GABAA positive modulator and NMDA antagonist-like discriminative stimulus effects of isoflurane vapor in mice

Abstract

Several neurotransmitter systems have been hypothesized to be involved in the in vivo effects of volatile anesthetics. Drug discrimination may represent a novel procedure to explore the neurochemical systems underlying the sub-anesthetic behavioral effects of these compounds. The purpose of the present study was to examine the contribution of GABA(A) and NMDA receptors to the discriminative stimulus effects of a behaviorally active sub-anesthetic concentration of isoflurane vapor. Sixteen B6SJLF1/J mice were trained to discriminate 10 min of exposure to 6,000 ppm isoflurane vapor from air. Substitution tests were conducted with volatile anesthetics, abused vapors, GABA(A) positive modulators, NMDA antagonists, and nitrous oxide. The volatile anesthetics, enflurane and halothane as well as the abused vapors toluene and 1,1,1-trichloroethane fully substituted for isoflurane. The GABA(A) positive modulators, pentobarbital, midazolam, and zaleplon but not the direct GABA(A) agonist, muscimol, produced high levels of partial substitution for isoflurane. The anticonvulsant, valproic acid fully substituted for isoflurane but a second, tiagabine, did not substitute. The competitive NMDA antagonist, CGS-19755, fully and the non-competitive NMDA antagonist, dizocilpine, partially substituted for isoflurane. The glycine-site NMDA antagonist, L-701,324 did not substitute for isoflurane. Gamma-hydroxybutric acid and nitrous oxide gas also failed to substitute for isoflurane. The discriminative stimulus effects of sub-anesthetic concentrations of isoflurane vapor are shared by other vapor anesthetics and abused inhalants. The discriminative stimulus effects of isoflurane vapor appear to be mediated by both positive allosteric modulation of GABA(A) receptors as well as antagonism of NMDA receptors.