Effect of nomifensine and other antidepressant drugs on acetylcholine turnover in various regions of rat brain.
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Biomedical subjects
Publications and source records attributed to D L Cheney.
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Acetylcholine and choline concentrations in brain structures of rats during anesthesia with halothane (0.7-1.0 per cent inspired), enflurane (2.7-3.0 per cent, inspired) and ketamine (40 mg/kg, iv) were measured by gas chromatography. The turnover rate (biosynthesis) of acetylcholine in vivo was estimated by infusing phosphoryl(Me-14C)choline intravenously, determining specific activities of choline and acetylcholine, and applying principles of steady-state kinetics to compute the fractional rate constant of acetylcholine. Acetylcholine concentrations in brain structures did not change during anesthesia. Halothane decreased the acetylcholine turnover rates in all parts of the brain. Enflurane decreased the acetylcholine turnover rate in the cerebral cortex only, but not in the caudate nucleus, the hippocampus, and the hypothalamic and thalamic regions. During anesthesia with ketamine, acetylcholine turnover rates were reduced in the caudate nucleus and the hippocampus, but not in the cerebral cortex and the hypothalamic and thalamic regions. The results suggest that acetylcholine turnover rate and utilization are related to anesthetic induced electrophysiologic changes in cortical and subcortical structures.
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The injection of various doses of morphine, subcutaneously, or of beta-endorphin, intraventricularly, changes the turnover rate of gamma-aminobutyric acid (TRGABA) in the substantia nigra, globus pallidus and nucleus caudatus. The TRGABA decreases in N. caudatus but increases in globus pallidus and substantia nigra. These changes are dose related and can be inhibited by naltrexone. The increased TRGABA in globus pallidus elicited by these opioid receptor agonists may be associated with catalepsy since muscimol, a specific GABA receptor agonist, injected into the globus pallidus causes a dose-related catalepsy. Since this GABA receptor agonist injected into the substantia nigra fails to cause catalepsy, one can exclude that the increase in the TRGABA of substantia nigra elicited by opiate receptor agonists is operative in mediating the catalepsy elicited by opioids.
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Intraventricular injection of substance P induced a dose-dependent decrease of acetylcholine (ACh) turnover rate (TRACh) in the hippocampus of rats. The highest dose used (20 nmol) decreased the hippocampal TRACh to 40% of the control value. No changes in the ACh or choline content were detected in the various brain areas 40 minutes after injection, but after 70 minutes an increase in ACh content in diencephalon was significant. Local injection of substance P into the medial nuclei of the septum decreased significantly the hippocampal TRACh. Neither intraventricular injection nor injection into the periaqueductal grey of high doses of substance P (30 nmol) induced analgesia, whereas beta-endorphin (1 nmol) and morphine (15 nmol) were effective. No specific change in the electroencephalograph pattern recorded from either cortex or hippocampus could be detected within the first 2 hours after intraventricular injection of substance P.
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Intraseptal administration of morphine (70 nmol) or beta-endorphin (0.7 nmol) reduced the rate of acetylcholine (ACh) turnover (TRACh) in rat hippocampus but not in striatum or cortex. These intraseptal injections failed to modify the ACh content and did not elicit analgesia. Naltrexone (15 mumol/kg, i.p.) completely antagonized the decrease of hippocampal TRACh elicited by the two opiate receptor agonists. Furthermore, intraseptal injections of naltrexone partially blocked the decrease in hippocampal TRACh induced by intraperitoneal administration of morphine (70 mumol/kg, i.p.). These data suggest that opiate agonists decrease hippocampal TRACh by regulating septal cholinergic neurons, and that this effect is not associated with analgesia.
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Muscimol (8.8 mumol/kg i.v.) and diazepam (7.04 mumol/kg i.p.) decreased the rate of turnover of acetylcholine in midbrain and cortex of rat brain but failed to change acetylcholine turnover in striatum and hippocampus. The similarity in the profile of the action of diazepam and muscimol on acetylcholine turnover in various brain structures adds support to the view that GABA participates in mediating the actions of diazepam. Since the striatum contains an abundance of GABA neurones and intrinsic cholinergic neurones, it is inferred that the metabolism of acetylcholine, and presumably the activity of striatal cholinergic neurones are not regulated by the activation of GABA receptors. Similar considerations apply to the cholinergic pathway projecting from the septum to the hippocampus.
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