Discriminative stimulus effects of pregnanolone in rats: Role of training dose in determining mechanism of action

Rationale Positive γ-aminobutyric acidA (GAB_AA) modulators acting at different binding sites often produce similar behavioral effects; however, their effects are not identical. Actions of neuroactive steroids at other receptors, in addition to GAB_AA receptors, might account for some differences between neuroactive steroids and other positive modulators, like benzodiazepines. Objective Multiple mechanisms of other drugs (e.g., ethanol) have been elucidated by comparing their discriminative stimulus effects across different training doses; the current study used that approach to examine the mechanisms of action of the neuroactive steroid pregnanolone. Methods Separate groups of rats (n=6-8/group) discriminated pregnanolone from vehicle while responding under a fixed-ratio 10 schedule of food presentation. Two groups initially discriminated 3.2 mg/kg; once stimulus control was established, the training dose was systematically decreased to 1.33 mg/kg in one group and increased to 7.5 mg/kg in the other group. Other rats discriminated either 1.33 or 7.5 mg/kg without training at another dose. Results Stimulus control was established in 24-28 sessions in all groups. Positive GAB _AA modulators produced ≥80 % pregnanolone-lever responding, regardless of training dose; rank-order potency was flunitrazepam< midazolam< pregnanolone0pentobarbital. Ethanol produced some druglever responding (42 %) only in rats discriminating 1.33 mg/kg, whereas the N-methyl-D-aspartate receptor antagonist ketamine and the serotonin receptor agonist 1-(m-chlorophenyl)- biguanide occasioned predominantly vehicle-lever responding in all rats. Conclusions There was little difference in discriminative stimulus effects of pregnanolone across different training conditions, confirming a predominant, if not exclusive, role of GAB_AA receptors in these effects of pregnanolone.