ς₁Receptor-Related Neuroactive Steroids Modulate Cocaine-Induced Reward

Abstract

The sigma1 receptor is critically involved in the rewarding effect of cocaine, as measured using the conditioned place preference (CPP) procedure in mice. Neuroactive steroids exert rapid neuromodulatory effects in the brain by interacting with GABA(A), NMDA, and sigma1 receptors. At the sigma1 receptor level, 3beta-hydroxy-5-androsten-17-one [dehydroepiandrosterone (DHEA)] and 3beta-hydroxy-5-pregnen-20-one (pregnenolone) act as agonists, whereas 4-pregnene-3,20-dione (progesterone) is an efficient antagonist. The present study sought to investigate the action of neuroactive steroids in acquisition of cocaine-induced CPP in C57BL/6 mice. None of these steroids induced CPP alone. However, pretreatment with DHEA or pregnenolone (5-20 mg/kg, s.c.) during conditioning with cocaine (10 mg/kg, i.p.) increased the conditioned score. On the contrary, pretreatment with either progesterone (10 or 20 mg/kg, s.c.) or finasteride (25 mg/kg, twice a day), a 5alpha-reductase inhibitor, blocked acquisition of cocaine (20 mg/kg)-induced CPP. A crossed pharmacology was observed between steroids and sigma1 ligands. The sigma1 antagonist N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(dimethylamino)ethylamine blocked cocaine-induced CPP and its potentiation by DHEA or pregnenolone. Progesterone blocked cocaine-induced CPP and its potentiation by the sigma1 agonist igmesine. These results showed that neuroactive steroids play a role in cocaine-induced appetence, through their interaction with the sigma1 receptor. Therefore, neuroendocrine control of cocaine addiction may not involve solely glucocorticoids. The importance of neuroactive steroids as factors of individual vulnerability to drug addiction should, thus, be considered.

σ1 Receptor Ligands and Related Neuroactive Steroids Interfere with the Cocaine-Induced State of Memory

“…Progesterone behaved also similarly as BD1047, by producing a clear masking effect of the cocaine-induced memory state. These observations bring a physiological substratum for the involvement of the s 1 receptor activation in the cocaine StD and suggest, together with previous conditioned place preference results (Romieu et al, 2003(Romieu et al, , 2004, that the endogenous neurosteroid tonus may influence cocaine vulnerability.…”

“…Cocaine self-administration and relapse are also mediated by glutamate neurotransmission in the nucleus accumbens (Cornish et al, 1999;Park et al, 2002). In addition, cocaine interacts with the s 1 receptor at a similar dose range as observed for the dopamine transporter (Sharkey et al, 1988), and the s 1 receptor is implicated in several of cocaine's effects such as locomotor stimulation, sensitization, acquisition and reactivation of conditioned place preference, convulsions, and lethality (Reith et al, 1986;Menkel et al, 1991;Ujike et al, 1992;Ritz and George, 1993;Romieu et al, 2000Romieu et al, , 2002Romieu et al, , 2003Romieu et al, , 2004; for a review, see Maurice et al, 2002). This intracellular protein sharing some characteristics of neuromodulatory receptors is also a target for several neuroactive steroids, including pregnenolone, dehydroepiandrosterone (3b-hydroxy-5a-androsten-17-one (DHEA)), their sulfate esters, or progesterone, but not pregnanolone or allopregnanolone (Su et al, 1988;Monnet et al, 1995;Bergeron et al, 1996;Maurice et al, 1999).…”

Repeated Cocaine Administration Induces Gene Expression Changes through the Dopamine D1 Receptors

“…IGFBP6 binds IGF-II with high affinity and may inhibit IGF-II actions and both IGFBP6 and IGF-II are expressed in the central nervous system (Murphy, 1998;Zumkeller and Westphal, 2001). The sigma 1 receptor is associated with both plasma and intracellular membranes and is expressed in the CPu, NAc, and amygdala in the brain (Matsumoto et al, 2002;Romieu et al, 2003). This receptor can modulate cocaine-induced behaviors (Matsumoto et al, 2002;Romieu et al, 2003).…”

“…The sigma 1 receptor is associated with both plasma and intracellular membranes and is expressed in the CPu, NAc, and amygdala in the brain (Matsumoto et al, 2002;Romieu et al, 2003). This receptor can modulate cocaine-induced behaviors (Matsumoto et al, 2002;Romieu et al, 2003). RGS proteins are a family of diverse and multifunctional signaling proteins that modulate G-protein functions (Zhong and Neubig, 2001;Hollinger and Hepler, 2002).…”

“…The sigma 1 receptor is involved in modulating the rewarding effects of cocaine (Romieu et al, 2003). Antagonists for this receptor block the acute locomotor stimulating effect of cocaine and attenuate cocaine-induced behavioral sensitization (Ujike et al, 1996;Matsumoto et al, 2002).…”