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)

Four rhesus monkeys were trained to discriminate apomorphine (APO) from saline in a two lever, food-reinforced drug discrimination paradigm. After acquisition of the discrimination (average = 161 sessions), they were tested with a series of compounds selected to characterize the neuronal mechanism(s) of the discrimination and to determine whether the site of action was central or peripheral. APO produced a dose-related increase in the percentage of responses that occurred on the drug lever during test sessions. The D2 dopamine (DA) agonist piribedil substituted completely for APO and the D2 DA antagonist pimozide antagonized the APO discriminative stimulus in a manner consistent with a competitive antagonism. On the other hand, the D1 agonist SKF 38393 engendered principally saline lever responding in all monkeys, whereas the D1 DA antagonist SCH 23390 was ineffective as an APO antagonist. The APO effect was neither mimicked by DA nor blocked by the D2DA antagonist domperidone, both of which fail to cross the blood-brain barrier to any significant extent. In substitution tests the norepinephrine reuptake blocker nisoxetine, the serotonin agonist quipazine and the cholinesterase inhibitor physostigmine, as well as d-amphetamine, cocaine and morphine engendered principally saline lever responding up to doses that substantially reduced rate of responding. Taken together these results suggest that the APO discriminative stimulus is based principally upon an action at a D2 receptor in the central nervous system and that this preparation can be used for studying the functional properties of central nervous system D2 receptors.
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PMID:Pharmacological analysis of the apomorphine discriminative stimulus in rhesus monkeys. 355 38

The tertiary analogute of phospholine, namely, (C(2)H(5)O)(2)P(O)SCH(2)CH(2)N(CH(3))(2), is a potent, irreversible inhibitor of cholinesterase which, when externally applied to the sqluid giant axon, readily penetrates in its inhibitory form into the axoplasm. However, even a 10(-2) molar solution of this compound does not block axonal conduction unless the axon is first treated with a low concentration of venom from the cottonmouth moccasin. The question of the activity of acetylcholinesterase in these axons is considered, and the possibility of subcellular permeability barriers for indivisual components of the excitable membrane is discussed.
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PMID:Penetration of an organphosphorus compound into squid axon and its effects on metabolism and function. 602 64

The interaction of human erythrocyte acetylcholinesterase, horse serum butyrylcholinesterase and rat liver carboxylesterase with insecticides (RO)2P(O)SCH(COOEt)SP(O)(OR)2 (I) and (RO)2P(O)SCH(COOEt)OP(S)(OR)2 (II) was studied. The type I and II compounds were not hydrolyzed by carboxylesterase and inhibited the esterases irreversibly. A complex pattern of inhibition of acetylcholinesterase and butyrylcholinesterase by these compounds was caused by kinetically-manifested formation of an enzyme-inhibitor complex. The compounds I and II were more selective towards butyrylcholinesterase than towards acetylcholinesterase and carboxylesterase (kII two orders of magnitude higher) because of effective binding in the butyrylcholinesterase active center (K alpha 10(-8)--10(-9) M) due to hydrophobic interaction. An important role of the thion-phosphoryl-containing fragment in the interaction of type II compounds with hydrophobic sites of butyrylcholinesterase and carboxylesterase active centers was established.
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PMID:[Interaction of bis-phosphorylated methanes with mammalian esterases]. 651 64

The neurochemical anatomy of the human nucleus accumbens was studied by comparing the distributional patterns of [3H]DAMGE (mu opioid receptor), [3H]bremazocine (kappa opioid receptor), [3H]SCH-23390 (D1-like dopamine receptor), [3H]7-OH-DPAT (D3 dopamine receptor) binding, preproenkephalin mRNA and acetylcholinesterase activity in sections of post mortem human striatum. Our results demonstrate the presence of at least two neurochemically distinct divisions within the human nucleus accumbens, which may be homologous to the 'shell' and 'core' divisions of the nucleus as found in the rat.
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PMID:Evidence for two neurochemical divisions in the human nucleus accumbens. 770 1

Facial electromyography (EMG) coupled with visual observation was used to investigate spontaneous and drug induced perioral movements in freely moving rats. Four separate perioral behaviours were identified; facial tremor, purposeless chewing, gaping and yawning. Facial tremor, yawning and gaping but not purposeless chewing produced characteristic EMG signals. Normal rats displayed a low level of purposeless chewing, occasional bursts of facial tremor but not gaping or yawning. Each burst of facial tremor was accompanied by a transient increase in purposeless chewing. Administration of the D1 agonist SKF 38393 induced a dose related increase in bursts of facial tremors and consequently an increase in the total number of purposeless chews. Gaping and yawning were not induced by SKF 38393 administration. Administration of the cholinesterase inhibitor physostigmine (0.1-0.4 mg/kg) induced a dose related increase in the total number of purposeless chews, but primarily these were not associated with facial tremor. Administration of physostigmine also increased gaping and yawning. Administration of the D1 antagonist SCH 23390 almost abolished facial tremor in normal treated rats but only partially reduced that induced by SKF 38393 and physostigmine. SCH 23390 reduced purposeless chewing in SKF 38393 treated rats but not in normal or physostigmine treated animals. Administration of the cholinergic antagonist atropine almost abolished facial tremor in normal and physostigmine treated rats, but only reduced by 46% that induced by SKF 38393. Atropine reduced purposeless chewing in normal, physostigmine and SKF 38393 treated animals. Physostigmine induced gaping and yawning were abolished by atropine administration.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Electromyographical differentiation of the components of perioral movements induced by SKF 38393 and physostigmine in the rat. 787 Oct 53

The discriminative stimulus effect of the novel centrally active cholinesterase inhibitor, NIK-247, was investigated in rats and compared with that of tetrahydroaminoacridine (THA). Rats were trained to discriminate either 10 mg/kg NIK-247 or 1.8 mg/kg THA from saline in a two-lever food-reinforced procedure. The stimulus effect of NIK-247 was substituted for by the cholinesterase inhibitors, THA and physostigmine. The THA stimulus was substituted for by NIK-247 and physostigmine. The muscarinic receptor agonist arecoline substituted for the NIK-247 and THA stimuli. Both stimulus effects of NIK-247 and THA were blocked by the muscarinic antagonist scopolamine. The dopaminergic-activating drugs amantadine and lisuride substituted for the stimulus effects of NIK-247 and THA. However, neither the NIK-247 nor the THA stimulus was antagonized by the dopamine antagonists haloperidol, SCH 23390, and sulpiride. These results suggest that the discriminative stimulus effects of NIK-247 and THA are mediated by muscarinic receptors, and that the dopaminergic activity resulting from cholinergic activation may account for some part of both stimuli.
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PMID:Discriminative stimulus properties of NIK-247 and tetrahydroaminoacridine, centrally active cholinesterase inhibitors, in rats. 846 88

Our experiments assessed the modulation of striatal acetylcholine (ACh) output by dopamine (DA) receptor subtypes under physiological conditions using in vivo microdialysis in awake rats. The degree to which the dopaminergic modulation of striatal cholinergic neurons might vary as a function of local extracellular ACh level also was examined by application of varying concentrations of the acetylcholinesterase (AChE), inhibitor neostigmine (NEO) in the microdialysis perfusate. Under physiological conditions (O NEO), the amount of ACh in the dialysates was 25.1 +/- 2.2 fmol/20-microliters sample (n = 20) whereas values of 67.9 +/- 3.5 (n = 35) and 527.7 +/- 56.1 (n = 13) fmol/20-microliters sample were obtained when the applied NEO concentration was 10 and 100 nM, respectively. In the absence of NEO, a low dose of the indirect DA agonist amphetamine (AMPH; 2 mg/kg i.p.) failed to affect striatal ACh output; a higher AMPH dose (10 mg/kg i.p.) significantly decreased the amount of ACh in dialysates. Under physiological conditions, the direct D2-selective agonist quinpirole (3 mg/kg i.p.) decreased extracellular ACh in striatum to nondetectable levels and the direct D1-selective agonist SKF-38393 (10 mg/kg i.p.) produced a significant increase in this measure. Analysis of the changes in striatal ACh output produced by administration of these DA compounds in the absence vs. presence of local NEO revealed that 10 nM NEO did not qualitatively alter the pharmacological responsivity of this system as compared to the physiological condition. However, in the presence of 100 nM NEO, 2 mg/kg AMPH elicited a significant increase in striatal ACh output. At the 100 nM NEO concentration it also was observed that the amplitude of the quinpirole-induced inhibition of ACh efflux did not increase further in proportion to basal ACh levels whereas the amplitude of the increase in ACh output produced by SKF-38393 was linearly related to basal ACh levels across all NEO concentrations. Under conditions where cholinergic pharmacological responsivity was minimally affected (10 nM NEO), the D2 receptor antagonist haloperidol (1 mg/kg i.p.) increased striatal ACh output by 50% and the D1 receptor antagonist SCH-23390 (0.5 mg/kg i.p.) decreased this variable by 41%. Under these conditions, the inhibitory action of quinpirole on ACh output could be reversed by subsequent administration of AMPH (5 mg/kg i.p.) and this effect of AMPH could then be blocked by administration of SCH-23390. Thus, under physiological or low NEO (10 nM) conditions a prevalent D2-mediated inhibition as well as an opposing D1-mediated excitation of striatal ACh output can be demonstrated. At a higher NEO concentration (100 nM), regulation of the striatal ACh system by DA receptor subtypes is differentially affected such that the D2-mediated inhibitory influence no longer predominates over the D1-mediated excitatory drive. Caution should be exercised when interpreting ACh efflux data obtained using microdialysis under conditions of AChE inhibition.
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PMID:Physiological release of striatal acetylcholine in vivo: modulation by D1 and D2 dopamine receptor subtypes. 862 58

Flinders Sensitive Line hypercholinergic rats, which exhibit augmented hypothermic responses to the cholinesterase inhibitor physostigmine and to the muscarinic agonist oxotremorine, have been proposed to represent a useful animal model for some aspects of human depression. With disturbance of reward processes considered to be a core feature of depression, the present studies were designed to investigate the neuropharmacology of brain stimulation-reward (BSR) in Flinders Sensitive Line (FSL) rats, Flinders Resistant Line (FRL) rats, and outbred control Sprague-Dawley rats. All animals were tested in a rate-free, current-threshold brain stimulation-reward paradigm, following acute challenges with the monoamine reuptake inhibitor cocaine, the dopamine D1 receptor antagonist SCH-23390, the cholinergic muscarinic antagonist scopolamine, and the serotonin reuptake inhibitor fluoxetine. Baseline BSR thresholds did not differ across the three groups. For all groups, cocaine lowered thresholds, SCH-23390 and scopolamine-elevated thresholds, while fluoxetine had no significant effect. Thresholds for the three groups were not differentially affected by pharmacological locomotor activity relative to outbred Sprague-Dawley controls. These results suggest that both Flinders lines exhibit behavioral differences from outbred control rats, but not with regard to reward processes as assessed by rewarding electrical stimulation of the lateral hypothalamus.
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PMID:Rewarding electrical brain stimulation: similar thresholds for Flinders Sensitive Line Hypercholinergic and Flinders Resistant Line Hypocholinergic rats. 873 6

Most organophosphorus (OP) insecticides impart their toxic action via inhibition of cholinesterases by reacting at an essential serine hydroxyl group. The inhibition process is dependent upon the reactivity, stereochemistry, leaving group, and the mechanism of phosphorylation and/or reactivation (or aging) inherent to the OP compound under consideration. Because a wide array of phosphorylated structures are possible following inhibition by an OP, a simple model system was sought to investigate the mechanistic details of these and related reactions. In the present study, the tripeptide N-CBZ-Glu-Ser(OH)-Ala-OEt (chosen as a truncated form of human serum cholinesterase) was chemically modified at the serine hydroxyl group by various O-methyl phosphate groups and the 31P NMR chemical shift recorded. Six tripeptides, representing (a) phosphorylation by dimethyl phosphorothionates (N-CBZ-Glu-Ser[O-P(S)(OMe)2]Ala-OEt; 5), (b) phosphorylation by dimethyl phosphates (N-CBZ-Glu-Ser[O-P(O)(OMe)2] Ala-Oet; 6), (c) phosphorylation by O,S-dimethyl phosphorothiolates (N-CBZ-Glu-Ser[O-P(O)(OMe)(SMe)]Ala-OEt; 7), (d) aging following inhibition by dimethyl phosphorothionates (N-CBZ-Glu-Ser[O-P(O)(OMe)(S-)]Ala-OEt; 8), (e) aging following inhibition by dimethyl phosphates (N-CBZ-Glu-Ser[O-P(O)(OMe)(O-)]Ala-OEt; 9), and (f) phosphorylation by R/S)PSc-isomalathion stereoisomers (N-CBZ-Glu-Ser[O-P(O)(OMe)(SCH(CO2CO2Et)CH2-CO2Et)]Ala-OEt; 10) have been synthesized. Tripeptides 5 and 6 were prepared via preliminary formation of an intermediate tripeptide phosphite followed by direct conversion to 5 using S8 or to 6 with m-CPBA, respectively. Tripeptides 8 and 9 were prepared by dealkylation of 5 and 6, respectively. Tripeptides 7 and 10 were prepared by reaction of 8 with dimethyl sulfate and (R)- or (S)-diethyl (trifluoromethanesulfonyl)malate, respectively.
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PMID:Synthesis and 31P chemical shift identification of tripeptide active site models that represent human serum acetylcholinesterase covalently modified at serine by certain organophosphates. 895 Dec 36

The role of dopamine (DA) D1 receptors in the regulation of acetylcholine (ACh) release in the striatum was studied using in vivo microdialysis in freely moving rats. Systemic administration of the full D1 DA receptor agonist A-77636 (4 micromol/kg) increased striatal ACh release by 53% above the base line and decreased DA release by 33%. Local application of A-77636 (10 and 100 microM) by reverse dialysis was without effect on either striatal ACh or DA release. Systemic administration of the D1 DA receptor antagonist SCH 23390 (0.74 micromol/kg) or SCH 39166 (1.42 micromol/kg) blocked the stimulation of striatal ACh release produced by systemic A-77636 (4 micromol/kg). Local perfusion of either SCH 23390 or SCH 39166 did not decrease basal ACh release. Furthermore, when applied locally via the dialysis probe, SCH 23390 (12 microM) or SCH 39166 (50 microM) failed to attenuate the stimulation of striatal ACh release produced by systemic A-77636. Similarly, d-amphetamine (5.42 micromol/kg)-induced increases in striatal ACh release were not modified by simultaneous local perfusion with SCH 39166 (50 microM). These findings are consistent with the hypothesis that D1 receptor activation stimulates ACh release in the striatum. However, because local application of D1 receptor agonists and antagonists fail to influence ACh release, the relevant D1 receptors are not located in the striatum. The use of unphysiological dialysis conditions (high concentrations of acetylcholinesterase (AChE) inhibitors, high Ca++ concentrations and an absence of Mg++ in the perfusion fluid) may account for some earlier suggestions that local D1 receptors regulate ACh release in the striatum.
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PMID:Nonstriatal dopamine D1 receptors regulate striatal acetylcholine release in vivo. 910 18


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