Using drug combinations to assess potential contributions of non-GABA sub(A) receptors in the discriminative stimulus effects of the neuroactive steroid pregnanolone in rats

• Published in: Physiology & behavior Vol. 137; pp. 33 - 41
• Main Authors: Eppolito, Amy K, Kodeih, Hanna R, Gerak, Lisa R
• Format: Journal Article
• Language: English
• Published: 01-10-2014
• DOI: 10.1016/j.physbeh.2014.07.003
• ISSN: 0031-9384

Neuroactive steroids are increasingly implicated in the development of depression and anxiety and have been suggested as possible treatments for these disorders. While neuroactive steroids, such as pregnanolone, act primarily at gamma -aminobutyric acid sub(A) (GABA sub(A)) receptors, other mechanisms might contribute to their behavioral effects and could increase their clinical effectiveness, as compared with drugs acting exclusively at GABA sub(A) receptors (e.g., benzodiazepines). The current study examined the role of non-GABA sub(A) receptors, including N-methyl-d-aspartate (NMDA) and serotonin sub(3) (5-HT sub(3)) receptors, in the discriminative stimulus effects of pregnanolone. Separate groups of rats discriminated either 3.2 mg/kg pregnanolone from vehicle or 0.32 mg/kg of the benzodiazepine midazolam from vehicle while responding under a fixed-ratio 10 schedule for food pellets. When administered alone in both groups, pregnanolone and midazolam produced greater than or equal to 80% drug-lever responding, the NMDA receptor antagonists dizocilpine and phencyclidine produced greater than or equal to 60 and greater than or equal to 30% drug-lever responding, respectively, and the 5-HT sub(3) receptor agonist 1-(m-chlorophenyl)-biguanide (CPBG) and morphine produced < 20% drug-lever responding up to doses that markedly decreased response rates. When studied together, neither dizocilpine, phencyclidine, CPBG nor morphine significantly altered the midazolam dose-effect curve in either group. Given that CPBG is without effect, it is unlikely that 5-HT sub(3) receptors contribute substantially to the discriminative stimulus effects of pregnanolone. Similarities across groups in effects of dizocilpine and phencyclidine suggest that NMDA receptors do not differentially contribute to the effects of pregnanolone. Thus, NMDA and 5-HT sub(3) receptors are not involved in the discriminative stimulus effects of pregnanolone.