Discriminative stimulus effects of pregnanolone in rhesus monkeys

Rationale: Neuroactive steroids and benzodiazepines can positively modulate GABA by acting at distinct binding sites on synaptic GABA_A receptors. Although these receptors are thought to mediate the behavioral effects of both benzodiazepines and neuroactive steroids, other receptors (e.g., extrasynaptic GABA_A, N-methyl-d-aspartate (NMDA), σ₁, or 5-HT₃ receptors) might contribute to the effects of neuroactive steroids, accounting for differences among positive modulators. Objective: The current study established the neuroactive steroid pregnanolone as a discriminative stimulus to determine whether actions in addition to positive modulation of synaptic GABA_A receptors might contribute to its discriminative stimulus effects. Methods: Four rhesus monkeys discriminated 5.6 mg/kg pregnanolone while responding under a fixed-ratio 10 schedule of stimulus-shock termination. Results: Positive modulators acting at benzodiazepine, barbiturate, or neuroactive steroid sites produced ≥80 % pregnanolone-lever responding, whereas drugs acting primarily at receptors other than synaptic GABA_A receptors, such as extrasynaptic GABA _A, NMDA, σ₁, and 5-HT₃ receptors, produced vehicle-lever responding. Flumazenil antagonized the benzodiazepines midazolam and flunitrazepam, with Schild analyses yielding slopes that did not deviate from unity and pA₂ values of 7.39 and 7.32, respectively. Flumazenil did not alter the discriminative stimulus effects of pregnanolone. Conclusion: While these results do not exclude the possibility that pregnanolone acts at receptors other than synaptic GABA_A receptors, they indicate a primary and possibly exclusive role of synaptic GABA_A receptors in its discriminative stimulus effects. Reported differences in the effects of benzodiazepines and neuroactive steroids are not due to differences in their actions at synaptic GABA_A receptors.