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 mechanism of anti-nicotinic actions of hexamethonium, mecamylamine and adenosine was investigated in guinea pig isolated ileum. Mecamylamine shifted the dose-response curves for nicotine to the right with a gradual depression. On the other hand, hexamethonium shifted the curves to the right without a depression and adenosine made only a gradual depression, suggesting the different modes of their antinicotinic actions. The transmurally-stimulated twitch response was unaffected, partially inhibited and abolis hed by hexamethonium, mecamylamine and adenosine, respectively. These three compounds also had little effect on direct muscle response to acetylcholine and on the acetylcholinesterase activity of the ileum. From these results, it is suggested that the antagonism to the effect of nicotine shown by mecamylamine does not appear to be a simple competitive blockade of ganglionic receptors as is the case with hexamethonium and that adenosine may antagonize the effect of nicotine non-competitively. The mechanism by which mecamylamine and adenosine showed anti-nicotinic action is discussed.
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PMID:Comparative studies on anti-nicotinic action of hexamethonium, mecamylamine and adenosine in the guinea pig isolated ileum. 59 56

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

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 cental actions of the lipophilic cholinesterase inhibitor physostigmine were investigated by infusing very low doses (0.8 micrograms up to 18 micrograms per kg) into the left vertebral artery of the anaesthetized cat. A dose as low as 2.7 micrograms per kg reduced blood pressure by about 35%. High doses caused bradycardia. Occlusion of the right vertebral artery shifted the dose-response curve to the left. It seems likely that the hypotension was due to stimulation of muscarinic receptors in the pontomedullary region, since pretreatment with dexetimide administered via the vertebral artery strongly reduced the effect. Mecamylamine and the adrenergic blocking agents metoprolol and piperoxan, infused into the vertebral artery, could not reduce the depressor response and the bradycardic action. Both bilateral cervical vagatomy and peripherally applied N-methylatropine did not change the hypotensive action of physostigmine. This observation points towards a reduction of sympathetic outflow as the possible cause of the depressor effect. Atenolol, given intravenously, diminished the bradycardia to a great extent, whereas N-methylatropine did not significantly alter the negative chronotropic action of physostigmine. These results suggest a dominant role for the sympathetic system in reducing cardiac frequency. After intravenous administration, only doses higher than 28 micrograms per kg evoked hypotension, which could not be blocked by intravenously administered N-methylatropine. However, centrally infused dexetimide considerably antagonized this effect, indicating that the hypotension was brought about by a central action and not evoked peripherally. Application of the drug via the external carotid arteries resulted in hypotension after considerably higher doses than those following administration via the vertebral artery, indicating the pontomedullary region as the main site of action. It is concluded that the present experimental data obtained with physostigmine support the hypothesis that ACh might have a transmitter role in the central haemodynamic control.
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PMID:Central cardiovascular effects of physostigmine in the cat; possible cholinergic aspects of blood pressure regulation. 611 63

In vitro studies in hypothalamic-pituitary explants in the rat have suggested cholinergic mediation of arginine vasopressin (AVP) osmoregulation. In this study we attempted to demonstrate, in humans, cholinergic mediation of AVP osmoregulation. Specifically, we tested the hypothesis that the plasma AVP response to an osmolar stimulus would be attenuated by pharmacologic blockade of central nervous system muscarinic or nicotinic receptors in humans. We also evaluated the effects of cholinergic blockade on the norepinephrine (NE) response to an osmolar stimulus. Young normal males underwent hypertonic saline infusion following administration of the centrally active muscarinic antagonist scopolamine or the centrally active nicotinic antagonist mecamylamine. Neither mecamylamine nor scopolamine affected the AVP response to hypertonic saline infusion. Mecamylamine reduced NE concentrations in a dose-dependent manner, but did not affect the slope of the NE increase during hypertonic saline infusion. In a second experiment, we evaluated the effects of scopolamine and mecamylamine on the AVP and NE responses to physostigmine, a cholinesterase inhibitor which stimulates AVP release into plasma through a non-osmolar central nervous system cholinergic mechanism. Scopolamine eliminated the AVP response to physostigmine. Mecamylamine reduced NE concentrations both before and after scopolamine administration but did not affect the slope of the AVP response. These results fail to support cholinergic regulation of the AVP response to osmolar stimulation in humans.
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PMID:Lack of cholinergic regulation of vasopressin and norepinephrine responses to hypertonic saline in humans. 884 15

The effects of various drugs were assessed in rats responding under a Differential-Reinforcement-of-Low-Rate 30-s (DRL 30-s) schedule. Atropine, scopolamine, and CEB-1957 (a new muscarinic blocker) increased response rate and decreased reinforcement rate, while methylatropine only decreased reinforcement rate. Physostigmine decreased response and reinforcement rates, when pyridostigmine had few effect on DRL responding. The irreversible acetylcholinesterase (AChE) inhibitors organophosphorus compounds (OPC) soman and sarin, injected at one-third of the LD50 did not consistently alter DRL performance, suggesting that they produce few behavioral effects in the rat when administered at subtoxic doses. Three oximes--pralidoxime, pyrimidoxime, and HI-6--decreased both response and reinforcement rates. Mecamylamine had few consistent effects on performance, and nicotine, d-amphetamine, diazepam, and the wakening drug modafinil increased response rate and decreased reinforcement rate. These two latter drugs also increased the number of very premature responses. These results, taken together, indicate that a DRL schedule is a useful tool to bring to light the existence of psychotropic effects of a drug. The explanation of drug-induced alterations of DRL performance, in terms of effects on cognition or on mood, is also discussed.
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PMID:Effects of various drugs including organophosphorus compounds (OPC) and therapeutic compounds against OPC on DRL responding. 958 69

1. Extracellular single-unit recording and iontophoresis were used to examine the effects of different cholinoceptor agonists and antagonists on the firing rate and firing pattern of A9 and A10 presumed dopaminergic neurones in the anaesthetized rat. 2. Administration of low currents (1-5 nA) of the selective muscarinic agonists oxotremorine M (Oxo M) and muscarine and of the non-selective muscarinic/nicotinic agonist carbamylcholine (CCh) produced a dose-dependent increase in firing rate in most of the A9 and A10 presumed dopaminergic neurones tested. Oxo M-induced activation could be completely blocked by iontophoretic application of the muscarinic antagonist butyl-scopolamine or systemic administration of the muscarinic antagonist scopolamine (300 microg kg(-1), i.v.). 3. Iontophoretic application of the selective nicotinic agonist methylcarbamylcholine (MCCh), but not nicotine, induced a consistent increase in firing rate. Surprisingly, the excitatory effect of MCCh was significantly reduced by the selective muscarinic antagonist scopolamine (300 microg kg(-1), i.v.), but not by the selective nicotinic antagonist mecamylamine (2.2 mg kg(-1), i.v.). Mecamylamine (3 mg kg(-1), i.v.) was also ineffective in reducing the CCh-induced activation of presumed dopamine neurones, suggesting that both CCh and MCCh increased the activity of dopamine neurones via an interaction with muscarinic receptors. 4. Iontophoretic application of the endogenous agonist acetylcholine (ACh) had no or little effect on the firing activity of A10 presumed dopaminergic neurones. However, concomitant application of neostigmine, a potent cholinesterase inhibitor, with acetylcholine induced a substantial activation of these neurones. This activation consisted of two components; one, which was prevalent, was scopolamine (300 microg kg(-1), i.v.)-sensitive, and the other was mecamylamine (2 mg kg(-1), i.v.)-sensitive. 5. In addition to their effect on firing activity, Oxo M, muscarine and concomitant neostigmine/ACh caused a significant increase in burst firing of A10 neurones, but not of A9 neurones. 6. These data suggest that dopamine cells, both in the A9 and A10 regions, possess functional muscarinic receptors, the activation of which can increase their firing rate and, for A10 neurones, their amount of burst activity. These cholinoceptors would be able to influence the activity of the midbrain dopamine system greatly and may play a role in, and/or be a therapeutic target for, brain disorders in which dopamine is involved (e.g., Parkinson's disease, drug addiction and schizophrenia).
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PMID:Activation of midbrain presumed dopaminergic neurones by muscarinic cholinergic receptors: an in vivo electrophysiological study in the rat. 964 68

The purpose of the present study was to determine the effects of muscarinic cholinergic receptor antagonists and agonists on prepulse inhibition (PPI) of the acoustic startle reflex in rats. The muscarinic receptor antagonist scopolamine (0.03-1.0 mg/kg) produced a significant dose-dependent decrease in PPI without affecting startle amplitude. In contrast, N-methyl scopolamine, the quaternary analog of scopolamine, had no effect on PPI, indicating that scopolamine disrupted PPI through a central cholinergic mechanism. Two other muscarinic receptor antagonists, trihexyphenidyl (0.3-10 mg/kg) and benztropine (0.03-10 mg/kg), produced significant decreases in PPI similar to scopolamine. On the other hand, the muscarinic receptor antagonists dicyclomine (0.03-10 mg/kg) and biperiden (0.03-10 mg/kg) had no effect on PPI but significantly decreased startle amplitude. Mecamylamine (0.1-10 mg/kg), a nicotinic receptor antagonist, also had no effect on PPI. Administered alone, the muscarinic receptor agonists pilocarpine (0. 03-10 mg/kg), oxotremorine (0.01-0.3 mg/kg), RS-86 (0.1-3.0 mg/kg), and arecoline (0.3-10 mg/kg), as well as the cholinesterase inhibitors physostigmine (0.01-0.3 mg/kg) and tacrine (0.03-10 mg/kg), had no effect on PPI, but each produced significant decreases in startle amplitude at the highest doses tested. In addition, the disruption of PPI by scopolamine was reversed in a dose-dependent manner by the muscarinic receptor agonist oxotremorine. The present findings demonstrate that the muscarinic cholinergic system plays an important role in the normal mechanisms of PPI.
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PMID:Muscarinic cholinergic modulation of prepulse inhibition of the acoustic startle reflex. 1094 54

The role of nicotinic and muscarinic receptors in the modulation of acetylcholine release was studied using field stimulated mouse cortex slices incubated with [(3)H]-choline. Both acetylcholine (100 microM) and the cholinesterase inhibitor neostigmine (100 microM) inhibited the stimulation-induced (S-I) outflow of radioactivity but in the presence of atropine (0.3 microM) an enhancement was seen, which may be indicative of facilitatory nicotinic receptors. Mecamylamine (100 microM) was unable to antagonize the enhancement seen in the presence of acetylcholine and atropine. The nicotinic agonist dimethylphenylpiperazinium (30 microM) did not facilitate S-I outflow of radioactivity. A range of nicotinic blockers had no effect on the enhancement seen in the presence of neostigmine and atropine, nor did indomethacin, the 5HT(3) antagonist MDL 7222 nor the NMDA antagonist MK-801. The inability to block this effect suggests that nicotinic receptors are not involved. We postulate, at least for neostigmine, that the facilitation is an artefact because of the use of [(3)H]-choline as a radiotracer whereby the efflux of radioactivity is enhanced because the radiolabelled acetylcholine is not metabolized to choline and therefore flows out of the tissue more readily.
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PMID:No involvement of nicotinic receptors in the facilitation of acetylcholine outflow in mouse cortex in the presence of neostigmine and atropine. 1095 94

We examined the mechanisms of the neuroprotective effects of two central-type acetylcholinesterase inhibitors, galanthamine and tacrine, on nitric oxide-mediated glutamate neurotoxicity using primary cultures from the cerebral cortex of fetal rats. Galanthamine and tacrine showed prominent protective effects against glutamate neurotoxicity. Mecamylamine, a nicotinic acetylcholine receptor antagonist, but not scopolamine, a muscarinic acetylcholine receptor antagonist, inhibited the protective effects of these inhibitors on glutamate neurotoxicity. Furthermore, dihydro-beta-erythroidine, an alpha4-nicotinic receptor antagonist, and methyllycaconitine, an alpha7-nicotinic receptor antagonist, inhibited the neuroprotective effects of galanthamine but not tacrine. Next, we investigated the site of action where galanthamine and tacrine prevent glutamate neurotoxicity. Both these acetylcholinesterase inhibitors prevented glutamate- and ionomycin-induced neurotoxicity, but only tacrine prevented S-nitrosocysteine-induced neurotoxicity. These results suggest that galanthamine and tacrine protect cortical neurons from glutamate neurotoxicity via different mechanisms.
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PMID:Neuroprotective effects of galanthamine and tacrine against glutamate neurotoxicity. 1699 97


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