Midazolam cue in rats: effects of drugs acting on GABA and 5-hydroxytryptamine systems, anticonvulsants and sedatives.

The discriminative stimulus effect of midazolam, a short-acting benzodiazepine, was used for testing the effects of related drugs including agents thought to act at different sites in the proposed benzodiazepine receptor complex. Rats were trained in a standard two- bar operant conditioning procedure with food reinforcers delivered on a tandem schedule. The 0.4 mg/kg dose of midazolam used for training was well discriminated, typically yielding about 95% correct responding. There was no generalization to the GABA agonists muscimol and THIP, to the 5-HT antagonists cyproheptadine and methergoline, to buspirone, CGS 9896, ethanol, Ro 5-4864, promethazine, phenytoin sodium or sodium valproate. Muscimol and THIP also failed to potentiate the effects of midazolam. The GABA antagonist bicuculline weakly attenuated the discriminative effect of midazolam without impairing generalization to pentobarbitone, whereas the benzodiazepine inverse agonist FG 7142 did not attenuate the effect of midazolam. The results provide additional evidence for the notable specificity of the midazolam cue but do little to link the behavioural effects of benzodiazepines to GABA or 5- HT systems. Perhaps the potency, efficacy or selectivity of the GABA agonists was inadequate to produce the expected results. Only the effects of bicuculline, and those reported previously for picrotoxin, provided some support for the hypothesis that midazolam cue is mediated by the GABA system.