Dizocilpine enhances the discriminative stimulus effects of midazolam in rats discriminating pregnanolone

Abstract

The discriminative stimulus effects of the neuroactive steroid pregnanolone are thought to be mediated by multiple neurotransmitter systems including positive modulation at GABAA receptors and antagonism of NMDA receptors. This study investigated the contribution of different receptor mechanisms by establishing pregnanolone as a discriminative stimulus and studying the NMDA receptor antagonist dizocilpine alone and in combination with the positive GABAA modulator midazolam. Male Sprague‐Dawley rats (n=10) discriminated pregnanolone (7.5 mg/kg, i.p.) and responded under a fixed ratio 10 schedule for food. Pregnanolone and midazolam produced >80% pregnanolone‐lever responding. In contrast, dizocilpine produced >80% pregnanolone‐lever responding in two rats and <20% pregnanolone‐lever responding in the remaining eight rats, while the mu opioid receptor agonist morphine produced predominantly vehicle‐lever responding. When administered 30 minutes before sessions, dizocilpine shifted the midazolam dose‐effect curve leftward 2‐ to 6‐fold; however, morphine did not alter the midazolam dose‐effect curve. Although dizocilpine did not substitute for pregnanolone, enhancement of the effects of midazolam by dizocilpine suggests that the pregnanolone discriminative stimulus has both GABAA and NMDA components.