title: Halothane and isoflurane differentially affect the regulation of dopamine and gamma-aminobutyric acid release mediated by presynaptic acetylcholine receptors in the rat striatum.
abstract: 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 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.
  
  
  METHODS
  Assay for GABA (dopamine) release consisted of 3H-GABA (3H-DA)-preloaded synaptosomes with artificial cerebrospinal fluid (0.5 ml/min, 37 degrees C) 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(-6)-10(-4) M) and/or atropine (10(-5) M) for experiments with 3H-GABA, and KC1 (15 mM) and nicotine (10(-7) - 5 x 10(-4) M) alone or with mecamylamine (10(-5) M) for experiments with 3H-DA.
  
  
  RESULTS
  Potassium chloride induced a significant, Ca(2+)-dependent release of both 3H-GABA and 3H-DA. Nicotine produced a concentration-related, mecamylamine-sensitive 3H-DA release that was significantly attenuated by nicotine (10(-7) M) preincubation. Acetylcholine elicited a dose-dependent, atropine-sensitive reduction of the KC1-evoked 3H-GABA release. Halothane and isoflurane significantly decreased the nicotine-evoked 3H-DA release but had only limited depressant effects on the KC1-stimulated 3H-DA and no action on the KC1-induced 3H-GABA release. The effects of acetylcholine on 3H-GABA release were reversed by halothane but not by isoflurane.
  
  
  CONCLUSIONS
  Clinically 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.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), Unité 408, Paris, France.
authors.forename: F
authors.initials: F
authors.lastname: Salord
authors.forename: H
authors.initials: H
authors.lastname: Keita
authors.forename: J B
authors.initials: JB
authors.lastname: Lecharny
authors.forename: D
authors.initials: D
authors.lastname: Henzel
authors.forename: J M
authors.initials: JM
authors.lastname: Desmonts
authors.forename: J
authors.initials: J
authors.lastname: Mantz
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D018685:Anesthetics, Inhalation / Q000494:pharmacology*; D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure*; D004298:Dopamine / Q000378:metabolism*; D006221:Halothane / Q000494:pharmacology*; D007530:Isoflurane / Q000494:pharmacology*; D008297:Male; D011189:Potassium Chloride / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011976:Receptors, Muscarinic / Q000187:drug effects* / Q000502:physiology*; D011978:Receptors, Nicotinic / Q000187:drug effects* / Q000502:physiology*; D013268:Stimulation, Chemical; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D018685:Anesthetics, Inhalation; D011976:Receptors, Muscarinic; D011978:Receptors, Nicotinic; D005680:gamma-Aminobutyric Acid; D011189:Potassium Chloride; D007530:Isoflurane; D000109:Acetylcholine; D006221:Halothane; D004298:Dopamine