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 present study examined the role of spinal cholinergic modulation of spinal mechanical and thermal transmission. Intrathecal administration of the cholinergic muscarinic receptor antagonists atropine or scopolamine in awake rats produced a dose-dependent decrease in the nociceptive mechanical withdrawal threshold of the rat tail. Pirenzepine, a selective muscarinic receptor type 1 antagonist, produced a similar effect at greater doses while mecamylamine, a nicotinic receptor antagonist, was without effect. The nociceptive tail flick (TF) reflex evoked by noxious heating was unaffected by the above drugs. Intrathecal administration of the cholinesterase inhibitor physostigmine produced a rapid, reversible and significant increase in the mechanical withdrawal threshold; TF latency was increased slightly but not significantly. Intrathecal administration of morphine, carbachol or clonidine all produced dose-dependent increases in TF latency; morphine and carbachol, but not clonidine, also increased the mechanical withdrawal threshold significantly. Intrathecal pretreatment with atropine reversed carbachol-produced increases in TF latency and the mechanical withdrawal threshold but did not affect increases in TF latency produced by intrathecal morphine or clonidine. The morphine-produced increase in the mechanical withdrawal threshold, however, was shifted rightward in a parallel fashion by intrathecal pretreatment with atropine. Intrathecal pretreatment with yohimbine did not affect the inhibitory effect of carbachol on either TF latency or the mechanical withdrawal threshold. These results suggest that a tonic, endogenous cholinergic muscarinic influence in the spinal cord, independent of spinal adrenergic mechanisms, modulates spinal mechanical transmission.
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PMID:Tonic cholinergic inhibition of spinal mechanical transmission. 166 Oct

Previous work in our laboratory has shown that the intradentate administration of colchicine produces time-dependent behavioral and neurochemical changes. Deficits in learning and memory and alterations in the signal transduction process for the cholinergic muscarinic receptor have been observed up to 12 weeks after colchicine treatment. To study the long-term effects of colchicine administration on cognitive function and the cholinergic system, 6 month-old male, Fischer-344 rats were injected with 2.5 micrograms of colchicine bilaterally in the dorsal and ventral hippocampus. Twelve months later the animals were tested for the acquisition of a spatial reference memory task in the Morris water maze for 8 days, with 4 trials of 60 seconds each day. At the completion of the behavioral testing, one set of rats from each treatment group was used for histochemical studies. The remaining animals were sacrificed, the hippocampi removed and used for the estimation of receptor-stimulated turnover of phosphoinositides (Pl). [3H]-inositol was incorporated into the hippocampal slices, and various receptor agonists (carbachol, norepinephrine, serotonin) used to stimulate Pl turnover in the presence of lithium. A significant deficit in acquisition in the water maze was observed in animals 1 year after colchicine administration. Neurochemical studies showed an increase in carbachol-induced Pl metabolism in the rat hippocampus 1 year post-lesion with colchicine. However, in contrast to results obtained 12 weeks after lesioning, no significant changes were observed in norepinephrine or serotonin-induced Pl metabolism 1 year after lesioning. Pirenzepine, a M1 receptor antagonist, produced a greater degree of inhibition (62%) in lesioned animals as compared to the age-matched controls (20%). Increased staining for acetylcholinesterase was found in the hippocampus of treated rats. This effect is similar to that observed 12 weeks after lesioning. These data suggest that the effects of colchicine on the cholinergic system are long-lasting and can be observed a year after treatment.
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PMID:Long-term behavioral and neurochemical effects of intradentate administration of colchicine in rats. 184 22

An impairment of cholinergic and somatostatinergic neurotransmission have been reported in dementia. Both acetylcholine and somatostatin are involved in the regulation of growth hormone (GH) secretion. The effects of GH-releasing hormone (GHRH) 1-44 on GH release have been studied before and after the pretreatment with pyridostigmine or pirenzepine in subjects with senile dementia of the Alzheimer type, multi-infarct dementia and mixed dementia. The data have been compared with those obtained in an age-matched healthy control group. The GH response to GHRH is similar in the patients and in the controls, though the peak occurrence is significantly delayed in dementia. The cholinesterase inhibitor pyridostigmine enhances significantly the GH response to GHRH in both groups. The responses obtained in demented subjects are significantly larger than those found in the controls. Pirenzepine, a muscarinic receptor blocker, inhibits the GHRH effect on GH secretion in both groups. The findings may be interpreted in terms of an underlying impairment of the hypothalamic cholinergic neurotransmission, with an acetylcholine receptor supersensitivity that becomes apparent when the cholinergic tonus is enhanced by the inhibition of cholinesterase by pyridostigmine. No significant differences, due to the type of dementia, have been observed.
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PMID:Cholinergic modulation of growth hormone-releasing hormone effects on growth hormone secretion in dementia. 198 29

Subacute (daily) administration of diisopropylfluorophosphate (DFP) to male swine (Yorkshire white) resulted in a 97% inhibition of cholinesterase and a decrease of [3H]quinuclidinyl benzilate [( 3H]QNB) binding sites in homogenates of striata by approximately 50% after 14 days. The maximal density of receptors (Bmax) decreased from 2.1 +/- 0.3 to 1.0 +/- 0.2 pmole/mg protein. There was no significant change in the dissociation constant (Kd) for [3H]QNB binding (control: 52.6 +/- 10.7 pM; 7-day: 57 +/- 2.8 pM). Carbachol displacement of [3H]QNB binding yielded data best fit by a two-binding site model. The dissociation constants were KiL = 115 +/- 62 microM (55 +/- 3%) and KiH = 1.8 +/- 0.7 microM (45 +/- 3%), respectively, for the low- and high-affinity states. Seven-Day treatment with DFP reduced the percentage of high-affinity receptors to 22 +/- 8.6%, but affected neither the low- nor the high-affinity Kd (100 +/- 20 and 2 +/- 0.6 microM). With the addition of Mg2+, striatal homogenates had low- and high-affinity receptors in the proportion of approximately 1 to 1. In the presence of Gpp(NH)p + Mg2+ the ratio of high- to low-affinity receptors was 3:1 in homogenates of control tissue (to 26 +/- 5%). This treatment had no effect on this ratio in homogenates of tissue from 7-day DFP-treated swine (3:1) since it was already 3:1. Pirenzepine displacement of [3H]QNB binding was best described by a two-binding site model, with Ki values of 38 +/- 14 and 201 +/- 78 nM, which represent 74 and 26% of the binding sites, respectively. The high affinity Kd value was unchanged following 7 days of DFP treatment (24 +/- 5 nM). There appears to be little change in the displacement curves for pirenzepine inhibition of [3H]QNB binding. This suggests that about 75% of the receptors are of the M1 subtype. Thus, subacute administration of DFP causes not only a decrease in the number of receptors, but also a change in the proportion of agonist affinity states which is related to the interaction of the guanine nucleotide binding protein and the muscarinic receptor.
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PMID:Down-regulation of muscarinic receptors in the striatum of organophosphate-treated swine. 238 34

The cholinergic modulation of histamine release and synthesis was studied in rat brain slices or synaptosomes labeled with L-[3H]histidine. Carbachol in increasing concentrations progressively reduced the K+-induced [3H]histamine release from cortical slices. Pirenzepine, a preferential M1-receptor antagonist, reversed the carbachol effect in an apparently competitive manner and with Ki values of 1-6 X 10(-8) M. 11-[(2-[(Diethylamino)methyl]-1-piperidinyl)acetyl]-5,11-dihydro-6H- pyrido[2,3-b][1,4]benzodiazepine-6-one (AF-DX 116), considered a preferential M2-receptor antagonist, reversed the carbachol effect with a mean Ki of approximately 2 X 10(-7) M. Oxotremorine behaved as a partial agonist in the modulation of histamine release. Neostigmine, an acetylcholinesterase inhibitor, inhibited the K+-induced release of [3H]histamine from cortical slices, and the effect was largely reversed by pirenzepine, an observation suggesting a modulation by endogenous acetylcholine. The effects of carbachol and pirenzepine were observed with slices of other brain regions known to contain histaminergic nerve terminals or perikarya, as well as with cortical synaptosomes. The two drugs also modified, in opposite directions, [3H]histamine formation in depolarized cortical slices. In vivo oxotremorine inhibited [3H]histamine formation in cerebral cortex, and this effect was reversed by scopolamine. When administered alone, scopolamine failed to enhance significantly the 3H- labeled amine formation, a finding suggesting that muscarinic receptors are not activated by endogenous acetylcholine released under basal conditions. It is concluded that muscarinic heteroreceptors, directly located on histaminergic nerve terminals, control release and synthesis of histamine in the brain. These receptors apparently belong to the broad M1-receptor category and may correspond to a receptor subclass displaying a rather high affinity for AF-DX 116.
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PMID:Regulation of histamine release and synthesis in the brain by muscarinic receptors. 246 19

1. Subacute (daily) treatment of male swine with the organophosphate acetylcholinesterase inhibitor diisopropylfluorophosphate (DFP) resulted in tolerance to the effects of DFP within 5-6 days. 2. Subacute administration of DFP resulted in a 98% inhibition of tissue cholinesterase after 7 days and in a decrease of [3H]quinuclidinyl benzilate [( 3H]QNB) binding sites in homogenates of tracheal smooth muscle by 77%. The maximal density of receptors (Bmax) decreased from 1.8 +/- 0.4 to 0.5 +/- 0.1 pmole mg-1 protein. There was no significant change in the dissociation constant (Kd) for [3H]QNB binding. 3. Pirenzepine displacement of [3H]QNB binding was best described by a single binding site model, with a Ki of 230 +/- 40 nM. This value was unchanged following seven days of DFP treatment (250 +/- 30 nM). The low affinity for this M1 antagonist suggests that there is predominantly a single population of [3H]QNB binding sites of the M2 subtype in tracheal smooth muscle. 4. Carbachol displacement of [3H]QNB binding yielded data best fit by a two-binding site model. The dissociation constants were KiL = 210 +/- 60 microM (61 +/- 1%) and KiH = 1.2 +/- 0.4 microM (39 +/- 1%) respectively (n = 7) for the low and high affinity states. Seven-day treatment with DFP reduced the percent of high affinity receptors to 25 +/- 4%. 5. Addition of Mg++ to the incubation medium prevented this shift in the proportion of low and high affinity receptors. Gpp(NH)p and Mg++ together decreased the proportion of the high affinity receptors when added to the incubation medium in control tissue (to 25%), but not tissue from 7-day DFP-treated swine. NEM increased the proportion of muscarinic receptors in the high affinity state both for controls and for the DFP-treated swine, in both cases yielding receptors with identical binding properties. 6. Thus, subacute administration of DFP causes not only a decrease in the number of receptors, but also a change in the affinity of the receptors for agonists which is related to the interaction of the guanine nucleotide binding protein and the muscarinic receptor.
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PMID:Changes in affinity states during down-regulation of muscarinic receptors in tracheal smooth muscle of organophosphate-treated swine. 317 Jun 29

Sensitivity to the hypnotic effects of ethanol was increased selectively by central administration of muscarinic agonists. Carbachol or oxotremorine, but not nicotine, i.c.v., enhanced hypnotic sensitivity to ethanol markedly, as measured by blood ethanol concentration at loss or righting response, in short-sleep (SS) but not long-sleep (LS) mice. Likewise, the acetylcholinesterase inhibitor, neostigmine, i.c.v., differentially enhanced hypnotic sensitivity to ethanol in these mouse lines. LS and SS mice were equally sensitive to the hypothermic effects of carbachol, neostigmine or oxotremorine i.c.v. The muscarinic antagonists, atropine or pirenzepine, i.c.v., were without effect on ethanol sensitivity, but these compounds antagonized muscarinic agonist-enhanced ethanol sensitivity in SS mice effectively. Pirenzepine, and M1 selective antagonist, produced a parallel shift in the oxotremorine dose-response curve, indicating that the enhanced hypnotic sensitivity to ethanol may be due to interaction of oxotremorine with M1 muscarinic receptors. This possibility was supported by the finding that atropine and pirenzepine which are known to have comparable affinities for M1 but not M2 receptors, had comparable potencies in antagonizing the action of oxotremorine or neostigmine. The results suggest that LS and SS mice differ genetically in neuronal processes activated by specific muscarinic agonists and are consistent with the hypotheses that ethanol acts in part via membrane receptor coupling to intracellular processes known to mobilize intracellular Ca++.
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PMID:Central muscarinic cholinergic influences on ethanol sensitivity in long-sleep and short-sleep mice. 320 20

Radioimmunoassay for acetylcholine (ACh) with a sensitivity of 10 pg/tube was applied to the direct determination of ACh output from the nerve endings in longitudinal muscle strips of guinea pig ileum. The strips were preincubated with an irreversible cholinesterase inhibitor and superfused with Krebs' solution under various experimental conditions. Pirenzepine (0.1-10 microM) and atropine (10-100 nM) produced an increase in electrically evoked ACh output through the inhibition of presynaptic muscarinic receptors. Contractile response to endogenous ACh released by electrical stimulation was enhanced by pirenzepine and atropine at lower concentrations, whereas the highest concentrations of pirenzepine (10 microM) and atropine (100 nM) caused a reduction in the enhanced contractile response and a significantly diminished response, respectively. These results demonstrate that the concentrations of pirenzepine and atropine, effective in inhibiting presynaptic muscarinic receptors, differ from those inhibiting postsynaptic muscarinic receptors and suggest the possibility that presynaptic M1 muscarinic receptors regulating ACh output may be present in the guinea pig ileum.
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PMID:Direct determination of acetylcholine release by radioimmunoassay and presence of presynaptic M1 muscarinic receptors in guinea pig ileum. 325 21

The specific binding of the muscarinic ligand [3H](-)quinuclidinyl benzilate [( 3H]QNB) to cell membranes of human SH-SY5Y neuroblastoma cells was studied. Saturation isotherms yielded a Kd = 0.28 +/- 0.06 nM and a Bmax of 337 +/- 47 pmol/g protein. Pirenzepine inhibited [3H]QNB binding; inhibition data showed best fit to a 2-site binding model revealing both a high affinity pirenzepine site (34%, KH = 10 nM) and a low affinity site (66%, KL = 1 microM). These results indicate that muscarinic receptors on SH-SY5Y cells may be subclassified as M1/M2 subtypes. Morphological and biochemical differentiation of these cells after treatment with 12-O-tetradecanoyl-phorbol-13-acetate (TPA) or retinoic acid (RA) resulted in a decrease and an increase in the number of muscarinic binding sites, respectively. Furthermore, TPA- and RA-treated cells showed a significant increase in acetylcholinesterase activity compared with non-treated cells. However, only RA-treated cells showed significant increase in choline acetyltransferase activity compared to non-treated cells. These findings demonstrate that TPA and RA can regulate both the number of muscarinic receptors and the acetylcholinesterase activity in human SH-SY5Y neuroblastoma cells.
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PMID:Muscarinic receptors in human SH-SY5Y neuroblastoma cell line: regulation by phorbol ester and retinoic acid-induced differentiation. 360 14

The distribution of M1 and M2 muscarine receptors in the rat brain was investigated by in vitro autoradiography. Muscarine receptors were visualized after complete receptor uncoupling in ethylenediaminetetraacetic acid buffer containing 1 mM N-ethyl maleimide and saturation with the ligand [3H]quinuclidinyl benzilate. Pirenzepine, an M1-selective antagonist, was used in our assays as a counter ligand to occlude M1 sites, allowing the primary ligand, [3H]quinuclidinyl benzilate, to label the remaining M2 muscarine receptors. In adjacent section, M1 muscarine receptors were labelled with [3H]quinuclidinyl benzilate in the presence of sufficient carbachol, and M2-selective agonist, to inhibit the binding to M2 sites. Our results reveal a heterogeneous distribution of M1 and M2 receptors. Increased densities of carbachol-resistant and pirenzepine-sensitive sites (M1 receptor subtype) were apparent over many forebrain structures including the olfactory tubercle, caudate-putamen, nucleus accumbens, hippocampus, amygdala and cerebral cortex. In contrast, pirenzepine-resistant and carbachol-sensitive sites (M2 receptor subtype) were distributed throughout the brain with increased densities apparent over regions known to contain large numbers of cholinergic cell bodies. M2 receptor localization patterns were largely coincident with the regional distribution and intensity of acetylcholinesterase positive sites. Since the M2 receptor pattern appears to parallel regional innervation densities, we conclude that the M2 receptor may serve as a marker for cholinergic pathways. The findings also suggest that M1 muscarine receptors are involved in the presumptive postsynaptic actions of acetylcholine in many forebrain structures.
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PMID:Autoradiographic localization of M1 and M2 muscarine receptors in the rat brain. 377 54


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