Halothane and Isoflurane Differentially Affect the Regulation of Dopamine and Gamma-aminobutyric Acid Release Mediated by Presynaptic Acetylcholine Receptors in the Rat Striatum

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BackgroundGeneral anesthetics are thought to produce their hypnotic effects mainly by acting at ligand-gated ionic channels in the central nervous system (CNS). Although it is well established that volatile anesthetics significantly modify the activity of the acetylcholine nicotinic receptors of the neuromuscular junction, little is known about their actions on the acetylcholine receptors in the CNS. In this study, the effects of halothane and isoflurane on the regulation of dopamine (DA) (gamma-aminobutyric acid [GABA]) depolarization-evoked release mediated by nicotinic (muscarinic) presynaptic receptors were studied in the rat striatum.MethodsAssay for GABA (dopamine) release consisted of3 H-GABA (sup 3 H-DA)-preloaded synaptosomes with artificial cerebrospinal fluid (0.5 ml/min, 37 degrees Celsius) and measuring the radioactivity obtained from 1-min fractions for 18 min, first in the absence of any treatment (spontaneous release, 8 min), then in the presence of depolarizing agents combined with vaporized halothane and isoflurane (0.5–5%, 5 min), and finally with no pharmacologic stimulation (5 min). The depolarizing agents were potassium chloride (KCl; 9 mM) alone or with acetylcholine (10 sup -6 - 10 sup -4 M) and/or atropine (10 sup -5 M) for experiments with3 H-GABA, and KCl (15 mM) and nicotine (10 sup -7 - 5 x 10 sup -4 M) alone or with mecamylamine (10 sup -5 M) for experiments with3 H-DA.ResultsPotassium chloride induced a significant, Ca2+ -dependent release of both3 H-GABA and3 H-DA. Nicotine produced a concentration-related, mecamylamine-sensitive3 H-DA release that was significantly attenuated by nicotine (10 sup -7 M) preincubation. Acetylcholine elicited a dose-dependent, atropine-sensitive reduction of the KCl-evoked3 H-GABA release. Halothane and isoflurane significantly decreased the nicotine-evoked3 H-DA release but had only limited depressant effects on the KCl-stimulated3 H-DA and no action on the KCl-induced3 H-GABA release. The effects of acetylcholine on3 H-GABA release were reversed by halothane but not by isoflurane.ConclusionClinically relevant concentrations of halothane and isoflurane significantly, but differentially, alter the presynaptic cholinergic regulation of the release of inhibitory neurotransmitters in the striatum. These results suggest that the cholinergic transmission may represent an important and specific presynaptic target for volatile anesthetics in the CNS.

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