Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020672 (hypothermia)
 17,327 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The main aim of the present study was to investigate if responses to the direct dopamine agonist, apomorphine, could be modified by changes in the activity of cholinergic neurones. A novel approach was adopted in which these responses were assessed following reduction of muscarinic receptor concentration (mAChR) in the brain (assessed from [3H] QNB binding) by the alkylating derivative of oxotremorine, N-[4-(2-chloroethylmethylamino)]-2-pyrrolidone (BM 123). Stereotyped responses elicited by apomorphine were significantly reduced when QNB binding was 12% and 50% of control values. No changes in [3H] spiperone binding were found. There was significant hypothermia in the group with 12% QNB binding sites which was significantly increased by apomorphine. Body temperature returned to normal when QNB binding was 50% of control values. There was a significant decrease in activity when QNB sites were reduced to 12% of normal and vertical activity was still significantly reduced at 50% QNB binding, though horizontal activity was not then different from controls. These data are consistent with the hypothesis that changes in the function of mAChR modify responses elicited by dopamine receptor stimulation in both the striatum and other brain regions.
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PMID:Pretreatment with an irreversible muscarinic agonist affects responses to apomorphine. 233 42

The synthesis of [1,2,3]triazolo[4,5-b][1,5]-, imidazolo[4,5-b][1,5]-, and pyrido[2,3-b][1,5]benzodiazepines is described. The antidopaminergic and anticholinergic activities of the compounds have been examined by the respective in vitro [3H]spiperone and [3H]QNB receptor binding assay. The neuroleptic potential has been further evaluated in terms of their ability to produce hypothermia and catalepsy in mice and a conditioned avoidance response in rats. Only compounds from the triazolobenzodiazepine series show antipsychotic potential. The lack of activity in the imidazolo- and pyridobenzodiazepine series indicates that the basicity of the heteroarene moiety may be determinant for activity.
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PMID:Synthesis and pharmacological evaluation of CNS activities of [1,2,3]triazolo[4,5-b][1,5]-, imidazolo[4,5-b][1,5]-, and pyrido[2,3-b][1,5]benzodiazepines. 10-Piperazinyl-4H-1,2,3-triazolo[4,5-b][1,5]benzodiazepines with neuroleptic activity. 257 31

Receptor plasticity is an important compensatory process by which the central nervous system adapts to pathological insult or long-term exposure to drugs. Senescent animals may show an age-related impairment of muscarinic receptor up- or down-regulation after chronic exposure to cholinergic drugs. The purpose of this study was to assess biochemical and pharmacological endpoints of muscarinic receptor plasticity in young, adult and senescent animals. Male, Fischer 344 rats (ages 3, 9, and 27 months) were administered methylatropine or oxotremorine intracerebroventricularly (IVT) for 3 weeks and tested for their functional response to a muscarinic agonist. The density of hypothalamic, muscarinic receptors was also estimated from analysis of 3H-QNB binding isotherms. In young rats, parallel changes in muscarinic receptors and response were noted, but chronic administration of cholinergic drugs to senescent animals had no effect. Thus, 3H-QNB binding in hypothalamus of young and adult rats was increased (31% and 17%) after chronic IVT methylatropine and decreased (20% and 15%) after IVT oxotremorine. Also, young rats treated with IVT methylatropine were supersensitive to the hypothermic effects of a muscarinic agonist (oxotremorine), while young and adult animals administered chronic IVT oxotremorine exhibited marked tolerance. In contrast, identically treated senescent rats showed no changes in 3H-QNB binding or oxotremorine-induced hypothermia. These results demonstrate the impaired ability of senescent rats to up- or down-regulate brain muscarinic receptors and to exhibit functional adaptations seen in young animals treated chronically with cholinergic drugs.
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PMID:Pharmacological adaptations and muscarinic receptor plasticity in hypothalamus of senescent rats treated chronically with cholinergic drugs. 314 21

The effects of the compound RS 86 (2-ethyl-8-methyl-2,8-diazaspiro-[4,5]-decan-1,3-dion hydrobromide) in a number of in vitro and in vivo test systems for muscarinic cholinergic activity were analyzed and compared to those of classical muscarinic receptor agonists. In radioligand binding assays RS 86 presented high nanomolar apparent affinity only for sites labeled by 3H-muscarinic receptor agonists while its apparent affinity for sites labeled by 3H-muscarinic receptor antagonists including [3H]QNB, [3H]NMS and [3H]pirenzepine was in the micromolar range. RS 86 had no or only low affinity (IC50 greater than 10 microM) for other neurotransmitter or drug receptor sites. The compound induced scopolamine-sensitive contractions of the isolated guinea-pig ileum showing a pD2 of 6 in this model. In the isolated rat superior cervical ganglion RS 86 was also an agonist with a pD2 of 6.7. When given to mice or rats by different routes RS 86 induced central and peripheral effects typical of a muscarinic receptor agonist, such as hypothermia, tremor, mydriasis, salivation, lacrimation, diarrhoea and modification of behavior as observed in an open field. In several of these tests RS 86 was about 10 times less potent than oxotremorine but more potent than arecoline, pilocarpine, aceclidine or the compound (cis) AF-30. The ED50 values for some central effects, including the induction of hypothermia and alert non-mobile behavior were lower than those for tremor and peripheral effects. Some of the effects lasted for up to 6 h, depending on the dose. Finally, RS 86 administration resulted in modifications of brain acetylcholine turnover and high affinity choline uptake typical of a central muscarinic receptor agonist. Taken together these results demonstrate clearly that RS 86 is a potent, centrally acting, selective muscarinic receptor agonist. RS 86 appears to be an adequate tool for the clinical examination of the cholinergic hypothesis of Alzheimer's disease.
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PMID:The pharmacological assessment of RS 86 (2-ethyl-8-methyl-2,8-diazaspiro-[4,5]-decan-1,3-dion hydrobromide). A potent, specific muscarinic acetylcholine receptor agonist. 373 91

Lithium (Li) has been previously reported to increase acetylcholine turnover and release in rat brain and to potentiate the neurotoxicity of cholinergic agents. We studied the effect of chronic Li administration, alone and in combination with the muscarinic antagonist, scopolamine, on two cholinergically-mediated responses and on muscarinic cholinergic receptor (MCR) binding in rat brain. Administered separately, Li and scopolamine enhanced the cataleptic and hypothermic responses to pilocarpine; combined administration resulted in an additive effect on both these measures. [3H]Quinuclidinyl benzilate ([3H]QNB) binding was increased by Li in the corpus striatum but not in the cortex, hippocampus and hypothalamus. Scopolamine increased [3H]QNB binding in the striatum, cortex and hippocampus; Li and scopolamine effects on striatal MCR were not additive. Contrary to a previous report, antagonist-induced MCR supersensitivity was not prevented by concurrent Li administration in any of the brain areas studied. The additive effect of Li and scopolamine on pilocarpine-induced catalepsy and a trend in this direction for pilocarpine-induced hypothermia suggest that the actions of the two agents to enhance cholinergically mediated responses may be achieved by different mechanisms. Supersensitive responses following scopolamine may be attributed to antagonist-induced up-regulation of postsynaptic muscarinic receptors as demonstrated in the binding studies. The effects of Li to enhance cholinergically-mediated catalepsy and hypothermia are interpreted as extending previous reports that Li stimulates brain cholinergic function by a presynaptic increase in acetylcholine turnover and release.
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PMID:Effect of chronic lithium on cholinergically mediated responses and [3H]QNB binding in rat brain. 404 71

Muscarinic systems are significantly altered in the brains of laboratory animals and man as a result of normal aging. Cholinergic neurotransmission in cerebral cortex and hippocampus is also severely impaired in a major age-related neurological disorder, Alzheimer's disease. The objective of these studies was to assess specific 3H-quinuclidinyl benzilate (3H-QNB) binding to brain muscarinic receptors in young, adult and senescent Fischer 344 rats, and to relate receptor changes to differences in the pharmacologic actions of cholinergic drugs. Muscarinic receptor density declined with advanced age in the frontal cortex, corpus striatum and hypothalamus, but no age-related changes in receptor affinity were observed. Specific binding of 3H-QNB in hippocampus was not significantly altered. In contrast, the in vivo effects of oxotremorine (hypothermia and antinociception) were markedly enhanced in aged rats, whereas scopolamine-induced locomotor activity was reduced. Hence, senescent rats were more sensitive to the pharmacologic actions of a cholinergic agonist, but less responsive than young rats to a muscarinic antagonist. These seemingly contradictory results of binding experiments and pharmacological studies could be due, in part, to changes in subtypes of brain muscarinic receptors with advanced age. Alternatively, the age-related differences in cholinergic drug effects may reflect a decreased ability of the senescent animal to adapt to changes in its environment.
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PMID:Cholinergic drug effects and brain muscarinic receptor binding in aged rats. 651 8

Trimethyltin (TMT) induced a dose-dependent antinociceptive and hypothermic effect in mice. Antinociception was not attenuated by naloxone but was reversed by atropine. TMT, however, was ineffective in displacing (3H)-QNB binding in vitro and did not affect (3H)-QNB binding or acetylcholinesterase activity after in vivo administration. The ethyl ester of nipecotic acid, a specific inhibitor of synaptosomal GABA uptake, exerted a similar antinociceptive effect that could be blocked by atropine. The GABA receptor antagonist bicuculline attenuated antinociception induced by TMT and nipecotic acid ethyl ester but not by morphine or oxotremorine. Gamma-Vinyl GABA, an irreversible inhibitor of GABA metabolism, prolonged TMT but not morphine-induced antinociception. In contrast, neither the dose-response nor the time course of TMT-induced hypothermia were affected by any of the drugs tested. The findings suggest that the GABAergic system may be involved in TMT induced antinociception; however, the mechanism responsible for the hypothermic effect of TMT is not apparent.
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PMID:Antinociceptive and hypothermic effects of trimethyltin. 689 Jun 11