Elucidating the neurotransmitter systems underlying the subanesthetic intoxicating effects of isoflurane vapor

Abstract

The present study utilized the drug discrimination paradigm to explore the neurotransmitter systems underlying isoflurane intoxication. Sixteen B6SJLF1/J mice were trained to discriminate 10 min of exposure to 6000 ppm isoflurane vapor from air using a standard 2‐lever operant task. The discriminative stimulus of the benzodiazepine midazolam and the barbiturate methohexital substantially overlapped with that of isoflurane. However, neither the benzodiazepine antagonist flumazenil nor the negative allosteric modulator Ro15‐4515 attenuated isoflurane's discriminative stimulus. The GABAA neurosteroid‐site positive modulator allopregnanolone and the extrasynaptic GABAA receptor agonist, gaboxadol, failed to substitute for isoflurane. Ethanol and the noncompetitive NMDA antagonist, ketamine partially substituted for isoflurane. These findings suggest that the discriminative stimulus effects of isoflurane are the result of GABAA positive modulation and to a lesser extent NMDA antagonism. However, they do not appear to be the result of a direct interaction with the benzodiazepine binding site on the GABAA receptor. Supported by NIDA grant RO1‐DA020553.