Changes In Acetylcholine Levels Research Articles

The protective effect of metformin in scopolamine-induced learning and memory impairment in rats.

Alzheimer's disease (AD) is the most common neurodegenerative disease in the world. One of the most commonly prescribed oral antidiabetic drug, metformin, has been shown to have beneficial effects on restoring impaired cognitive function. In the present study, we investigated the effects of metformin on spatial memory in terms of alleviating scopolamine-induced learning and memory impairments in rats by using the Morris water maze (MWM) test and the modified elevated plus-maze (mEPM) test. Furthermore, we investigated the possible mechanisms of action of metformin in preventing cognitive dysfunction. Male Wistar rats received metformin (50, 100, or 200 mg/kg/day) via gavage feeding for three weeks. Scopolamine was administered intraperitoneally before the probe step of the MWM test or the acquisition session of the mEPM test. The learning and memory impairment induced by scopolamine was reversed by metformin. In addition, metformin improved the level of phosphorylated AMP-activated protein kinase and cAMP responsive element binding protein. However, metformin pretreatment had no impact on inhibiting the scopolamine-induced changes in acetylcholine levels. Furthermore, metformin exerted its antioxidant effect by significantly reversing scopolamine-induced changes in malondialdehyde, total antioxidant status, and superoxide dismutase levels in the hippocampus. Our results indicate that one of the most commonly used antidiabetic drug, metformin, has the potential to prevent the development of dementia and be a novel therapeutic drug for the amelioration of cognitive dysfunction in AD.

Imaging of cerebral α4β2* nicotinic acetylcholine receptors with (−)-[18F]Flubatine PET: Implementation of bolus plus constant infusion and sensitivity to acetylcholine in human brain

The positron emission tomography (PET) radioligand (−)-[18F]flubatine is specific to α4β2⁎ nicotinic acetylcholine receptors (nAChRs) and has promise for future investigation of the acetylcholine system in neuropathologies such as Alzheimer's disease, schizophrenia, and substance use disorders. The two goals of this work were to develop a simplified method for α4β2⁎ nAChR quantification with bolus plus constant infusion (B/I) (−)-[18F]flubatine administration, and to assess the radioligand's sensitivity to acetylcholine fluctuations in humans. Healthy human subjects were imaged following either bolus injection (n=8) or B/I (n=4) administration of (−)-[18F]flubatine. The metabolite-corrected input function in arterial blood was measured. Free-fraction corrected distribution volumes (VT/fP) were estimated with modeling and graphical analysis techniques. Next, sensitivity to acetylcholine was assessed in two ways: 1. A bolus injection paradigm with two scans (n=6), baseline (scan 1) and physostigmine challenge (scan 2; 1.5mg over 60min beginning 5min prior to radiotracer injection); 2. A single scan B/I paradigm (n=7) lasting up to 240min with 1.5mg physostigmine administered over 60min beginning at 125min of radiotracer infusion. Changes in VT/fP were measured. Baseline VT/fP values were 33.8±3.3mL/cm3 in thalamus, 12.9±1.6mL/cm3 in cerebellum, and ranged from 9.8 to 12.5mL/cm3 in other gray matter regions. The B/I paradigm with equilibrium analysis at 120min yielded comparable VT/fP values with compartment modeling analysis of bolus data in extrathalamic gray matter regions (regional means <4% different). Changes in VT/fP following physostigmine administration were small and most pronounced in cortical regions, ranging from 0.8 to 4.6% in the two-scan paradigm and 2.8 to 6.5% with the B/I paradigm. These results demonstrate the use of B/I administration for accurate quantification of (−)-[18F]flubatine VT/fP in 120min, and suggest possible sensitivity of (−)-[18F]flubatine binding to physostigmine-induced changes in acetylcholine levels.

Striatal cholinergic interneuron regulation and circuit effects.

The striatum plays a central role in motor control and motor learning. Appropriate responses to environmental stimuli, including pursuit of reward or avoidance of aversive experience all require functional striatal circuits. These pathways integrate synaptic inputs from limbic and cortical regions including sensory, motor and motivational information to ultimately connect intention to action. Although many neurotransmitters participate in striatal circuitry, one critically important player is acetylcholine (ACh). Relative to other brain areas, the striatum contains exceptionally high levels of ACh, the enzymes that catalyze its synthesis and breakdown, as well as both nicotinic and muscarinic receptor types that mediate its postsynaptic effects. The principal source of striatal ACh is the cholinergic interneuron (ChI), which comprises only about 1–2% of all striatal cells yet sends dense arbors of projections throughout the striatum. This review summarizes recent advances in our understanding of the factors affecting the excitability of these neurons through acute effects and long term changes in their synaptic inputs. In addition, we discuss the physiological effects of ACh in the striatum, and how changes in ACh levels may contribute to disease states during striatal dysfunction.

Concurrent administration of atypical antipsychotics and donepezil: drug interaction study in rats.

Psychotic and behavioral symptoms are common in patients with dementia. Thus, it is rational to assume that patients with dementia would gain benefit from combination therapy of an antipsychotic agent and a cognitive enhancer. Antipsychotics are not approved by the US FDA in elderly patients with dementia but their use is still prevalent in other population. In the current study, we investigate the effect of atypical antipsychotics on acetylcholine modulation by donepezil. In addition, the plasma pharmacokinetics on concurrent administration of these drugs was studied. Acetylcholine modulation was carried out in the ventral hippocampus of Sprague-Dawley rats using brain microdialysis technique. In a parallel group of animals, pharmacokinetic parameters were evaluated on administration of donepezil (5.0mgkg(-1), ip) alone and in combination with olanzapine, clozapine, or quetiapine. Donepezil produced 348% increase in hippocampal acetylcholine levels. Coadministration of olanzapine and donepezil produced 393% increase in extracellular acetylcholine, and the effect was supported by a significantly (p<0.05) decreased clearance of donepezil in plasma. Whereas, other plasma pharmacokinetic parameters of donepezil "AUC(0-24h), T (1/2) and T (max)" were moderately altered after this combination treatment. Concurrent administrations of clozapine or quetiapine with donepezil produced a non-significant change in acetylcholine levels in comparison to donepezil alone. The plasma pharmacokinetics of donepezil was unaltered. Results from this preclinical investigation indicate that extrapyramidal side effects may precipitate upon coadministration of donepezil with olanzapine. Care must be exercised by physicians and caregivers while administering these two drugs together.

Chapter 1 Neuromodulation and the hippocampus: memory function and dysfunction in a network simulation

Neuromodulators, such as acetylcholine, norepinephrine and serotonin, alter the functional state of cortical networks by changing the processing characteristics of cortical neurons. This chapter presents the evidences for the functioning of the neuromodulatory changes. Computational modeling of the cellular effects of modulators suggests a behavioral role for the state changes. The changes in acetylcholine levels are particularly relevant to a current theory of memory involving two functional stages of memory formation. In the first stage, during active waking, information processed according to existing cortical representations is rapidly encoded in the hippocampus in an intermediate term episodic representation. This involves a strong feed forward influence of neocortex on hippocampus, with weaker feedback for the ongoing retrieval during waking (stored memories are only evoked by new afferent input). In the second stage, during quiet waking and slow-wave sleep, there is stronger feedback influence of hippocampus on neocortex, and spontaneous reactivation of stored memory representations even without afferent input. Activity then spreads from the hippocampus back to the neocortex, mediating a gradual consolidation of memories, (formation of semantic or long-term episodic memory in the neocortex).

The Anticonvulsant Effect of Deprenyl on Pentylenetetrazol-Induced Seizures in Lewis Rats

There is recent evidence that deprenyl may have anticonvulsant action in a rat kindling model of epilepsy as well as in a maximal electroshock model. We therefore investigated the effect of deprenyl on the brain sensitivity threshold to pentylenetetrazol (PTZ)-induced maximal seizures in Lewis rats, in a model that provides pharmacodynamic information free of pharmacokinetic interference. The novel finding of this investigation was the anticonvulsant effect of deprenyl following repetitive administration whereas a single deprenyl dose did not affect the PTZ concentrations required to induce maximal seizures. The data suggests that the mechanism of this effect is not associated with the dopaminergic activity of deprenyl since pretreatment with both bromocriptine (a dopamine D2 agonist) and haloperidol (dopamine antagonist) did not affect the seizure threshold, whereas levodopa caused a proconvulsant effect. It was also concluded that the mechanism is not related to changes in acetylcholine levels since prolonged pretreatment with deprenyl did not attenuate the brain sensitivity to pilocarpine-induced seizures. The fact that long term administration of deprenyl was needed to produce its anticonvulsant effect may indicate that the anticonvulsant effect of deprenyl may be due to changes in levels of certain endogenous compounds or down or up-regulation of relevant receptor/ effector units.

Acute neurochemical changes in mouse brain following cerebral ischemia

Acute changes in neurochemical levels induced by ischemia were studied in the mouse brain. Contents of neurochemicals in the frontal, parietal and occipital cortices and hippocampus were determined immediately after 15 min of ischemia (0), and then at 15, 30, 90 and 180 min after recirculation following ischemia. These data were compared with those for sham-operated control mice. Choline (Ch) contents in ischemic animals increased by 530–630% from control levels immediately after ischemia, and returned to control levels by 90 min. Decreases in levels of norepinephrine (NE) and serotonin (5-HT) were observed during 30 min after recirculation. There were no significant changes in levels of acetylcholine (ACh) or dopamine (DA), throughout recirculation. On the other hand, DA and 5-HT metabolites (3,4-dihydroxyphenylacetic acid and 5-hydroxyindoleacetic acid) significantly increased. Thus, comprehensively investigating the various neurotransmitters will provide meaningful information regarding the disturbance of central nervous system induced by cerebrovascular disease.

Changes in Acetylcholine Levels Following Leaf Wilting and Leaf Recovery by Heat Stress in Plant Cultivars.

To study for physiological role of acetylcholine (ACh) in plant cultivars of yard-long bean, cucumber and radish, the relationship between ACh levels and leaf response with leaf wilting and its recovery by heat stress was compared between cultivars adapted to the tropical zone (tropical evergreen lowland rain forest zone) and to the temperate zone. Potted-plants were exposed to a jet air of warm (30°C) air for 2 min or 3 min using a hair-dryer. Acetylcholine content was determined by a pyrolysis gas chromatograph equipped with a flame ionization detector. Cultivars from the tropical zone were distinguished by low degree of wilting and a rapid recovery from wilting. And then, the amount of ACh in tissues was more than 2-10 fold in leaf, stem, node, root than that of cultivars from the temperate zone without stress. Futhermore, ACh content after heat stress changed significantly in leaf, stem, pulvini, node, leaf-blade, petiole and root of plants. Little to no change in ACh content following leaf wilting and recovery by stress was found in cultivars adapted to the temperate zone. Thus, a quick leaf response with leaf wilting and its recovery in cultivars from the tropical zone may be controlled by a rapid ACh movement resulting the enzyme activity of ACh hydrolysis in pulvini, node or root of plants.

Changes in ACh levels in the rat brain during subacute administration of diisopropylfluorophosphate

Rats were treated with diisopropylfluorophosphate (DFP) acutely and daily for 14 days. The total, free, and bound acetylcholine (ACh) levels were monitored in striatum, hippocampus, and frontal cortex after DFP administration. Thirty minutes after daily administration of DFP, the total and free ACh levels were significantly increased and remained constant after each successive dose. The bound ACh levels in striatum and frontal cortex were also significantly increased; however, they were comparable to control levels after the 14th injection of DFP. The total ACh levels 30 min after a challenge dose of 2 mg/kg DFP in saline and DFP subacutely treated rats were significantly increased in hippocampus (34 and 76%) and frontal cortex (49 and 64%) and were not significantly different between the two groups. However, the level of total ACh in striatum was increased less in the tolerant rats (10%) than in the acutely treated rats (36%). The levels of free and bound ACh after acute administration of 2 mg/kg DFP were markedly increased in three brain regions. After subacute administration, the levels of bound ACh were significantly increased in hippocampus (84%) and frontal cortex (40%); however, that in striatum did not change. The increase in the bound ACh level in the subacute treatment group was less than that in acutely treated rats in all three brain regions; however, the duration of the elevation of the free ACh in striatum was shorter in subacutely treated rats. These results suggest that the presynaptic cholinergic storage sites for ACh might be changed during subacute administration of DFP.

Effect of cholinergic deficit induced by ethylcholine aziridinium on serotonergic parameters in rat brain

The consequence of loss of cholinergic input on the function of serotonergic neurons has been studied in rat brain after bilateral intracerebroventricular injections of various doses of the cholinotoxin ethylcholine aziridinium ion (1 to 5 nmoles/ventricle). This treatment resulted in a dose-dependent decrease in acetylcholine content in hippocampus, which occurred 2 days after injection and persisted during the 28 day observation period. The reduction in acetylcholine content ranged from 50.3 ± 6.0% to 76.9 ± 3.8% when compared to vehicle-injected rats. Other brain areas, including cortex, striatum and hypothalamus, showed only minor and transient changes in acetylcholine levels. Treatment with ethylcholine aziridinium was accompanied by a dose-dependent response of serotonergic neurons. The predominant reaction, which we observed in all areas studied, was an initial increase in 5-hydroxyindoleacetic acid content, a decrease in serotonin content, and consequently an increase in the molar ratio of metabolite/amine, indicating an increase in serotonin turnover. As with acetylcholine, the decrease in serotonin content was most pronounced in the hippocampus, ranged from 19.4 ± 2.9% to 53.4 ± 4.1%, and even persisted at 28 days after injection of 3 and 5 nmoles of the toxin/ventricle, although serotonin levels returned towards normal at that time point after injection of 1 or 2 nmoles of the toxin/ventricle. These data suggest that, in the rat, withdrawal of cholinergic input to the hippocampus might have a considerable impact on serotonergic function. This includes an initial increase in activity and, as cholinergic degeneration progresses, a decrease in serotonergic function. The most likely explanation for the serotonergic deficit is that it may reflect adaptation of these neurons to the withdrawal of cholinergic input. Such a phenomenon might help to increase our understanding of the events taking place in the brains of patients with Alzheimer's disease as the cholinergic system starts to degenerate.

Acetylcholine and choline levels in rabbit fetuses exposed to anticholinergics

It has been hypothesized that acetylcholine, choline acetylase and acetylcholinesterase may have an ontogenic and trophic influence in the embryo, and that therefore certain drugs may produce malformations via their effect on the acetylcholine and choline levels in the fetus. Thalidomide and the anticholinergics, scopolamine hydrobromide and orphenadrine hydrochloride, and doxylamine succinate, an antihistamine with secondary anticholinergic action, were administered to pregnant New Zealand White rabbit does from day 8 to day 15 of gestation. Ceasarean sections were performed on gestational day 16, the fetuses removed and the acetylcholine and choline contents of the fetuses and placentas were estimated by organic extraction and derivation for injection into a GCMS. These acetylcholine and choline levels were compared with those of the fetuses and placentas of the control animals mated with the same buck on the same day as the treated animals.Thalidomide (50 mg/kg) did not affect acetylcholine or choline levels in the fetuses or the placentas obtained from the treated animal. Scopolamine (approximately 100 μg/kg) reduced the choline level in the placenta and fetus but not the acetylcholine levels. Orphenadrine (approximately 24 mg/kg) reduced acetylcholine and choline levels in the fetus and choline levels in the placenta. Doxylamine succinate (10 mg/kg) reduced the acetylcholine levels in the fetus and the choline levels in the placenta.The placenta is a fetal organ and the significance of acetylcholine production by the placenta is as yet unknown. The reduction in acetylcholine levels in the fetus exposed to drugs with an anticholinergic action may be of significance in the production of malformations. However, it appears that thalidomide does not produce malformations through a change in acetylcholine levels in the fetus.

Profound effects of combining choline and piracetam on memory enhancement and cholinergic function in aged rats

In an attempt to gain some insight into possible approaches to reducing age-related memory disturbances, aged Fischer 344 rats were administered either vehicle, choline, piracetam or a combination of choline or piracetam. Animals in each group were tested behaviorally for retention of a one trial passive avoidance task, and biochemically to determine changes in choline and acetylcholine levels in hippocampus, cortex and striatum. Previous research has shown that rats of this strain suffer severe age-related deficits on this passive avoidance task and that memory disturbances are at least partially responsible. Those subjects given only choline (100 mg/kg) did not differ on the behavioral task from control animals administered vehicle. Rats given piracetam (100 mg/kg) performed slightly better than control rats ( p<0.05), but rats given the piracetam/choline combination (100 mg/kg of each) exhibited retention scores several times better than those given piracetam alone. In a second study, it was shown that twice the dose of piracetam (200 mg/kg) or choline (200 mg/kg) alone, still did not enhance retention nearly as well as when piracetam and choline (100 mg/kg of each) were administered together. Further, repeated administration (1 week) of the piracetam/choline combination was superior to acute injections. Regional determinations of choline and acetylcholine revealed interesting differences between treatments and brain area. Although choline administration raised choline content about 50% in striatum and cortex, changes in acetylcholine levels were much more subtle (only 6–10%). No significant changes following choline administration were observed in the hippocampus. However, piracetam alone markedly increased choline content in hippocampus (88%) and tended to decrease acetylcholine levels (19%). No measurable changes in striatum or cortex were observed following piracetam administration. The combination of choline and piracetam did not potentiate the effects seen with either drug alone, and in certain cases the effects were much less pronounced under the drug combination. These data were discussed as they relate to possible effects of choline and piracetam on cholinergic transmission and other neuronal function, and how these effects may reduce specific memory disturbances in aged subjects. The results of these studies demonstrate that the effects of combining choline and piracetam are quite different than those obtained with either drug alone and support the notion that in order to achieve substantial efficacy in aged subjects it may be necessary to reduce multiple, interactive neurochemical dysfunctions in the brain, or affect activity in more than one parameter of a deficient metabolic pathway.

Central cholinergic involvement in behavioral hyper-reactivity

The present experiments were designed to test the hypothesis that behavioral reactivity to changes of environmental stimulation varies concomitantly with changes induced acutely by pharmacological and chronically by morphological manipulations of acetylcholine in the central cholinergic system. Acute reduction of acetylcholine levels was achieved by cerebroventricular injections of hemicholinium-3 at five dosages and chronic reduction by electrolytic lesions in the septum. Significant and quantitatively equivalent hyper-reactivity occurred when animals were exposed to a variety of stimulus changes at peak effect times for the two experimental treatments. Such concordance of behavioral effects was not observed during non-contingent shock stimulation, when septal animals were significantly hyper-reactive and hemicholinium-3 animals were not. These findings may be interpreted in terms of results of recent multivariate analyses showing that several independent behavioral factors constitute the septal “syndrome”: a particular factor, e.g., reactivity, may be related to a neurochemical substrate which is not shared by other factors. The present experiments revealed a highly precise relation between acute changes in acetylcholine levels and dose effect trends in hyper-reactivity, i.e., hyper-reactivity followed hemicholinium-3 injections (IVt) which reduced acetylcholine and returned to control levels when acetylcholine recovered. Under conditions of chronic acetylcholine reduction (septal lesion) initial hyper-reactivity disappeared with time, an observation consistent with the “imbalance” hypothesis about interactions between transmitter systems which assumes that changes in one system may be followed by compensatory changes in a related system.

Regional differences in the sensitivity of cholinergic neurons to dopaminergic drugs and quipazine in the rat striatum

Marked differences were found in the activity of choline acetylase (ChAc) in various discrete areas of the rat striatum. The richest cholinergic innerbation was observed in the centrolateral part of the structure. A similar distribution was obtained by measuring acetylcholine (ACh) levels in punches taken from frozen frontal serial slices. As revealed by the analysis of the topographical distributions of ChAc activity, ACh, 5-HT and DA, the regional cholinergic innervation differed markedly from that of aminergic terminals. Changes in ACh levels induced by drugs could be estimated in microdiscs of tissues punched from frozen slices. Apomorphine and haloperidol, which increased and decreased ACh levels respectively, induced similar effects in the various striatal areas examined. By contrast quipazine, a drug acting on 5-HT uptake and release and on serotoninergic recptors, selectively increased ACh levels in some areas of the striatum but not in others. The regional changes in ACh levels induced by quipazine were satisfactorily correlated with the regional distribution of 5-HT but not with that of DA. These results suggest that a limited population of striatal cholinergic neurons is under the inhibitory control of serotoninergic neurons. They also indicate that some striatal cholinergic neurons influenced by dopaminergic neurons are not controlled by serotoninergic neurons.

Changes in regional brain acetylcholine levels during drug-induced convulsions

Acetylcholine (ACh) levels were determined in the brain of rats killed by decapitation or focussed microwave radiation during drug-induced convulsions. During metrazol or strychnine-induced convulsions a diffuse decrease in ACh levels was found in rats killed by decapitation. When the rats were killed by radiation and the brain was only divided into three large regions, strychnine caused no changes in ACh levels; metrazol caused a decrease in the cerebral cortex and lower brainstem. When discrete brain regions were investigated in rats killed by radiation, metrazol-induced convulsions were associated with a decrease in ACh level in all regions dissected and strychnine-induced convulsions with a decrease in the hippocampus and caudate nucleus only. Picrotoxin-induced convulsions were associated with a decrease in ACh level in the cerebral cortex, hippocampus, midbrain and medullapons, those induced by bicuculline with an increase in ACh level in the frontal cortex, hippocampus, midbrain and medulla-pons, by dimefline with an increase in the frontal cortex, midbrain and medulla-pons and a decrease in the caudate nucleus. The experiments show that each type of convulsant affects ACh levels in discrete brain regions in a different way.

Regional brain acetylcholine levels in rats acutely treated with ethanol or rendered ethanol-dependent

Abstract : A study of brain acetylcholine (ACh) levels was undertaken in an attempt to reconcile discrepancies reported on the effects of ethanol treatment on the cholinergic system. ACh levels were measured in six areas of brains of male Sprague-Dawley rats after a single dose of ethanol or after the induction of ethanol dependence. At various times after treatment the rats were euthanatized by focused microwave irradiation. The excised brains were dissected into the following parts: cerebellum, brain stem, hypothalamus, hippocampus, caudate nucleus and cerebral cortex. After an acute dose of ethanol, ACh levels increased in most areas of the brain when blood ethanol concentrations were quite high. As blood ethanol declined, ACh levels decreased to below control values with similar results observed in ethanol-dependent rats still intoxicated. No significant changes in ACh levels were observed in ethanol-dependent rats undergoing a withdrawal syndrome. These data suggest that ethanol treatment exerts multiple effects on the cholinergic system, but they do not as yet support a role of ACh in the expression of the ethanol withdrawal syndrome. The results of this study provide further information on the development and exploration of models for chronic insults to the brain, such as long-term exposure to toxic chemicals and ionizing and nonionizing radiation. (Author)

Regional levels of choline and acetylcholine in rat brain following head focussed microwave sacrifice: Effect of (+)-amphetamine and (±)-parachloroamphetamine

The effect of (+)-amphetamine and (±) p-chloroamphetamine on the levels of choline and acetylcholine (ACh) in discrete regions of rat brain were studied. Animals were sacrificed by head focussed microwave irradiation which terminated all measurable enzymatic activity in brain within two seconds. Both p-chloroamphetamine and amphetamine induced short term ( < 48 hr) increases in ACh levels in the striatum and cerebellum and simultaneous decreases in ACh levels in the hippocampus and cortex. In addition, p-chloroamphetamine caused a long term (> 48 hr) increase in ACh levels in the striatum and cerebellum. It is suggested that the short-term change in ACh levels induced by p-chloroamphetamine and amphetamine are mediated via release of dopamine. while the long term changes in ACh levels caused by p-chloroamphetamine are related to serotonin and may indicate that serotonin is involved in the regulation of ACh turnover in the striatum.

Metabolism and mentation.

The ultimate supreme function of the body is mentation; the other portions of the body are subservient to it. Dysmentation is very common, highly distressing, and enormously expensive. All abnormalities in mentation are presumably associated with altered metabolism. Dysmetabolism causes dysmentation and vice versa. Altered cerebral metabolism is produced by primary or secondary cerebral disorders in the body, and by extracorporeal influences—abnor- malities in diet, climate, social status, and num- erous other environmental factors; there fre- quently is a polycyclic interplay of influences. Dysmentation is often found in many genetic disorders, hyper- and hypoparathyroidism, hy- per- and hypoadrenocorticism, and hypothy- roidism. There are indications that it also occurs frequently in many other endocrine and metab- olic disorders, but data are inadequate. Many neurotransmitters have been described, includ- ing especially acetylcholine, norepinephrine, dopamine and serotonin. Abnormalities in the metabolism of one or more of these have been reported in various types of dysmentation. In mental depression and mania there are ab- normalities in catecholamine metabolism, with lesser changes in serotonin. Certain observations have suggested abnormalities in serotonin me- tabolism in schizophrenia, but data remain in- adequate. Hallucinations and other marked be- havioral changes have accompanied altered serotonin metabolism and/or ingestion of sero- tonin-like compounds. Changes in acetylcholine levels have produced anger, rage, anxiety and other behavioral states. Sleep seems to be as- sociated with increased serotonin and decreased catecholamine levels; insomnia accompanies the reverse. Learning and memory are influenced by the metabolism of protein, nucleotides, carbo- hydrate, fat, vitamins, minerals, and numerous other factors. The brain has richer contents of adenosine-3',5'-phosphate, adenyl cyclase and phosphodiesterase than any other organ, but relatively little is known about the functions there of this nucleotide. As endocrinologists and metabolists, problems of dysmentation con- front us as highly interesting, and probably richly rewarding areas for research, teaching and prac- tice. (J Clin Endocr 31: 461, 1970)

Sleep deprivation and brain acetylcholine.

Rats deprived of D-state sleep (and, to some extent, of slow-wave sleep) for 96 hours show a significant fall in brain acetylcholine in the telencephalon; there were no significant changes in the diencephalon and brain stem. Restraint stress and activity wheel stress produced no significant change in acetylcholine levels in any of these regions; the telencephalic response to sleep deprivation, therefore, cannot be attributed to nonspecific stress. The effects of D-state deprivation and the psychoactive anticholinergic drugs on telencephalic acetylcholine levels are similar.