Self-administration of progesterone and synthetic neuroactive steroids by male rhesus monkeys

Abstract

Background: Progesterone-derived neuroactive steroids have shown promise clinically (e.g., anti-seizure medications) but, as with other GABAA receptor modulators (e.g., benzodiazepines), may have the potential for abuse.

Methods: We evaluated the reinforcing effects of progesterone, a steroid precursor of endogenous neuroactive steroids, with and without pretreatments with the neuroactive steroid synthesis inhibitor, finasteride, in rhesus monkeys trained under a progressive-ratio (PR) schedule of i.v. midazolam injection. We also assessed reinforcing effects of the short-acting neuroactive steroid alphaxolone and the long-acting neuroactive steroid ganaxolone in comparison with the short-acting benzodiazepine triazolam and the long-acting benzodiazepine clonazepam.

Results: At least one dose of progesterone, alphaxolone, and ganaxolone was self-administered significantly above vehicle levels in all monkeys tested (n=4 for progesterone, n=3 for alphaxolone and ganaxolone). The 5α-reductase inhibitor finasteride attenuated progesterone self-administration, consistent with the reinforcing effects of progesterone being mediated by the in vivo synthesis of neuroactive steroids. The comparison drugs, triazolam and clonazepam, were self-administered significantly above vehicle by all monkeys. Although the maximum number of injections/session maintained by the neuroactive steroids was below that maintained by the midazolam training dose, analysis of break points (i.e., highest response requirement achieved) suggested modest differences in relative reinforcing effectiveness for neuroactive steroids compared with benzodiazepines.

Conclusions: Our results are consistent with endogenous and synthetic neuroactive steroids having reinforcing effects similar to that of benzodiazepines, with reinforcing effectiveness possibly lower for the neuroactive steroids compared with benzodiazepines based on some measures.

Keywords: Benzodiazepine; GABA(A) receptor; Neuroactive steroid; Reinforcement; Rhesus monkey (Macaca mulatta); Self-administration.

Figure 1

Self-administration of reproductive hormone progesterone and the synthetic neuroactive steroids alphaxolone and ganaxolone by male rhesus monkeys trained under a progressive-ratio schedule of i.v. midazolam injection. The top two and lower left panels represent the number of injections/session self-administered by individual subjects (N=3–4 monkeys). Error bars represent 95% confidence intervals for 3 determinations of either the midazolam training dose (0.03 mg/kg/injection) or vehicle. Note that symbols obscure error bars in some instances. The lower right panel shows the group data, represented as mean number of injections/session + SEM. Asterisks indicate significance from vehicle for group data (Bonferroni t-tests, p<0.05). The F value and dotted lines represent results from a repeated measures ANOVA showing a main effect of alphaxolone dose (no multiple comparisons were significant).

Figure 2

Self-administration of benzodiazepines triazolam and clonazepam under a progressive-ratio schedule of reinforcement in rhesus monkeys (N=3). Data are from individual animals (top and middle panel) and the group monkeys (bottom panel). Other applicable details as in Figure 1.