HALOTHANE AND ISOFLURANE DIFFERENTIALLY AFFECT THE REGULATION OF DOPAMINE AND GAMMA-AMINOBUTYRIC-ACID RELEASE MEDIATED BY PRESYNAPTIC ACETYLCHOLINE-RECEPTORS IN THE RAT STRIATUM

Background: General 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 a nesthetics significantly modify the activity of the acetylcholine nico tinic receptors of the neuromuscular junction, Little is known about t heir 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 m ediated by nicotinic (muscarinic) presynaptic receptors mere studied i n the rat striatum. Methods: Assay for GABA (dopamine) release consist ed of H-3-GABA (H-3-DA)-preloaded synaptosomes with artificial cerebro spinal fluid (0.5 ml/min, 37 degrees C) and measuring the radioactivit y obtained from 1-min fractions for 18 min, first in the absence of an y treatment (spontaneous release, 8 min), then in the presence of depo larizing 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(-6)-10(-4) M) and/or atropine (10(-5) M) for experi ments with H-3-GABA, and KCl (15 mM) and nicotine (10(-7) - 5 x 10(-4) M) alone or with mecamylamine (10(-5) M) for experiments with H-3-DA. Results: Potassium chloride induced a significant, Ca2+-dependent rel ease of both H-3-GABA and H-3-DA. Nicotine produced a concentration-re lated, mecamylamine-sensitive H-3-DA release that mas significantly at tenuated by nicotine (10(-7) M) preincubation. Acetylcholine elicited a dose-dependent, atropine-sensitive reduction of the KCl-evoked H-3-G ABA release. Halothane and isoflurane significantly decreased the nico tine-evoked H-3-DA release but had only limited depressant effects on the KCl-stimulated H-3-DA and no action on the KCl-induced H-3-GABA re lease, The effects of acetylcholine on H-3-GABA release mere reversed by halothane but not by isoflurane. Conclusion: Clinically relevant co ncentrations of halothane and isoflurane significantly, but differenti ally, alter the presynaptic cholinergic regulation of the release of i nhibitory neurotransmitters in the striatum. These results suggest tha t the cholinergic transmission may represent an important and specific presynaptic target for volatile anesthetics in the CNS.