Pregnanolone Hemisuccinate Inhibits Priming‐Induced Reinstatement of Cocaine Seeking in Rats

Abstract

Glutamate receptors within the nucleus accumbens (NAc) play an important role in relapse following withdrawal in cocaine addiction. Animal studies indicate that inhibition of AMPA receptors in the NAc inhibits reinstatement of cocaine seeking (Cornish and Kalivas, 2000), while selective inhibition of NMDA receptors induces reinstatement (Park et al., 2002). Neuroactive steroids such as pregnanolone hemisuccinate (3α5βHS) and pregnenolone hemisuccinate (PHS) have been shown to modulate glutamatergic neurotransmission (Yagoubi et al., 1998; Sadri-Vakili et al., 2003). We investigated the therapeutic potential of 3α5βHS and PHS using priming-induced reinstatement of cocaine seeking behavior in rats as a model of human relapse. Male Sprague Dawley rats were trained to self-administer cocaine on a fixed ratio reinforcement schedule for 21 days, following which cocaine was replaced with saline to extinguish the behavior. The neuroactive steroids were administered 10 minutes before the priming injection of cocaine (10mg/kg), which was delivered immediately before initiation of the next self-administration session. Pretreatment with 1 mg/kg of 3α5βHS did not inhibit reinstatement. However, ANOVA indicated that 10 mg/kg of 3α5βHS significantly (F = 20.664; p < 0.003) reduced active lever pressing as compared with vehicle. No measurable changes in locomotor activity or food seeking behavior were associated with this dose of 3α5βHS. By contrast, 10 mg/kg of PHS did not significantly inhibit reinstatement. These data indicate 3α5βHS inhibits cocaine-priming induced reinstatement of drug seeking behavior in rats and suggest that neuroactive steroids that act as allosteric modulators of ionotropic glutamate receptors may be useful for treating cocaine addiction.