Discriminative stimulus effects of pregnanolone in rhesus monkeys

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.

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.

Four rhesus monkeys discriminated 5.6 mg/kg pregnanolone while responding under a fixed-ratio 10 schedule of stimulus-shock termination.

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.

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.