blank"
><span>striate cortex</span></a> that occurs during <a
href="http://en.wikipedia.org/wiki/Monocular_deprivation"
target="_blank"
><span>monocular deprivation</span></a> is reduced when there is a depletion of cholinergic projections
to that region of cortex.<a
href="http://en.wikipedia.org/wiki/Acetylcholine#cite_note-23"
target="_blank"
><span>[23]</span></a> Kilgard et al. (1998) found that repeated stimulation of the <a
href="http://en.wikipedia.org/wiki/Basal_forebrain"
target="_blank"
><span>basal forebrain</span></a>, a primary source of ACh neurons, paired with presentation of a tone at a
specific frequency, resulted in remapping of the <a
href="http://en.wikipedia.org/wiki/Auditory_cortex"
target="_blank"
><span>auditory cortex</span></a> to better suit processing of that tone.<a
href="http://en.wikipedia.org/wiki/Acetylcholine#cite_note-24"
target="_blank"
><span>[24]</span></a>Baskerville et al. (1996) investigated the role of ACh in <a
href="http://en.wikipedia.org/w/index.php?title=Experience-dependent_plasticity&action=edit&redlink=1"
target="_blank"
><span>experience-dependent plasticity</span></a> by depleting cholinergic inputs to the <a
href="http://en.wikipedia.org/wiki/Barrel_cortex"
target="_blank"
><span>barrel cortex</span></a> of rats.<a
href="http://en.wikipedia.org/wiki/Acetylcholine#cite_note-25"
target="_blank"
><span>[25]</span></a> The cholinergic depleted animals had a significantly reduced amount of
whisker-pairing plasticity. Apart from the cortical areas, Crespo et al. (2006) found that the activation of
nicotinic and muscarinic receptors in the <a
href="http://en.wikipedia.org/wiki/Nucleus_accumbens"
target="_blank"
><span>nucleus accumbens</span></a> is necessary for the acquisition of an appetitive task.<a
href="http://en.wikipedia.org/wiki/Acetylcholine#cite_note-achcorrelation-26"
target="_blank"
><span>[26]</span></a>
</p>
<p>
ACh has been implicated in the reporting of expected uncertainty in the environment <a
href="http://en.wikipedia.org/wiki/Acetylcholine#cite_note-27"
target="_blank"
><span>[27]</span></a> based both on the suggested functions listed above and results recorded while
subjects perform a behavioral cuing task. <a
href="http://en.wikipedia.org/wiki/Reaction_time"
target="_blank"
><span>Reaction time</span></a> difference between correctly cued trials and incorrectly cued
trials, <span><strong>called the cue validity, was found to vary inversely with ACh </strong
></span>levels in primates with pharmacologically (e.g. Witte et al., 1997) and surgically (e.g. Voytko
et al., 1994) altered levels of ACh.<a
href="http://en.wikipedia.org/wiki/Acetylcholine#cite_note-28"
target="_blank"
><span>[28]</span></a>
<a href="http://en.wikipedia.org/wiki/Acetylcholine#cite_note-29" target="_blank"><span>[29]</span></a
> The result was also found in <a
href="http://en.wikipedia.org/wiki/Alzheimer%27s_disease"
target="_blank"
><span>Alzheimer's disease</span></a> patients (Parasuraman et al., 1992) and smokers after nicotine
(an ACh agonist) consumption.<a
href="http://en.wikipedia.org/wiki/Acetylcholine#cite_note-30"
target="_blank"
><span>[30]</span></a>
<a href="http://en.wikipedia.org/wiki/Acetylcholine#cite_note-31" target="_blank"><span>[31]</span></a
> The inverse covariance is consistent with the interpretation of ACh as representing expected
uncertainty in the environment, further supporting this claim.
</p>
<li>
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1. Pharmacol Res. 2011 Jun;63(6):525-31. Endothelin receptor antagonists: potential in Alzheimer's
disease. Palmer J, Love S. Dementia Research Group, Institute of Clinical Neurosciences, School of
Clinical Sciences, University of Bristol, Frenchay Hospital, Bristol BS16 1LE, United Kingdom. <a
href="mailto:jen.palmer@bristol.ac.uk"
target="_blank"
>jen.palmer@bristol.ac.uk</a>
Alzheimer's disease (AD) is believed to be initiated by the accumulation of neurotoxic forms of Aβ peptide
within the brain. AD patients show reduction of cerebral blood flow (CBF), the extent of the reduction
correlating with the impairment of cognition. <span><strong>There is evidence that cerebral hypoperfusion
precedes</strong></span>
<span><strong>and may even trigger the onset of dementia in AD. Cerebral hypoperfusion impairs </strong
></span>
<span><strong>neuronal function, reduces the clearance of Aβ peptide and other toxic</strong></span>
<span><strong>metabolites from the brain, and upregulates Aβ production. Studies in animal</strong></span>
<span><strong>models of AD have shown the reduction in CBF to be more than would be expected</strong></span>
<span><strong>for the reduction in neuronal metabolic activity. </strong></span>Aβ may contribute to the
reduction in CBF in AD, as both Aβ<span>₁₋₄₀</span> and Aβ<span>₁₋₄₂</span> induce cerebrovascular
dysfunction. Aβ<span>₁₋₄₀</span> acts directly on cerebral arteries to cause cerebral smooth muscle cell
contraction. Aβ<span>₁₋₄₂</span> causes increased neuronal production and release of endothelin-1
(ET-1), a potent vasoconstrictor, and upregulation of endothelin-converting enzyme-2 (ECE-2), the enzyme which
cleaves ET-1 from its inactive precursor. ET-1 and ECE-2 are also elevated in AD, making it likely that
upregulation of the ECE-2-ET-1 axis by Aβ<span>₁₋₄₂</span> contributes to the chronic reduction of CBF in
AD. At present, only a few symptomatic treatment options exist for AD. The involvement of ET-1 in the
pathogenesis of endothelial dysfunction associated with elevated Aβ indicates the potential for endothelin
receptor antagonists in the treatment of AD. It has already been demonstrated that the endothelin receptor
antagonist bosentan, preserves aortic and carotid endothelial function in Tg2576 mice, and our findings suggest
that endothelin receptor antagonists may be beneficial in maintaining CBF in AD. Copyright © 2011 Elsevier Ltd.
All rights reserved. Fiziol Zh SSSR Im I M Sechenova. 1975 Oct;61(10):1466-72. [Amine receptors in brain
vessels]. [Article in Russian] Edvinsson L, Owman Ch. Isolated middle cerebral arteries from cats and pial
arteries from humans (obtained during lobe resection) were studied in a sensitive in vitro system allowing a
detailed pharmacological characterization of various amine receptors and related dissociation constants. It was
found that the adrenergic receptors comprise contractile (alpha) and dilatory (beta) receptors.<strong
> Acetylcholine induced</strong>
<strong>dilation (at low doses) as well as constriction (at high doses) both responses</strong>
<strong>being inhibited in a comparative way by atropine.</strong> Experiments with selective inhibitors
showed the presence of specific histamine H2 (dilatory) receptors; <strong>at </strong>
<strong>high doses histamine contracted the vessels in a non-specific way.</strong>
<strong>5-Hydroxytryptamine was the most efficient vasoconstrictor agent, and the</strong>
response could be blocked by the serotonin-antagonist, methysergide. Behav Neurosci. 2007 Jun;121(3):491-500.
Exposure to enriched environment improves spatial learning performances and enhances cell density <strong
>but not choline acetyltransferase activity in the hippocampus of ventral subicular-lesioned rats.</strong>
Dhanushkodi A, Bindu B, Raju TR, Kutty BM. Department of NeurophysiologyNational Institute of Mental Health and
Neuro Sciences (NIMHANS Deemed University), Bangalore, India. The authors demonstrated the efficacy of enriched
housing conditions in promoting the behavioral recovery and neuronal survival following subicular lesion in
rats. Chemical lesioning of the ventral subiculum impaired the spatial learning performances in rats. The lesion
also induced a significant degree of neurodegeneration in the CA1 and CA3 areas of the hippocampus and
entorhinal cortex. Exposure to enriched housing conditions improved the behavioral performance and partially
attenuated the neurodegeneration in the hippocampus. The choline acetyl transferase (ChAT) activity in the
hippocampus remained unchanged following ventral subicular lesion and also following exposure to an enriched
environment. The study implicates the effectiveness of activity-dependent neuronal plasticity induced by
environmental enrichment in adulthood following brain insult. Copyright (c) 2007 APA, all rights reserved. Horm
Behav. 2013 Jul 27. pii: S0018-506X(13)00139-6. Progesterone and vitamin D: Improvement after traumatic brain
injury in middle-aged rats. Tang H, Hua F, Wang J, Sayeed I, Wang X, Chen Z, Yousuf S, Atif F, Stein DG.
Department of Emergency Medicine, Emory University, Atlanta, GA 30322, USA. Progesterone (PROG) and vitamin D
hormone (VDH) have both shown promise in treating traumatic brain injury (TBI). Both modulate apoptosis,
inflammation, oxidative stress, and<strong>excitotoxicity.</strong> We investigated whether 21days of VDH
deficiency would alter cognitive behavior after TBI and whether combined PROG and VDH would improve behavioral
and morphological outcomes more than either hormone alone in VDH-deficient middle-aged rats given bilateral
contusions of the medial frontal cortex. PROG (16mg/kg) and VDH (5μg/kg) were injected intraperitoneally 1h
post-injury. Eight additional doses of PROG were injected subcutaneously over 7days post-injury. VDH deficiency
itself did not significantly reduce baseline behavioral functions or aggravate impaired cognitive outcomes.
Combination therapy showed moderate improvement in preserving spatial and reference memory but was not
significantly better than PROG monotherapy. However, combination therapy significantly reduced neuronal loss and
the proliferation of reactive astrocytes, and showed better efficacy compared to VDH or PROG alone in preventing
MAP-2 degradation. VDH+PROG combination therapy may attenuate some of the potential long-term, subtle,
pathophysiological consequences of brain injury in older subjects. © 2013. KEYWORDS: Yang, glutamate stimulates
DNA repair; methylation of dna during stress, hydrophobic Life Sci 1998;62(17-18):1717-21 Induction of
inducible nitric oxide synthase and heme oxygenase-1 in rat glial cells. Kitamura Y, Matsuoka Y, Nomura Y,
Taniguchi T Department of Neurobiology, Kyoto Pharmaceutical University, Japan. Recent observations
suggest a possible interaction between the nitric oxide (NO)/NO synthases and carbon monoxide (CO)/heme
oxygenases systems. We examined the effects of lipopolysaccharide (LPS), interferon-gamma (IFN-gamma), and NO
donor such as S-nitroso-N-acetylpenicillamine (SNAP) on induction of inducible NO synthase (iNOS) and heme
oxygenase-1 (HO-1) in mixed glial cells and in rat hippocampus. In in vitro glial cells, treatment with LPS
induced the expression of 130-kDa iNOS after 6 h, and NO2- accumulation and enhancement of the protein level of
33-kDa HO-1 after 12 h. In addition, treatment with SNAP induced HO-1 expression after 6 h. Although a NOS
inhibitor, such as N(G)-nitro-L-arginine (NNA), did not change LPS-induced iNOS expression, the inhibitor
s<strong>uppressed both NO2- accumulation and the enhancement of HO-1.</strong> Immunocytochemistry showed
that LPS-treatment induced iNOS-immunoreactivity predominantly in microglia, while this treatment induced
HO-1-immunoreactivity in both microglia and astrocytes. These results suggest that endogenous NO production by
iNOS in microglia causes autocrine- and paracrine-induction of HO-1 protein in microglia and astrocytes in rat
brain.
<p> </p>
4. Proc Soc Exp Biol Med. 1994 Oct;207(1):43-7. Dietary restriction modulates the norepinephrine content and
uptake of the heart and cardiac synaptosomes. Kim SW, Yu BP, Sanderford M, Herlihy JT. Department of
Physiology, University of Texas Health Science Center at San Antonio 78284. The present study was designed to
examine the effects of long-term dietary restriction on cardiac sympathetic nerves and neurotransmitter. The
food intake of male, 6-week-old Fischer 344 rats was reduced to 60% of the intake of control rats fed ad
libitum. The body and heart weights of rats diet restricted for 4.5 months were less than those of the ad
libitum fed animals, while the heart weight to body weight ratios were higher<strong>. The norepinephrine (NE)
content of hearts from</strong>
<strong>restricted rats (1073 +/- 84 ng/g wet wt) was higher than controls (774 +/- 38</strong>
<strong>ng/g wet wt), although the total amoun</strong>t of NE per heart was unchanged. Similarly, the cardiac
synaptosomal P2 fraction from restricted rats possessed a higher NE content (24.1 +/- 2.4 ng/mg protein) than
the P2 fraction of ad libitum fed controls (13.7 +/- 1.3 ng/mg protein). The desmethylimipramine-sensitive
norepinephrine uptake of the P2 fraction from restricted rats was significantly higher than that of control rats
(9.44 +/- 1.33 vs 4.75 +/- 0.35 ng/mg protein/hr). The NE uptakes of the two groups were similar when uptake was
normalized to endogenous NE levels. These results demonstrate that long-term dietary restriction affects cardiac
sympathetic nerve endings and suggest that part of the beneficial action of life-long dietary restriction on the
age-related decline in cardiovascular regulation may be related to changes in cardiac sympathetic nerves. Int J
Cancer. 1985 Apr 15;35(4):493-7. Muscarinic cholinergic receptors in pancreatic acinar carcinoma of rat. Taton
G, Delhaye M, Swillens S, Morisset J, Larose L, Longnecker DS, Poirier GG. The active enantiomer of tritiated
quinuclidinyl benzilate (3H(-)QNB) was used as a ligand to evaluate the muscarinic receptors. The 3H(-)QNB
binding characteristics of muscarinic cholinergic receptors obtained from normal and neoplastic tissues were
studied to determine changes in receptor properties during neoplastic transformation. Saturable and
stereospecific binding sites for 3H(-)QNB are present in homogenates of rat pancreatic adenocarcinoma. The
proportions of high- and low-affinity agonist binding sites are similar for neoplastic and normal tissues. The
density of muscarinic receptors is higher in neoplastic (200 femtomoles/mg protein) than in normal pancreatic
homogenates (80 femtomoles/mg protein). The muscarinic binding sites of the neoplastic and fetal
pancreas show similar KD values which are higher than those observed for normal pancreas. 17: Cancer Res. 1986
Nov;46(11):5706-14. Muscarinic receptor coupling to intracellular calcium release in rat pancreatic acinar
carcinoma. Chien JL, Warren JR. Analysis by sodium dodecyl sulfate-polyacrylamide gel electrophoresis of
cholinergic receptor protein affinity labeled with the muscarinic antagonist [3H]propylbenzilylcholine mustard
revealed a major polypeptide with molecular weight of 80,000-83,000 in both acinar carcinoma and normal acinar
cells of rat pancreas. Muscarinic receptor protein is therefore conserved in pancreatic acinar carcinoma. A
small but significant difference was detected in the affinity of carcinoma cell receptors (Kd approximately 0.6
nM) and normal cell receptors (Kd approximately 0.3 nM) for reversible binding of the muscarinic
antagonist drug, N-methylscopolamine. In addition, carcinoma cell muscarinic receptors displayed homogeneous
binding of the agonist drugs carbamylcholine (Kd approximately 31 microM) and oxotremorine (Kd approximately 4
microM), whereas normal cell receptors demonstrated heterogeneous binding, with a minor receptor population
showing high affinity binding for carbamylcholine (Kd approximately 3 microM) and oxotremorine (Kd approximately
160 nM), and a major population showing low affinity binding for carbamylcholine (Kd approximately 110 microM)
and oxotremorine (Kd approximately 18 microM). Both carcinoma and normal cells exhibited concentration-dependent
carbamylcholine-stimulated increases in cytosolic free Ca2+, as measured by 45Ca2+ outflux assay and
intracellular quin 2 fluorescence. However, carcinoma cells were observed to be more sensitive to Ca2+
mobilizing actions of submaximal carbamylcholine concentrations, demonstrating 50% maximal stimulation of
intracellular Ca2+ release at a carbamylcholine concentration (approximately 0.4 microM) approximately one order
of magnitude below that seen for normal cells. These results indicate altered muscarinic receptor coupling to
intracellular Ca2+ release in acinar carcinoma cells, which manifests as a single activated receptor state
for agonist binding, and increased sensitivity of Ca2+ release in response to muscarinic receptor stimulation.
1: Anticancer Drugs. 2008 Aug;19(7):655-71. Neurotransmission and cancer: implications for prevention and
therapy. Schuller HM. Experimental Oncology Laboratory, Department of Pathobiology, College of Veterinary
Medicine, University of Tennessee, 2407 River Drive, Knoxville, TN 37996, USA. <a
href="mailto:hmsch@utk.edu"
target="_blank"
>hmsch@utk.edu</a>
Published evidence compiled in this review supports the hypothesis that the development, progression, and
responsiveness to prevention and therapy of the most common human cancers is strongly influenced, if not
entirely orchestrated, by an imbalance in stimulatory and inhibitory neurotransmission. The neurotransmitters
acetylcholine, adrenaline, and noradrenaline of the autonomic nervous system act as powerful upstream regulators
that orchestrate numerous cell and tissue functions, by releasing growth factors, angiogenesis factors and
metastasis factors, arachidonic acid, proinflammatory cytokines, and local neurotransmitters from cancer cells
and their microenvironment. In addition, they modulate proliferation, apoptosis, angiogenesis, and metastasis of
cancer directly by intracellular signaling downstream of neurotransmitter receptors. Nicotine and the
tobacco-specific nitrosamines have the documented ability to hyperstimulate neurotransmission by both branches
of the autonomic nervous system. The expression and function of these neurotransmitter pathways are cell type
specific. Lifestyle, diet, diseases, stress, and pharmacological treatments modulate the expression and
responsiveness of neurotransmitter pathways. Current preclinical testing systems fail to incorporate the
modulating effects of neurotransmission on the responsiveness to anticancer agents and should be amended
accordingly. The neurotransmitter gamma-aminobutyric acid has a strong inhibitory function on sympathicus-driven
cancers whereas stimulators of cyclic adenosine monophosphate/protein kinase A signaling have strong inhibitory
function on parasympathicus-driven cancers. Marker-guided restoration of the physiological balance in
stimulatory and inhibitory neurotransmission represents a promising and hitherto neglected strategy for
the prevention and therapy of neurotransmitter-responsive cancers. Psychological stress in IBD: new insights
into pathogenic and ...
<a href="http://www.ncbi.nlm.nih.gov/" target="_blank">www.ncbi.nlm.nih.gov</a> › Journal List › Gut ›
v.54(10); Oct 2005 by JE Mawdsley - 2005 - Cited by 255 - Related articles Psychological stress has long been
reported anecdotally to increase disease ..... atropine and was more marked in cholinesterase deficient
Wistar-Kyoto rats. Neuropsychopharmacology. 2002 May;26(5):672-81. Sexual diergism of
hypothalamo-pituitary-adrenal cortical responses to low-dose physotigmine in elderly vs. young women and men.
Rubin RT, Rhodes ME, O'Toole S, Czambel RK. Center for Neurosciences Research, MCP Hahnemann University School
of Medicine, Allegheny General Hospital, Pittsburgh, PA 15212, USA. <a
href="mailto:rubin@wpahs.org"
target="_blank"
>rubin@wpahs.org</a>
We previously demonstrated that the reversible cholinesterase inhibitor, physostigmine (PHYSO), administered to
normal young adult women and men (average age 35 years) at a dose that produced few or no side effects, resulted
in a sex difference (sexual diergism) in hypothalamo-pituitary-adrenal cortical (HPA) axis responses:
Plasma <strong>ACTH(1-39), cortisol, and arginine vasopressin (AVP)</strong>
<strong>concentrations increased to a significantly greater extent in the men than in</strong>
<strong>the women. </strong>To explore the effect of age on these sexually diergic hormone responses, in
the present study we used the same dose of PHYSO (8 microg/kg IV) to stimulate ACTH(1-39), cortisol, and AVP
secretion in normal elderly, non-estrogen-replaced women and elderly men (average ages 73 years and 70 years,
respectively). The subjects underwent three test sessions 5-7 days apart: PHYSO, saline control, and a second
session of PHYSO. Serial blood samples were taken for hormone analyses before and after pharmacologic
challenge.As with the previously studied younger subjects, PHYSO administration produced no side effects in
about half the elderly subjects and mild side effects in the other half, with no significant female-male
differences. <span><strong>The hormone responses were</strong></span>
<span><strong>2-5 fold greater in the elderly subjects t</strong></span>han in the younger subjects, but in
contrast to the younger subjects, the elderly men did not have significantly greater hormone responses to PHYSO
administration than did the elderly women. The ACTH(1-39) and AVP responses to PHYSO for the two sessions were
significantly positively correlated in the men (+0.96, +0.91) but not in the women. None of the hormone
responses was significantly correlated with the presence or absence of side effects in either group of
subjects.These results indicate<span><strong> a greater sensitivity of the HPA axis to low-dose PHYSO, and
a loss of</strong></span>
<span><strong>overall sex differences in hormone responses, in elderly compared with younger</strong></span>
<span><strong>subjects. </strong></span>The lack of a difference in side effects between the elderly women
and men and the lack of significant correlations between presence or absence of side effects and hormone
responses suggest that the increase in hormone responses with aging is due to correspondingly increased
responsiveness of central cholinergic systems and/or the HPA axis, and not to a nonspecific stress response.
Horm Behav. 2013 Feb;63(2):284-90. Progesterone and neuroprotection. Singh M, Su C. Department of
Pharmacology and Neuroscience, Institute for Aging and Alzheimer's Disease Research, Center FOR HER, University
of North Texas Health Science Center at Fort Worth, Fort Worth, TX 76107, USA. <a
href="mailto:meharvan.singh@unthsc.edu"
target="_blank"
>meharvan.singh@unthsc.edu</a>
Numerous studies aimed at identifying the role of estrogen on the brain have used the ovariectomized rodent as
the experimental model. And while estrogen intervention in these animals has, at least partially, restored
cholinergic, neurotrophin and cognitive deficits seen in the ovariectomized animal, it is worth considering that
the removal of the ovaries results in the loss of not only circulating estrogen but of circulating progesterone
as well. As such, the various deficits associated with ovariectomy may be attributed to the loss of progesterone
as well. Similarly, one must also consider the fact that the human menopause results in the precipitous decline
of not just circulating estrogens, but in circulating progesterone as well and as such, the increased risk for
diseases such as Alzheimer's disease during the postmenopausal period could also be contributed by this loss of
progesterone. In fact, progesterone has been shown to exert neuroprotective effects, both in cell models, animal
models and in humans. <strong>Here, we review the evidence that supports the neuroprotective effects of
progesterone and discuss the various mechanisms that are thought to mediate these protective
effects.</strong> We also discuss the receptor pharmacology of progesterone's neuroprotective effects
and present a conceptual model of progesterone action that supports the complementary effects of
membrane-associated and classical intracellular progesterone receptors.<strong> In addition, we discuss
fundamental differences in the neurobiology of progesterone and the clinically used, synthetic progestin,
medroxyprogesterone acetate that may offer an explanation for the negative findings of the combined
estrogen/progestin arm of the Women's Health Initiative-Memory Study (WHIMS) and suggest that the type of
progestin used may dictate the outcome of either pre-clinical or clinical studies that addresses brain
function.</strong>
Brain Res. 2005 Jul 5;1049(1):112-9. <strong>Progesterone treatment inhibits the inflammatory agents that
accompany traumatic brain injury.</strong> Pettus EH, Wright DW, Stein DG, Hoffman SW. Department of
Cell Biology, Emory University, Atlanta, GA 30322, USA. Progesterone given after traumatic brain injury (TBI)
has been shown to reduce the initial cytotoxic surge of inflammatory factors. We used Western blot techniques to
analyze how progesterone might affect three inflammation-related factors common to TBI: complement factor C3
(C3), glial fibrillary acidic protein (GFAP), and nuclear factor kappa beta (NFkappaB). One hour after bilateral
injury to the medial frontal cortex, adult male rats were given injections of progesterone (16 mg/kg) for 2
days. Brains were harvested 48 h post-TBI, proteins were extracted from samples, each of which contained tissue
from both the contused and peri-contused areas, then measured by Western blot densitometry. Complete C3, GFAP,
and NFkappaB p65 were increased in all injured animals. However, in animals given progesterone post-TBI,<strong
> NFkappaB p65 and the</strong>
<strong>inflammatory metabolites of C3 (9 kDa and 75 kDa)</strong> were decreased in comparison to
vehicle-treated animals. J Leukoc Biol 1996 Mar;59(3):442-50 Progesterone inhibits inducible nitric oxide
synthase gene expression and nitric oxide production in murine macrophages. Miller L, Alley EW, Murphy WJ,
Russell SW, Hunt JS Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas
City, USA. The purpose of this study was to determine whether the female hormones estradiol-l7 beta (E2)
and progesterone (P4) influence inducible nitric oxide synthase (iNOS) and the production of nitric oxide (NO)
by interferon-gamma(IFN-gamma)-and lipopolysaccharide (LPS)-activated mouse macrophages. Treatment with P4 alone
caused a time- and dose-dependent inhibition of NO production by macrophage cell lines (RAW 264.7, J774) and
mouse bone marrow culture-derived macrophages as assessed by nitrite accumulation. RAW 264.7 cells transiently
transfected with an iNOS gene promoter/luciferase reporter-gene construct that were stimulated with
IFN-gamma/LPS in the presence of P4 displayed reduced luciferase activity and NO production. Analysis of RAW
264.7 cells by Northern blot hybridization revealed concurrent P4-mediated reduction in iNOS mRNA. These
observations suggest that P4-mediated inhibition of NO may be an important gender-based difference within
females and males that relates to macrophage-mediated host defense. J Reprod Immunol 1997 Nov
15;35(2):87-99 Female steroid hormones regulate production of pro-inflammatory molecules in uterine
leukocytes. Hunt JS, Miller L, Roby KF, Huang J, Platt JS, DeBrot BL Department of Anatomy and Cell Biology,
University of Kansas Medical Center, Kansas City 66160-7400, USA. <a
href="mailto:jhunt@kumc.edu"
target="_blank"
>jhunt@kumc.edu</a> Estrogens and progesterone could be among the environmental signals that govern
uterine immune cell synthesis of pro-inflammatory substances. In order to investigate this possibility, we first
mapped expression of the inducible nitric oxide synthase (iNOS) and tumor necrosis factor-alpha (TNF-alpha)
genes in the leukocytes of cycling and pregnant mouse uteri, then tested the ability of estradiol-17 beta (E2)
and progesterone to influence gene expression. Immunohistochemistry, in situ hybridization, and other
experimental approaches, revealed that the iNOS and TNF-alpha genes are expressed in mouse uterine mast cells,
macrophages and natural killer cells (uNK). Gene expression in each cell type was noted to be dependent upon
stage of the cycle or stage of gestation, implying potential relationships with levels of female hormones and
state of cell differentiation or activation. Further in vivo and in vitro experiments showed that individual
hormones have cell type-specific effects on synthesis of iNOS and TNF-alpha that are exerted at the level of
transcription. In uterine mast cells, iNOS and TNF-alpha are promoted by E2 whereas preliminary studies in
macrophages suggest that transcription and translation of the two genes are unaffected by E2 but are inhibited
by progesterone. Hypothyroidism increases NO; T3, vs helpless; hypothyroid, escape deficit, Levine, et
1990.
<strong>choline is increased in AD CSF Elble R;, Carriere;</strong>
Genes Nutr. 2009 December; 4(4): 309–314.<strong> Dietary polyunsaturated fatty acids improve cholinergic
transmission in the aged brain</strong> Willis LM, Shukitt-Hale B, Joseph JA. 28. Bloj B, Morero RD,
Farias RN, Trucco RE (1973) Membrane lipid fatty acids and regulation of membrane-bound enzymes. Allosteric
behaviour of erythrocyte Mg 2+-ATPase (Na++ K+)-ATPase and acetylcholinesterase from rats fed different
fat-supplemented diets. Biochim Biophys Acta 311:67–79. [PubMed] 29. Vajreswari A, Narayanareddy K (1992) Effect
of dietary fats on erythrocyte membrane lipid composition and membrane-bound enzyme activities. Metabolism
41:352–358. [PubMed] 30. Vajreswari A, Rupalatha M, Rao PS (2002) Effect of altered dietary n-6-to-n-3 fatty
acid ratio on erythrocyte lipid composition and membrane-bound enzymes. J Nutr Sci Vitaminol 48:365–370.
[PubMed] 31. Foot M, Cruz TF, Clandinin MT (1983) <strong>Effect of dietary lipid on synaptosomal
acetylcholinesterase activity.</strong> Biochem J 211:507–509. [PMC free article] [PubMed] 33.
Srinivasarao P, Narayanareddy K, Vajreswari A, Rupalatha M, Prakash PS, Rao P (1997) Influence of dietary fat on
the activities of subcellular membrane-bound enzymes from different regions of the brain. Neuochem Int
31:789–794. [PubMed]
<em>The protective effect of anticholinergic drugs, such as atropine or scopolamine, against various
degenerative brain processes might lead a person to wonder whether the Berkeley enrichment experiments might
not have been neurologically exactly the opposite of the stress experiments of Richter and Seligman, that
is, reducing cholinergic processes with enrichment, increasing them with impoverishment of choices and
experience. A drug, pilocarpine, </em>
USING THE BRAIN FOR LIFE Living is development; the choices we make create our individuality. If genetically
identical mice grow up in a large and varied environment, small differences in their experience will affect cell
growth in their brains, leading to large differences in their exploratory behavior as they age (Freund, et al.,
2013). Geneticists used to say that "genes determine our limits," but this experiment shows that an environment
can provide both limitations and opportunities for expanding the inherited potential. If our environment
restricts our choices, our becoming human is thwarted, the way rats' potentials weren't discovered when they
were kept in the standard little laboratory boxes. An opportunity to be complexly involved in a complex
environment lets us become more of what we are, more humanly differentiated. A series of experiments that
started at the University of California in 1960 found that rats that lived in larger spaces with various things
to explore were better at learning and solving problems than rats that were raised in the standard little
laboratory cages (Rosenzweig, 1960). Studying their brains, they found that the enzyme cholinesterase, which
destroys the neurotransmitter, acetylcholine, was increased. They later found that the offspring of these rats
were better learners than their parents, and their brains contained more cholinesterase. Their brains were also
larger, with a considerable thickening of the cortex, which is considered to be the part mainly responsible for
complex behavior, learning and intelligence. These processes aren't limited to childhood. For example,
London taxi drivers who learn all the streets in the city develop a larger hippocampus, an area of the brain
involved with memory. The 1960s research into environmental enrichment coincided with political changes in
the US, but it went against the dominant scientific ideas of the time. Starting in 1945, the US government had
begun a series of projects to develop techniques of behavior modification or mind control, using drugs,
isolation, deprivation, and torture. In the 1950s, psychiatry often used lobotomies (about 80,000, before they
were generally discontinued in the 1980s) and electroconvulsive "therapy," and university psychologists tortured
animals, often as part of developing techniques for controlling behavior. The CIA officially phased out
their MKultra program in 1967, but that was the year that Martin Seligman, at the University of Pennsylvania,
popularized the idea of "learned helplessness." He found that when an animal was unable to escape from torture,
even for a very short time, it would often fail to even try to escape the next time it was tortured.
Seligman's lectures have been attended by psychologists who worked at Guantanamo, and he recently received a
no-bid Pentagon grant of $31,000,000, to develop a program of "comprehensive soldier fitness," to train marines
to avoid learned helplessness.
<p> </p>
Curt Richter already in 1957 had described the "hopelessness" phenomenon in rats (“a reaction of hopelessness is
shown by some wild rats very soon after being grasped in the hand and prevented from moving. They seem literally
to give up,”) and even how to cure their hopelessness, by allowing them to have an experience of escaping once
(Richter, 1957). Rats which would normally be able to keep swimming in a tank for two or three days, would
often give up and drown in just a few minutes, after having an experience of "inescapable stress." Richter made
the important discovery that the hearts of the hopeless rats slowed down before they died, remaining relaxed and
filled with blood, revealing the dominant activity of the vagal nerve, secreting acetylcholine. The
sympathetic nervous system (secreting noradrenaline) accelerates the heart, and is usually activated in stress,
in the "fight or flight" reaction, but this radically different (parasympathetic) nervous activity hadn't
previously been seen to occur in stressful situations. The parasympathetic, cholinergic, nervous system had been
thought of as inactive during stress, and activated to regulate processes of digestion, sleep, and repair.
Besides the cholinergic nerves of the parasympathetic system, many nerves of the central nervous system also
secrete acetylcholine, which activates smooth muscles, skeletal muscles, glands, and other nerves, and also has
some inhibitory effects. The parasympathetic nerves also secrete the enzyme, cholinesterase, which destroys
acetylcholine. However, many other types of cell (red blood cells, fibroblasts, sympathetic nerves, marrow
cells), maybe all cells, can secrete acetylcholine. Because cholinergic nerves have been opposed to the
sympathetic, adrenergic, nerves, there has been a tendency to neglect their nerve exciting roles, when looking
at causes of excitotoxicity, or the stress-induced loss of brain cells. Excessive cholinergic stimulation,
however, can contribute to excitotoxic cell death, for example when it's combined with high cortisol and/or
hypoglycemia. Drugs that block the stimulating effects of acetylcholine (the anticholinergics) as well as
chemicals that mimic them, such as the organophosphate insecticides, can impair the ability to think and learn.
This suggested to some people that age-related dementia was the result of the deterioration of the cholinergic
nerves in the brain. Drugs to increase the stimulating effects of acetylcholine in the brain (by inactivating
cholinesterase) were promoted as treatment for Alzheimer's disease. Although herbal inhibitors were well
known, profitable new drugs, starting with Tacrine, were put into use. It was soon evident that Tacrine was
causing serious liver damage, but wasn't slowing the rate of mental deterioration. As the failure of the
cholinergic drug Tacrine was becoming commonly known, another drug, amantadine (later, the similar memantine)
was proposed for combined treatment. In the 1950s, the anticholinergic drug atropine was proposed a few times
for treating dementia, and amantadine, which was also considered anticholinergic, was proposed for some
mental conditions, including Creutzfeldt-Jacob Disease (Sanders and Dunn, 1973). It must have seemed odd to
propose that an anticholinergic drug be used to treat a condition that was being so profitably treated with a
pro-cholinergic drug, but memantine came to be classified as an anti-excitatory "NMDA blocker," to protect the
remaining cholinergic nerves, so that both drugs could be prescribed simultaneously. The added drug seems to
have a small beneficial effect, but there has been no suggestion that this could be the result of its
previously-known anticholinergic effects. Over the years, some people have suspected that Alzheimer's disease
might be caused partly by a lack of purpose and stimulation in their life, and have found that meaningful,
interesting activity could improve their mental functioning. Because the idea of a "genetically determined
hard-wired" brain is no longer taught so dogmatically, there is increasing interest in this therapy for all
kinds of brain impairment. The analogy to the Berkeley enrichment experience is clear, so the association of
increasing cholinesterase activity with improving brain function should be of interest. The after-effect of
poisoning by nerve gas or insecticide has been compared to the dementia of old age. The anticholinergic drugs
are generally recognized for protecting against those toxins. Traumatic brain injury, even with improvement in
the short term, often starts a long-term degenerative process, greatly increasing the likelihood of dementia at
a later age. A cholinergic excitotoxic process is known to be involved in the traumatic degeneration of nerves
(Lyeth and Hayes, 1992), and the use of anticholinergic drugs has been recommended for many years to treat
traumatic brain injuries (e.g., Ward, 1950: Ruge, 1954; Hayes, et al., 1986). In 1976 there was an experiment
(Rosellini, et al.) that made an important link between the enrichment experiments and the learned helplessness
experiments. The control animals in the enrichment experiments were singly housed, while the others shared a
larger enclosure. In the later experiment, it was found that the rats "who were reared in isolation died
suddenly when placed in a stressful swimming situation," while the group-housed animals were resistant,
effective swimmers. Enrichment and deprivation have very clear biological meaning, and one is the negation of
the other. The increase of acetylcholinesterase, the enzyme that destroys acetylcholine, during
enrichment, serves to inactivate cholinergic processes. If deprivation does its harm by increasing the activity
of the cholinergic system, we should expect that a cholinergic drug might substitute for inescapable stress, as
a cause of learned helplessness, and that an anticholinergic drug could cure learned helplessness. Those tests
have been done: "Treatment with the anticholinesterase, physostigmine, successfully mimicked the effects of
inescapable shock." "The centrally acting anticholinergic scopolamine hydrobromide antagonized the effects of
physostigmine, and when administered prior to escape testing antagonized the disruptive effects of previously
administered inescapable shock." (Anisman, et al., 1981.) This kind of experiment would suggest that the
anticholinesterase drugs still being used for Alzheimer's disease treatment aren't biologically helpful. In an
earlier newsletter I discussed the changes of growth hormone, and its antagonist somatostatin, in association
with dementia: Growth hormone increases, somatostatin decreases. The cholinergic nerves are a major factor in
shifting those hormones in the direction of dementia, and the anticholinergic drugs tend to increase the ratio
of somatostatin to growth hormone. Somatostatin and cholinesterase have been found to co-exist in single nerve
cells (Delfs, et al., 1984). Estrogen, which was promoted so intensively as prevention or treatment for
Alzheimer's disease, was finally shown to contribute to its development. One of the characteristic effects of
estrogen is to increase the level of growth hormone in the blood. This is just one of many ways that estrogen is
associated with cholinergic activation. During pregnancy, it's important for the uterus not to contract.
Cholinergic stimulation causes it to contract; too much estrogen activates that system, and causes miscarriage
if it's excessive. An important function of progesterone is to keep the uterus relaxed during pregnancy. In the
uterus, and in many other systems, progesterone increases the activity of cholinesterase, removing the
acetylcholine which, under the influence of estrogen, would cause the uterus to contract. Progesterone is being
used to treat brain injuries, very successfully. It protects against inflammation, and in an early study,
compared to placebo, lowered mortality by more than half. It's instructive to consider its anticholinergic role
in the uterus, in relation to its brain protective effects. When the brain is poisoned by an organophosphate
insecticide, which lowers the activity of cholinesterase, seizures are likely to occur, and treatment with
progesterone can prevent those seizures, reversing the inhibition of the enzyme (and increasing the activity of
cholinesterase in rats that weren't poisoned) (Joshi, et al., 2010). Similar effects of progesterone on
cholinesterase occur in women (Fairbrother, et al., 1989), implying that this is a general function of
progesterone, not just something to protect pregnancy. Estrogen, with similar generality, decreases the activity
of cholinesterase. DHEA, like progesterone, increases the activity of cholinesterase, and is brain protective
(Aly, et al., 2011). Brain trauma consistently leads to decreased activity of this enzyme (Östberg, et al.,
2011; Donat, et al., 2007), causing the acetylcholine produced in the brain to accumulate, with many interesting
consequences. In 1997, a group (Pike, et al.) created brain injuries in rats to test the idea that a
cholinesterase inhibitor would improve their recovery and ability to move through a maze. They found instead
that it reduced the cognitive ability of both the injured and normal rats. An anticholinergic drug, selegeline
(deprenyl) that is used to treat Parkinson's disease and, informally, as a mood altering antiaging drug, was
found by a different group (Zhu, et al., 2000) to improve cognitive recovery from brain injuries. One of
acetylcholine's important functions, in the brain as elsewhere, is the relaxation of blood vessels, and this is
done by activating the synthesis of NO, nitric oxide. (Without NO, acetylcholine constricts blood vessels;
Librizzi, et al., 2000.) The basic control of blood flow in the brain is the result of the relaxation of the
wall of blood vessels in the presence of carbon dioxide, which is produced in proportion to the rate at which
oxygen and glucose are being metabolically combined by active cells. In the inability of cells to produce CO2 at
a normal rate, nitric oxide synthesis in blood vessels can cause them to dilate. The mechanism of relaxation by
NO is very different, however, involving the inhibition of mitochondrial energy production (Barron, et al.,
2001). Situations that favor the production and retention of a larger amount of carbon dioxide in the tissues
are likely to reduce the basic "tone" of the parasympathetic nervous system, as there is less need for
additional vasodilation. Nitric oxide can diffuse away from the blood vessels, affecting the energy metabolism
of nerve cells (Steinert, et al., 2010). Normally, astrocytes protect nerve cells from nitric oxide (Chen, et
al., 2001), but that function can be altered, for example by bacterial endotoxin absorbed from the intestine
(Solà, et al., 2002) or by amyloid-beta (Tran, 2001), causing them to produce nitric oxide themselves. Nitric
oxide is increasingly seen as an important factor in nerve degeneration (Doherty, 2011). Nitric oxide activates
processes (Obukuro, et al., 2013) that can lead to cell death. Inhibiting the production of nitric oxide
protects against various kinds of dementia (Sharma & Sharma, 2013; Sharma & Singh, 2013). Brain trauma
causes a large increase in nitric oxide formation, and blocking its synthesis improves recovery (Hüttemann, et
al., 2008; Gahm, et al., 2006). Organophosphates increase nitric oxide formation, and the protective
anticholinergic drugs such as atropine reduce it (Chang, et al., 2001; Kim, et al., 1997). Stress, including
fear (Campos, et al., 2013) and isolation (Zlatković and Filipović, 2013) can activate the formation of nitric
oxide, and various mediators of inflammation also activate it. The nitric oxide in a person's exhaled breath can
be used to diagnose some diseases, and it probably also reflects the level of their emotional well-being. The
increase of cholinesterase by enriched living serves to protect tissues against an accumulation of
acetylcholine. The activation of nitric oxide synthesis by acetylcholine tends to block energy production, and
to activate autolytic or catabolic processes, which are probably involved in the development of a thinner
cerebral cortex in isolated or stressed animals. Breaking down acetylcholine rapidly, the tissue renewal
processes are able to predominate in the enriched animals. Environmental conditions that are favorable for
respiratory energy production are protective against learned helplessness and neurodegeneration, and other
biological problems that involve the same mechanisms. Adaptation to high altitude, which stimulates the
formation of new mitochondria and increased thyroid (T3) activity, has been used for many years to treat
neurological problems, and the effect has been demonstrated in animal experiments (Manukhina, et al., 2010).
Bright light can reverse the cholinergic effects of inescapable stress (Flemmer, et al., 1990). During the
development of learned helplessness, the T3 level in the blood decreases (Helmreich, et al., 2006), and removal
of the thyroid gland creates the "escape deficit," while supplementing with thyroid hormone before exposing the
animal inescapable shock prevents its development (Levine, et al., 1990). After learned helplessness has been
created in rats, supplementing with T3 reverses it (Massol, et al., 1987, 1988). Hypothyroidism and excess
cholinergic tone have many similarities, including increased formation of nitric oxide, so that similar
symptoms, such as muscle inflammation, can be produced by cholinesterase inhibitors such as Tacrine, by
increased nitric oxide, or by simple hypothyroidism (Jeyarasasingam, et al., 2000; Franco, et al., 2006).
Insecticide exposure has been suspected to be a factor in the increased incidence of Alzheimer's disease
(Zaganas, et al., 2013), but it could be contributing to many other problems, involving inflammation, edema, and
degeneration. Another important source of organophosphate poisoning is the air used to pressurize airliners,
which can be contaminated with organophosphate fumes coming from the engine used to compress it. Possibly
the most toxic component of our environment is the way the society has been designed, to eliminate meaningful
choices for most people. In the experiment of Freund, <em>et al.</em>, some mice became more exploratory
because of the choices they made, while others' lives became more routinized and limited. Our culture reinforces
routinized living. In the absence of opportunities to vary the way you work and live to accord with new
knowledge that you gain, the nutritional, hormonal and physical factors have special importance. Supplements of
thyroid and progesterone are proven to be generally protective against the cholinergic threats, but there are
many other factors that can be adjusted according to particular needs. Niacinamide, like progesterone, inhibits
the production of nitric oxide, and also like progesterone, it improves recovery from brain injury (Hoane, et
al., 2008). In genetically altered mice with an Alzheimer's trait, niacinamide corrects the defect (Green, et
al., 2008). Drugs such as atropine and antihistamines can be used in crisis situations. Bright light, without
excess ultraviolet, should be available every day. The cholinergic system is much more than a part of the
nervous system, and is involved in cell metabolism and tissue renewal. Most people can benefit from reducing
intake of phosphate, iron, and polyunsaturated fats (which can inhibit cholinesterase; Willis, et al., 2009),
and from choosing foods that reduce production and absorption of endotoxin. And, obviously, drugs that are
intended to increase the effects of nitric oxide and acetylcholine should be avoided. © Ray Peat Ph.D. 2016. All
Rights Reserved. www.RayPeat.com
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