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

Abstract

Rationale Several neurotransmitter systems have been hypothesized to be involved in the in vivo effects of volatile anesthetic. Drug discrimination may represent a novel procedure to explore the neurochemical systems underlying the sub-anesthetic behavioral effects of these compounds. Objectives The purpose of the present study was to examine the contribution of GABAA and NMDA receptors to the discriminative stimulus effects of a behaviorally-active sub-anesthetic concentration of isoflurane vapor. Methods Sixteen B6SJLF1/J mice were trained to discriminate 10 min of exposure to 6000 ppm isoflurane vapor from air. Substitution tests were conducted with volatile anesthetics, abused vapors, GABAA positive modulators, NMDA antagonists and nitrous oxide. Results The volatile anesthetics, enflurane and halothane as well as the abused vapors toluene and 1,1,1-trichloroethane fully substituted for isoflurane. The GABAA positive modulators, pentobarbital, midazolam and zaleplon but not the direct GABAA 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. GHB and nitrous oxide gas also failed to substitute for isoflurane. Conclusions The discriminative stimulus effects of subanesthetic 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 GABAA receptors as well as antagonism of NMDA receptors.

Pharmacological Classification of the Abuse-Related Discriminative Stimulus Effects of Trichloroethylene Vapor

“…As we have previously demonstrated with the vapor inhalants toluene[47; 49], 1,1,1-trichloroethane [36; 37] and isoflurane [46], in the present study a 6000 ppm trichloroethylene vapor versus air discrimination could be readily established in mice.The kinetics of the onset and offset of stimulus effects resulting from trichloroethylene administration differed from those of the previous inhalants we have examined. Specifically, the rate of decay of trichloroethylene’s discriminative stimulus was quite slow.…”

“…In general, the present results suggest that attenuation of NMDA receptor function plays little if any role in the discriminative stimulus effects of chlorinated hydrocarbons.This overarching finding extends to toluene as well where we have demonstrated that competitive, uncompetitive and glycine-site NMDA antagonists do not elicit toluene-like discriminative stimulus effects [38], again despite very strong evidence that toluene inhibits NMDA receptor function in other assays [6; 13; 17; 18; 60; 63; 64]. Interestingly, although NMDA receptor antagonism does not appear to underlie the discriminative stimulus effects of chlorinated or aromatic hydrocarbons it, in addition to GABA A receptor positive modulation, does appear to be involved in transducing the stimulus effects of the volatile anesthetic isoflurane [46]. …”

Neurotoxic effects of dexmedetomidine in fetal cynomolgus monkey brains

“…Dexmedetomidine is a sedative and anesthetic with a different mechanism of action than ketamine and isoflurane. Specifically, ketamine induces anesthesia by blocking the glutamate N-methyl-D-aspartate (NMDA) receptors (Franks and Lieb, 1994) while isoflurane exerts its effect by potentiating γ-amino butyric-acid type A (GABA A ) receptors (Franks and Lieb, 1994), and inhibits receptor activity in the NMDA glutamate receptor subtypes (Shelton and Nicholson, 2010;Brosnan, 2011). Dexmedetomidine is a selective α2 adrenoceptor agonist at low (pharmacologic) doses and α2 adrenoceptors are believe to play an important role in cellular signaling in the central nervous system early in life (Song et al, 2004;Winzer-Serhan and Leslie, 1999).…”

Effects of Long-Duration Administration of 1% Isoflurane on Resting Cerebral Blood Flow and Default Mode Network in Macaque Monkeys

“…It is known that isoflurane induces suppression effect to neuronal activities via exerting antagonistic actions on N-methyl-d-aspartate receptors and enhancing GABA A receptor-mediated functions (Brosnan, 2011;Dong et al, 2013;Harrison et al, 1993;Shelton and Nicholson, 2010). The suppression effect is dose dependent, as seen in the isoflurane-induced burst suppression pattern (Ferron et al, 2009).…”