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:3.1.1.8 (cholinesterase)
12,691 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. Contractile responses and acetylcholine release evoked by nicotine in guinea-pig detrusor strips were determined by isotonic transducer and radioimmunoassay, respectively. Nicotine stimulated acetylcholine release and a contractile response in guinea-pig detrusor strips treated with the cholinesterase inhibitor, methanesulphonyl fluoride (MSF). Both actions evoked by nicotine were antagonized by the nicotinic receptor antagonist, hexamethonium but were insensitive to tetrodotoxin. 2. A sympathetic nerve blocker, guanethidine and a tachykinin antagonist, [D-Arg1, D-Pro2, D-Trp7,9, Leu11]-substance P (rpwwL-SP) partially inhibited the acetylcholine release evoked by nicotine to much the same degree. The inhibitory effects of guanethidine and rpwwL-SP on acetylcholine release were significantly greater than corresponding effects on the contraction evoked by nicotine. 3. In preparations treated with rpwwL-SP to block the tachykinin receptors, guanethidine had no effect on the response to nicotine. Conversely, after treatment with guanethidine to block release of a mediator from sympathetic nerve endings, nicotine-induced responses were not affected by rpwwL-SP. 4. Nicotine-induced contraction was reduced to 30% by the muscarinic cholinoceptor antagonist, atropine and completely abolished after desensitization of P2-purinoceptors with alpha,beta-methylene ATP in the presence of atropine. 5. A concentration-contractile response curve to neurokinin A (NKA) was shifted to the left after cholinesterase inhibition with MSF. Atropine abolished the facilitatory effect of MSF and partially inhibited contractions induced by NKA at 100 nM to 1 microM. The contractile responses to substance P methyl ester (SPOMe) and Tyr0-neurokinin B (Tyr0-NKB) were not influenced by MSF or atropine. 6. After desensitization of NK, tachykinin receptors with SPOMe or preincubation with senktide, the cholinergic component of the nicotine-induced contraction was the same as the control value (100%). 7. Our findings give further support to our previous results: nicotine stimulates acetylcholine release in a tetrodotoxin-resistant manner in guinea-pig bladder and acetylcholine release evoked by nicotine is increased by the coordinated action of sympathetic nerves and tachykinin(s). It is suggested that the tachykinin receptor subtype involved in acetylcholine release is NK,.
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PMID:Contrasting effects of tachykinins and guanethidine on the acetylcholine output stimulated by nicotine from guinea-pig bladder [corrected]. 171 27

Behavioral effects of nicotine and cytisine, and the cholinesterase inhibitors physostigmine and 9-amino-1,2,3,4-tetrahydroacridine (THA), administered intrathecally (IT) at the lumbar level in the rat have been evaluated. Antinociceptive dose relationships were established using the tail immersion test. Total activity, locomotion and rearing were also measured in computerized test boxes. The nicotinic receptor antagonist, mecamylamine, and the muscarinic receptor antagonist, atropine, were used to study the selectivity of the effects. Physostigmine and THA significantly decreased total activity, locomotion and rearing as compared to control animals. The motor effects of physostigmine were completely antagonized only partly. Mecamylamine had no antagonistic effect. Nicotine did not affect any activity parameter. Cytisin reduced total activity and locomotion 1-6 min after dose. IT physostigmine, 15 micrograms, increased tail immersion latency for 30 min. No significant increase in response latency in this test was observed after the IT administration of nicotine or THA, whereas cytisine elicited a small increase. The IT administration of THA, nicotine and cytisine was also associated with gnawing, vocalization and hyperactivity and in the case of THA, diarrhoea. These effects were blocked by mecamylamine. Physostigmine antinociception as well as the behavioral effects including total activity, locomotion and rearing caused by physostigmine and by THA are most probably due to an action on spinal muscarinic receptors. Nicotinic receptors do not seem to be involved in spinal antinociception. Some aversive behavioral effects caused by the IT administration of nicotinic receptor agonists could, however, be attenuated by the spinal administration of the antagonist mecamylamine, which may indicate the involvement of nicotinic receptors in afferent sensory transmission.
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PMID:Behavioral effects after intrathecal administration of cholinergic receptor agonists in the rat. 232 Jul 7

The effects of hemicholinium-3 (HC-3) on spatial discrimination learning were studied. Rats were equipped with indwelling cannulae in the right lateral ventricle and, following recovery, were trained on a two platform spatial discrimination task in a water maze. In this task a visible escape platform remains in a fixed position in the pool during a single training session, whilst the location of an identical "float" (which affords no escape) is randomly varied. For each session the location of the fixed escape platform was changed and the rats were retrained to criterion following pretreatment either with artificial cerebrospinal fluid (CSF) or HC-3 (2.5, 5.0 micrograms/rat/ICV) 1 h before training. Each rat received every treatment according to a latin square design. The results showed that spatial learning was dose dependently impaired by HC-3, choice accuracy being reduced to chance levels by the higher dose. There was no evidence of motoric difficulty, as choice latencies were not significantly increased. Experiments were then conducted to test for reversal of the deficit using a range of psychotropic drugs. Rats were treated with CSF or HC-3 (5 micrograms/rat ICV) 60 min prior to testing and test drugs were injected 15 min before testing. Some doses of physostigmine (46-460 micrograms/kg/SC) and tetrahydroaminoacridine (THA) (2.2-10 mg/kg/SC) reversed the spatial learning deficit. The muscarinic agonists arecoline (0.046-1 mg/kg/SC), aceclidine (1-10 mg/kg/SC), oxotremorine (30-100 micrograms/kg/SC) and RS-86 (0.46, 1.0 microgram/kg/SC) were also effective. Pilocarpine (0.22-2.2 mg/kg/SC) showed marginal activity and isoarecoline (4.6-10 mg/kg/SC) was inactive. Nicotine (0.32, 1, 3.2 mg/kg/SC) and piracetam (10, 30, 100 mg/kg IP) were also inactive. The alpha 2 agonist, clonidine (46, 100 micrograms/kg SC) and the antagonist idazoxan (32, 100 micrograms/kg SC) were also inactive. Learning deficits were not reversed by haloperidol (20, 60 micrograms/kg), amphetamine (0.1, 0.46 mg/kg), the selective 5-HT1A agonist 8-OH-DPAT (30, 100 micrograms/kg) or by the benzodiazapine antagonist ZK-93426 (1, 3.2, 10 mg/kg). The results show that forebrain Ach depletion by HC-3 impairs spatial discrimination learning and these deficits are reversed by cholinesterase inhibitors and some muscarinic receptor agonists. Some degree of pharmacological selectivity is indicated by the failure of a range of other drugs to reverse the impairments.
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PMID:Hemicholinium-3 impairs spatial learning and the deficit is reversed by cholinomimetics. 252 45

1. Nicotine produced a transient contraction of isolated strips of guinea-pig urinary bladder. The response to nicotine was antagonized by the nicotinic receptor antagonist, hexamethonium but was insensitive to tetrodotoxin. 2. The nicotine-induced contraction was potentiated by the cholinesterase inhibitor, physostigmine, and was reduced to 50% and 70% by the muscarinic cholinoceptor antagonist, atropine and the sympathetic neurone blocking drug, guanethidine, respectively. Chemical denervation with 6-hydroxydopamine abolished the inhibitory effect of guanethidine. Simultaneous treatment with atropine and guanethidine did not abolish the response to nicotine, but the degree of inhibition was comparable to that obtained with atropine alone. 3. The nicotine-induced contraction was insensitive to bunazosin and yohimbine (alpha 1- and alpha 2-adrenoceptor antagonists, respectively), and exogenously applied noradrenaline did not cause a contraction even in the presence of blockade of noradrenaline uptake mechanisms with desipramine and normetanephrine and of beta-adrenoceptors with propranolol, suggesting a non-adrenergic nature of the sympathomimetic effect of nicotine in this tissue. 4. The nicotine-induced contraction in the presence of atropine was abolished after desensitization of P2-purinoceptors with alpha, beta-methylene adenosine 5'-triphosphate, a slowly degradable ATP analogue selective for P2-purinoceptors. By this desensitization, the response to ATP, but not to histamine, was also abolished. 5. A cyclo-oxygenase inhibitor flurbiprofen partially inhibited the nicotine-induced contraction. The degree of the inhibition was more pronounced in the presence of atropine than in its absence. Flurbiprofen antagonized the response to exogenously applied ATP in an unsurmountable manner, but not that to carbachol. 6. The present results suggest that nicotine might induce a contraction through an interaction with nicotinic receptors located on the terminals of, possibly, (i) parasympathetic cholinergic, (ii) sympathetic non-adrenergic and (iii) non-sympathetic purinergic nerves in guinea-pig detrusor preparations, and that a portion of the contraction due to the purine nucleotide released is possibly potentiated by intramural prostaglandin(s). Parasympathetic cholinergic output might be modulated by an unknown excitatory substance released by nicotine from sympathetic nerve. 7. Nicotine reveals a latent excitatory effect of the sympathetic hypogastric nerve which innervates guinea-pig detrusor.
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PMID:Mechanism of action of nicotine in isolated urinary bladder of guinea-pig. 322 73

Drugs which alter nicotinic cholinergic transmission were administered to female rats to examine the neurochemical regulation of feminine sexual behavior. Nicotine (50, 100 or 200 micrograms/kg, IP) facilitated lordosis behavior 5 minutes after injection in estrogen-primed ovariectomized (OVX) rats. Pretreatment with the nicotinic antagonist, mecamylamine (MECA, 2.5 or 10 mg/kg) prevented this effect, while atropine pretreatment (30 mg/kg) reduced it. Mecamylamine pretreatment also reduced lordotic behavior induced by bilateral intracerebroventricular (ICV) injection of the cholinesterase inhibitor, eserine (5 micrograms/cannula). However, MECA treatment (5 or 10 micrograms/cannula, bilaterally, ICV, or 5 or 10 mg/kg, IP) did not reduce sexual receptivity in OVX rats made highly receptive with estrogen plus progesterone priming. By comparison with previously published results, MECA is apparently less effective than muscarinic antagonists in disrupting sexual receptivity in several paradigms. There appears to be a critical muscarinic link in the neural circuit for sexual receptivity, but there does not appear to be a comparable nicotinic link. In fact, the lordosis-facilitating effect of nicotine may be a pharmacological effect unrelated to the normal neurochemical regulation of sexual receptivity.
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PMID:Nicotinic cholinergic influences on sexual receptivity in female rats. 357 59

The effects of nicotine and 1,1-dimethyl-4-phenylpiperazinium (DMPP) on the release of newly synthesized [3H]acetylcholine in mouse cerebral cortical synaptosomes were examined. Nicotine and DMPP produced increases in [3H]acetylcholine release, over the level of spontaneous release, of 24% and 30%, respectively, of a maximum depolarization-induced release produced by 50 mM potassium. The maximum effect was achieved at a concentration of 1 X 10(-4) M for both agents. The time course of release indicated a slow onset of action, reaching a maximum effect at 15 min of incubation. Both nicotine and DMPP also produced a slightly greater release of total tritium, measured in the absence of cholinesterase inhibition, than of [3H]acetylcholine. The release induced by nicotine was completely antagonized by hexamethonium and was largely (58%) calcium-dependent. Nicotine also produced an increase in [3H]choline accumulation into synaptosomes. These results indicate that the nicotinic agonists nicotine and DMPP can produce a moderate enhancement of acetylcholine release by a receptor-mediated action on cholinergic nerve terminals in the central nervous system.
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PMID:Nicotinic stimulation of [3H]acetylcholine release from mouse cerebral cortical synaptosomes. 614 66

The nicotinic cholinergic antagonist, dihydro-beta-erythroidine, binds to two sites in rat cortical membranes with dissociation constants of 4 and 22 nM and respective apparent Bmax values of 52 and 164 fmol/mg of protein. Binding to the higher affinity site, defined by the use of 2 nM [3H]dihydro-beta-erythroidine, was saturable, reversible, and susceptible to protein denaturation. Binding was highest in the thalamus and lowest in the spinal cord and showed preferential enrichment in a synaptosomal subfraction of rat brain. Nicotine displaced [3H]dihydro-beta-erythroidine in a stereospecific manner, the (-)-isomer being approximately 6 times more potent than the (+)-isomer. The alkaloid nicotinic agonists, cytisine and lobeline, were potent inhibitors of binding, while acetylcholine in the presence of the cholinesterase inhibitor di-isopropylfluorophosphate was equipotent with (+)-nicotine. Binding was also inhibited by the muscarinic ligands, arecoline, atropine, and oxotremorine. The nicotinic antagonists mecamylamine, hexamethonium, and pempidine were essentially inactive in displacing [3H]dihydro-beta-erythroidine. These findings indicate that dihydro-beta-erythroidine binds to a nicotinic recognition site in rat brain which is neuromuscular, rather than ganglionic, in nature and that such binding is similar in several respects to that seen with nicotinic agonists. Whether such binding is to a nicotinic, as opposed to nicotinic cholinergic, recognition site or to a "common" nicotinic/muscarinic site is an issue that requires further study.
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PMID:Binding of the nicotinic cholinergic antagonist, dihydro-beta-erythroidine, to rat brain tissue. 650 10

Previous work from this laboratory showed that daily s.c. injections of the organophosphate diisopropylfluorophosphate caused prolonged inhibition of cholinesterase (ChE) activity in whole blood and brain and downregulation of muscarinic receptors in the central nervous system; these changes were accompanied by progressive, persistent deterioration of working memory and motor function. Further, a single s.c. injection of the organophosphate insecticide chlorpyrifos (O,O',-diethyl O-3,5,6-trichloro-2-pyridyl phosphorothionate, CPF), caused neurochemical changes of the same magnitude and duration, but transient impairment of working memory and motor slowing. In the present study, weekly injections of CPF (0, 15, 30 or 60 mg/kg s.c.) inhibited ChE activity in whole blood of rats by 60% to 90% after 5 weeks; the highest dose also induced tremor, working memory impairment and motor slowing in daily delayed matching-to-position/visual discrimination tests. Reducing the CPF injection frequency to every other week relieved the inhibition of whole blood ChE activity (to 50%-75% of control) and ameliorated all the behavioral deficits. Reinstatement of weekly CPF injections (0, 15, 30, or 45 mg/kg) for 10 weeks inhibited whole blood ChE activity by 75% to 90%. Tremor was not observed during this period; however, motor slowing and working memory impairment persisted throughout the dosing period in all treated groups. Pharmacological evidence for tolerance to the muscarinic effects of CPF was observed on trial completion in the daily delayed matching-to-position/visual discrimination task: CPF-treated rats were supersensitive to scopolamine and subsensitive to pilocarpine. Nicotine reversed the reduction in trial completion associated with CPF. Changes in sensitivity to mecamylamine, d-amphetamine and haloperidol were not observed. Taken together, these studies indicate that inhibition of ChE activity by repeated injection of CPF produces a constellation of behavioral effects not evident after a single CPF treatment, even though both treatment regimens caused prolonged inhibition of ChE activity and downregulation of central muscarinic receptors.
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PMID:Repeated inhibition of cholinesterase by chlorpyrifos in rats: behavioral, neurochemical and pharmacological indices of tolerance. 751 12

The present study was designed to investigate the hypothesis that concurrent degeneration of serotonin and acetylcholine cells may decrease the therapeutic effects of cholinergic drugs on cognitive functioning in Alzheimer dementia. Therefore, we compared the effects of pretraining injections of a cholinesterase inhibitor, tetrahydroaminoacridine (1, 3 and 5 mg/kg i.p.), and nicotine (0.03, 0.1 and 0.3 mg/kg i.p.) on spatial navigation (water maze) and passive avoidance in nucleus basalis- and nucleus basalis+p-chlorophenylalanine-lesioned rats. Nicotine (0.1 and 0.3 mg/kg) promoted passive avoidance performance of nucleus basalis-lesioned rats, but nicotine did not improve performance of combined-lesioned rats. Tetrahydroaminoacridine (3 mg/kg) facilitated passive avoidance performance of nucleus basalis- and combined-lesioned rats. However, tetrahydroaminoacridine-treated nucleus basalis+p-chlorophenylalanine-lesioned rats were not performing better than vehicle-treated nucleus basalis-lesioned rats. Spatial navigation of nucleus basalis and nucleus basalis+p-chlorophenylalanine-lesioned rats was slightly impaired during the first training day and tetrahydroaminoacridine 3 mg/kg restored the performance of combined-lesioned rats. Combined-lesioned rats performed as well as the controls during the other training days. The present results suggest that, in Alzheimer's disease, combined degeneration of nucleus basalis cholinergic and brainstem serotonergic cells decreases the therapeutic effect of nicotine, but not that of tetrahydroaminoacridine.
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PMID:Effects of tetrahydroaminoacridine and nicotine in nucleus basalis and serotonin-lesioned rats. 755 84

The existence in the mammalian CNS of release-inhibiting muscarinic autoreceptors is well established. In contrast, few reports have focused on nicotinic autoreceptors mediating enhancement of acetylcholine (ACh) release. Moreover, it is unclear under what conditions the function of one type of autoreceptor prevails over that of the other. Rat cerebrocortex slices, prelabeled with [3H]choline, were stimulated electrically at 3 or 0.1 Hz. The release of [3H]ACh evoked at both frequencies was inhibited by oxotremorine, a muscarinic receptor agonist, and stimulated by atropine, a muscarinic antagonist. Nicotine, ineffective at 3 Hz, enhanced [3H]ACh release at 0.1 Hz; mecamylamine, a nicotinic antagonist, had no effect at 3 Hz but inhibited [3H]ACh release at 0.1 Hz. The cholinesterase inhibitor neostigmine decreased [3H]ACh release at 3 Hz but not at 0.1 Hz; in the presence of atropine, neostigmine potentiated [3H]ACh release, an effect blocked by mecamylamine. In synaptosomes depolarized with 15 mM KCl, ACh inhibited [3H]ACh release; this inhibition was reversed to an enhancement when the external [Ca2+] was lowered. The same occurred when, at 1.2 mM Ca2+, external [K+] was decreased. Oxotremorine still inhibited [3H]ACh release at 0.1 mM Ca2+. When muscarinic receptors were inactivated with atropine, the K+ (15 mM)-evoked release of [3H]ACh (at 0.1 mM Ca2+) was potently enhanced by ACh acting at nicotinic receptors (EC50 approximately 0.6 microM). In conclusion, synaptic ACh concentration does not seem to determine whether muscarinic or nicotinic autoreceptors are activated. Although muscarinic autoreceptors prevail under normal conditions, nicotinic autoreceptors appear to become responsive to endogenous ACh and to exogenous nicotinic agents under conditions mimicking impairment of ACh release. Our data may explain in part the reported efficacy of cholinesterase inhibitors (and nicotinic agonists) in Alzheimer's disease.
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PMID:Nicotinic autoreceptors mediating enhancement of acetylcholine release become operative in conditions of "impaired" cholinergic presynaptic function. 886 3


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