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.
Methods
Four rhesus monkeys discriminated 5.6 mg/kg pregnanolone while responding under a fixed-ratio 10 schedule of stimulus-shock termination.
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.
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, σ&sub1;, and 5-HT&sub3; receptors, produced vehicle-lever responding. Flumazenil antagonized the benzodiazepines midazolam and flunitrazepam, with Schild analyses yielding slopes that did not deviate from unity and pA&sub2; values of 7.39 and 7.32, respectively. Flumazenil did not alter the discriminative stimulus effects of pregnanolone.