Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.1.7 (acetylcholinesterase)
28,390 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The purpose of our studies was to determine the effects of muscarinic receptor agonists on conditioned avoidance responding in the rat. Rats were trained to avoid or escape an electric shock delivered to the feet in a discrete trial procedure. The muscarinic receptor agonists pilocarpine and [2-ethyl-8-methyl-2,8-diazaspiro(4. 5)decane-1,3-dione] hydrochloride (RS86) and the cholinesterase inhibitor physostigmine all decreased the percentage of avoidance responses at doses that produced less than approximately 30% response failures. Similar results were obtained with the antipsychotic drugs haloperidol, trifluoperazine, chlorpromazine, and clozapine. However, the benzodiazepine anxiolytic diazepam did not decrease avoidance responding up to doses that produced ataxia. On the other hand, oxotremorine and arecoline decreased avoidance responding only by producing response failures, whereas aceclidine produced intermediate changes. The muscarinic receptor antagonists scopolamine, trihexyphenidyl, and benztropine were without effect when administered alone but antagonized the decreases in avoidance responding produced by pilocarpine and RS86. Scopolamine had little effect on the decreases in avoidance responding produced by haloperidol. The newer muscarinic receptor partial agonists or agonist/antagonists [R-(Z)-(+)-alpha-(methoxyimino)-1-azabicyclo[2.2. 2]octane-3-acetonitrile] hydrochloride, talsaclidine, milameline, and xanomeline also produced dose-related decreases in avoidance responding. Our results demonstrate that muscarinic receptor agonists can decrease avoidance responding in a manner similar to dopamine-receptor antipsychotic drugs, suggesting that muscarinic receptor agonists may provide an alternative approach to the treatment of psychosis.
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PMID:Muscarinic receptor agonists, like dopamine receptor antagonist antipsychotics, inhibit conditioned avoidance response in rats. 1041 7

Location precues were used to manipulate the spatial scale of attention in visual search for a target in an array of letters in patients with dementia of the Alzheimer type (DAT) and in age-matched older controls. Cue size varied in the amount of spatial precision conferred. Scopolamine, a muscarinic antagonist, decreased overall arousal and broadened spatial attention after a precise precue (small and valid) to target location for DAT patients but not for controls, suggesting a selective effect for attentional impairment induced by cholinergic blockade. In contrast, physostigmine, a cholinesterase inhibitor, did not alter the distribution of spatial attention relative to no-drug baseline testing for patients. Results support a differential role for cholinergic mechanisms in the modulation of the spatial scale of visual attention.
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PMID:Acetylcholine affects the spatial scale of attention: evidence from Alzheimer's disease. 1079 68

Donepezil is a member of a new class of centrally acting cholinesterase inhibitors which preferentially inhibit acetylcholinesterase rather than butyrylcholinesterase. The effects of donepezil on learning impairments were investigated in some hypocholinergic models in rats. In nucleus basalis magnocellularis (NBM)-lesioned rats, donepezil alleviated deficits in passive avoidance response at a dose of 0.125 mg/kg and higher, while tacrine had only a tendency toward improved performance. Donepezil at 0.5 mg/kg effectively counteracted acquisition impairments in the water maze task induced by lesions of the medial septum; tacrine had no significant effects on impairments in this task. Scopolamine caused an increase of errors in the 8-arm radial maze. Donepezil significantly decreased scopolamine-induced errors in the radial maze at 0.5 mg/kg, whereas tacrine decreased errors at 2 mg/kg. These results suggest that donepezil can clearly minimize learning impairments induced by treatments that cause central cholinergic deficiencies in rats. These findings support the clinical efficacy of donepezil in Alzheimer's disease.
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PMID:Donepezil, a centrally acting acetylcholinesterase inhibitor, alleviates learning deficits in hypocholinergic models in rats. 1084 91

Statistical analysis of EEG spectra averaged over 10-min periods showed that inhibitor of acetylcholinesterase physostigmine induced the long-term (tens of minutes) characteristic changes in the electric activity of the dorsal hippocampus (CA1 field) and somatosensory cortex of unrestrained rats. With increasing the physostigmine dose from 0.05 to 0.5 or 1 mg/kg the averaged power of the theta-rhythm did not rise in the range of 3.6-4.9 Hz and was suppressed in the range of 5.7-11.9 Hz both in the hippocampus and neocortex. The maximal frequency shifted to the left (from 3.6-6.4 to 3.6-4.9 Hz). In contrast to this, the averaged power in the delta (1-1.5 Hz)-I and beta-2 ranges (20.3-26.5 Hz) significantly nonlinearly increased and that of the beta-1 substantially decreased. Scopolamine eliminated all extrema of the hippocampal and neocortical EEG spectra induced by physostigmine, which is indicative of the role of M-cholinoreceptors in these effects. The increased dose of physostigmine (1 mg/kg) produced inversion of the ratio between the averaged power of beta-2 in neocortex and hippocampus: it became significantly higher than in the neocortex. All these data suggest that the mechanisms of cholinergic modulation of the theta- and beta-rhythms are essentially different. We think that significant enhancement of the content of endogenous acetylcholine content produce a long-term tonic decay of the functional activity of the hippocampus and neocortex and play an important role in the mechanisms of dissociated states of memory and consciousness, contextual learning and conditioned switching.
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PMID:[Long-term changes in EEG spectra of the hippocampus and neocortex during pharmacological action on the cholinergic system]. 1119 98

This study presents a comparison between two inhibitors of acetylcholinesterase, tacrine and E2020 (Donepezil), the 5-HT(3) receptor antagonist ondansetron, and the H(3) receptor antagonist thioperamide, in models of cholinergic function and cognition in male, Lister hooded rats. The cognitive tests used were an operant VI20 task, the delayed match to position task (short-term memory) and the 5-choice serial reaction time task (attention). Scopolamine (SCOP) (0.075mg/kg s.c.) was utilised in both the short-term memory and attention tasks to impair performance. Both tacrine (1-30mg/kg) and E2020 (1-10mg/kg) similarly produced overt cholinomimetic signs of likely central origin (hypothermia, tremor), although tacrine produced more profound peripheral cholinomimetic signs (miosis, secretory signs) than E2020. Tacrine (30mg/kg) and E2020 (10mg/kg) reduced the number of reinforcements gained in the VI20 schedule. Similarly, both drugs attenuated the SCOP-impairment models in the short-term memory and attention tasks (1-3mg/kg). Ondansetron (10ng/kg-1mg/kg) and thioperamide (0.2-10mg/kg) failed to elicit overt cholinomimetic signs or influence the number of food reinforcements gained in the VI20 schedule. Neither ondansetron nor thioperamide attenuated the SCOP-induced impairment in either cognitive task. From the present studies, both E2020 and tacrine showed a similar behavioural profile in the models used, although E2020 was about three times more potent. Furthermore, E2020 but not tacrine appeared to show some discrimination in eliciting central and peripheral cholinomimetic signs. The failure of ondansetron and thioperamide to reverse a SCOP-induced deficit in these models is discussed.
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PMID:Effects of anticholinesterase drugs tacrine and E2020, the 5-HT(3) antagonist ondansetron, and the H(3) antagonist thioperamide, in models of cognition and cholinergic function. 1122 48

The hypothalamic-pituitary-adrenal (HPA) axis has differential physiological activity in male and female animals (sexual diergism). Central cholinergic systems stimulate this endocrine axis. In the present study we investigated muscarinic and nicotinic cholinergic influences on HPA axis activity in male and female rats by pretreatment with selective cholinergic receptor antagonists followed by stimulation with physostigmine (PHYSO), an acetylcholinesterase inhibitor. Hormonal measures were plasma arginine vasopressin (AVP), adrenocorticotropic hormone (ACTH), and corticosterone (CORT). Male rats had significantly greater AVP and ACTH responses to PHYSO alone than did females. Scopolamine (SCOP) enhanced the AVP response to PHYSO to a greater extent in males than in females. In contrast, mecamylamine (MEC) enhanced the AVP response in females but decreased it in males. SCOP potentiated, and MEC inhibited, the stimulatory effect of PHYSO on ACTH in both sexes, but SCOP potentiation was greater in males, and MEC inhibition was greater in females. Absolute CORT increases following PHYSO were greater in females, but percent increases over baseline were greater in males. Similar to their effects on ACTH responses, MEC attenuated, and SCOP enhanced, CORT responses to PHYSO. These results suggest that cholinergic receptor subtypes may influence HPA axis activity differentially in male and female rats.
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PMID:Sexual diergism in rat hypothalamic-pituitary-adrenal axis responses to cholinergic stimulation and antagonism. 1122 19

This study was designed to investigate the central and peripheral activity profile of cholinesterase inhibitors in rats. Intravenous injection of cholinesterase inhibitors caused fasciculation, a fine involuntary muscular movement. This peripheral cholinergic sign was tightly correlated with in vitro anti-acetylcholinesterase activity by cholinesterase inhibitors, suggesting that fasciculation is a valid index of peripheral cholinergic activation. Yawning, used as a marker of central cholinergic activation, was also monitored. E2030 (3-(2-(1-(1,3-dioxolan-2-ylmethyl)-4-piperidyl)ethyl)-2H-3,4-dihydro-1,3-benzoxazin-2,4-dione hydrochloride) elicited yawning at more than 4 mg/kg, while fasciculation was significantly intensified only at a dose of 16 mg/kg. Donepezil and tacrine induced both yawning and fasciculation at doses greater than 4 mg/kg, whereas physostigmine induced both behaviors at a dose of 8 mg/kg and above. Finally, ipidacrine elicited yawning at a dose of 16 mg/kg and fasciculation at doses greater than 8 mg/kg. Thus, all putative centrally acting cholinesterase inhibitors elicited yawning. TAK-147 (3-[1-(phenylmethyl)-4-piperidinyl]-1-(2,3,4,5-tetrahydro-1H-benzazepin-8-yl)-1-propanone fumarate) did not significantly elicit yawning at doses under 16 mg/kg, but elicited fasciculation at a dose of more than 4 mg/kg. Distigmine, a peripherally acting cholinesterase inhibitor, evoked fasciculations, but not yawning. When mild to moderate fasciculation was evoked, donepezil and E2030 elicited more than nine yawns over 30 min, while the other cholinesterase inhibitors elicited approximately five yawns at most during this period. These results indicated that E2030 and donepezil exhibited the most marked preferential central cholinergic activity, relative to peripheral activity, among cholinesterase inhibitors tested. Scopolamine, a centrally acting antimuscarinic drug, completely inhibited E2030-induced yawning, while peripherally acting methylscopolamine did not. Haloperidol, a dopamine receptor antagonist, partially blocked E2030-induced yawning, but did not block donepezil-induced yawning. These results suggest that central cholinergic and, in part, dopaminergic mechanisms are involved in E2030-induced yawning.
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PMID:Central and peripheral activity of cholinesterase inhibitors as revealed by yawning and fasciculation in rats. 1127 94

Systemically administered cholinomimetics or cholinesterase inhibitors can depress behavior in humans and animals, whereas antimuscarinic agents reverse this effect or even produce euphoria. Although these effects have been well documented, the specific brain regions that mediate them remain largely unknown. In the present experiments, muscarinic agonists and antagonists were locally injected into the nucleus accumbens of female Sprague-Dawley rats to test for their effects on behavioral depression in the Porsolt swim test and locomotor activity. Local, microinjections of the drugs in the accumbens elicited behaviors that were similar to the systemic effects reported in other studies. Injection of the non-specific agonist arecoline (40 and 80 microg) dose-dependently inhibited swimming and escape behavior. This may be mediated in part by accumbens M1 receptors because blocking these receptors with the specific antagonist pirenzepine (17.5 and 35.0 microg) did the opposite by increasing swimming. Gallamine (0.13, 0.44, and 0.88 microg), an antagonist at M2 receptors, dose-dependently decreased swimming. Two-way microdialysis suggested that this was in part due to the release of ACh by blocking M2 autoreceptors. Scopolamine, a mixed M1/M2 receptor antagonist, also released ACh but did not decrease swimming, probably because the M1 receptors were blocked; the drug (1.0 microg) increased swimming time, much like pirenzepine. With the exception of arecoline, none of the drugs significantly affected locomotor activity in a photocell cage. Arecoline (40 microg), which had decreased swimming, reduced activity. The present study suggests that muscarinic receptors in the nucleus accumbens can control immobility in the Porsolt swim test. The onset of immobility may depend on the activation of post-synaptic M1 receptors.
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PMID:Nucleus accumbens muscarinic receptors in the control of behavioral depression: antidepressant-like effects of local M1 antagonist in the Porsolt swim test. 1144 Aug 10

Statistical analysis of EEG spectra averaged over 10-min intervals showed that in rats performing free behavior, peripheral administration of the acetylcholinesterase inhibitor physostigmine induced long-lasting characteristic changes (lasting tens of minutes) in the electrical activity of the dorsal hippocampus (field CAI) and the somatosensory cortex. An increase in the physostigmine dose from 0.05 to 1 mg/kg shifted the peak of the theta rhythm to lower frequencies (3.6-4.9 Hz) without a change in power at this frequency, though there was a decrease in power at 5.7-11.9 Hz. The power of the beta-1 rhythm (13.8-16.4 Hz) was also strongly suppressed. In contrast, the power of the beta-2 rhythm (20.3-26.5 Hz) increased several-fold in a non-linear fashion. Scopolamine suppressed all the changes induced by physostigmine, demonstrating the important role of m-cholinoceptors in changes in EEG spectra. The high dose of physostigmine caused inversion of the power of the beta-2 rhythm: unlike the situation obtaining in controls, the beta-2 power in the hippocampus became significantly greater than that in the neocortex. These data suggest the conclusion that overall significant increases in endogenous acetylcholine levels lead to decreases in the functional activity of the hippocampus and neocortex and that the mechanisms of cholinergic modulation of the theta and beta rhythms are significantly different. It is suggested that conditioned reflex switching, contextual learning, and dissociated sates of memory and consciousness are to a significant extent dependent on long-term changes in the oscillatory activity of the hippocampus and neocortex.
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PMID:Long-term changes in hippocampus and neocortex EEG spectra in response to pharmacological treatments affecting the cholinergic system. 1176 95

In the present study, the effects of vitamins E and C on the levels of neurotransmitters and acetylcholinesterase activity in the brains of rats treated with scopolamine, an inducer of dementia, were examined. Fifty male Sprague-Dawley rats at the age of 5 wk were divided into five groups after 1 wk of adaptation and fed five different diets for 6 wk: a no-scopolamine group, which was a scopolamine-untreated group fed only a basal diet: a scopolamine-treated group fed a basal diet; a vitamin E-supplemented scopolamine-treated group: a vitamin C-supplemented scopolamine-treated group; and a vitamins E and C-supplemented scopolamine-treated group. Scopolamine was twice administered by intraperitoneal injection (300 mg/kg, body weight), 3 d and 20 min prior to sacrifice. Brain acetylcholinesterase activity was markedly reduced by scopolamine injection. However, the supplementation of vitamins E and C in the diet significantly increased the reduced brain acetylcholinesterase activity up to the level of the scopolamine-untreated group. Brain serotonin concentration in the vitamin C-supplemented scopolamine-treated group was significantly higher than that in the scopolamine-treated group. However, there were no significant differences in brain dopamine and norepinephrine concentrations among all groups. In conclusion, supplementation with vitamin E and/or vitamin C might be useful in maintaining brain acetylcholinesterase activity at the normal level and serotonin concentration for some extent under the condition to induce dementia by scopolamine administration.
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PMID:Effect of supplementation of vitamin E and vitamin C on brain acetylcholinesterase activity and neurotransmitter levels in rats treated with scopolamine, an inducer of dementia. 1181 46


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