Self-administration of neuroactive steroids by rhesus monkeys responding under a progressive-ratio schedule of i.v. midazolam injection

Abstract

Aims: Neuroactive steroids (NSs) are natural or synthetic steroids that can rapidly alter the excitability of neurons via GABAA receptors. We previously have shown that the endogenous (progesterone-derived) NS pregnanolone, but not a synthetic NS (Co 8-7071), was self-administered by rhesus monkeys. Co 8-7071 had discriminative stimulus effects similar to benzodiazepines (BZs). Therefore, its lack of reinforcing effects might be due to DM/PKvariables (e.g., durationof action, efficacydifferences inparent compound vs. metabolites). In this study, we investigated the reinforcing effects of the synthetic NS ganaxalone (long duration of action) and alphaxalone (short duration of action). Methods: A progressive-ratio (PR) schedule of i.v. midazolam self-administration was used for determining the reinforcing effects of these NSs, in comparison with BZ-type drugs (alprazolam and zolpidem). Four adult rhesus monkeys were trained to press a lever that resulted in an i.v. midazolam injection (0.056mg/kg/injection) via a chronic venous catheter. Reinforcing effects of a drug were determined by comparing the average number of injections/session and the average break point (highest response requirement completed in a session) to results fromsaline tests. Results: Both NSs were self-administered above levels maintained by saline availability. The maximal level of selfadministration, measured by breakpoint, did not differ across the test drugs. Conclusions: These results demonstrated that two synthetic NSs were self-administered to a degree similar to the BZ-like drugs alprazolam and zolpidem. Because ganaxolone was selfadministered and has a relatively long duration of action, the previous demonstration of a lack of reinforcing effects of Co 8-7071 likelywasdue topro-drugproperties rather thandurationof action. Financial support: DA011792, DA033795 and OD011103.