The extra-adrenal effects of metyrapone and oxazepam on ongoing cocaine self-administration

Role of GABA-active neurosteroids in the efficacy of metyrapone against cocaine addiction

“…We have recently focused on metyrapone, both alone and in combination with oxazepam, as possible therapeutics for drug dependence [18,[29][30][31]33]. The experiments described herein demonstrate that metyrapone pretreatment resulted in a dose-dependent decrease in cocaine-reinforced responding.…”

“…Furthermore, this MET/OX combination is effective in reducing craving and decreasing urinary cocaine metabolites in cocaine-dependent human subjects [31]. However, the mechanism(s) by which MET reduces cocaine's behavioral effects is unknown at this time, especially since the reductions in cocaine self-administration and cocaine use were not correlated with changes in plasma glucocorticoid hormones, suggesting that the suppression of adrenal glucocorticoid synthesis is not a prerequisite for metyrapone's behavioral effects [24,29,[31][32][33]. For example, MET, especially when combined with a sub-effective dose of oxazepam, decreases cocaine self-administration in rats without significantly reducing plasma corticosterone or altering the pharmacokinetics of these drugs [29].…”

“…In addition, the effects of metyrapone on cocaine-related behaviors are quite rapid, occurring within a 30-min pretreatment window, suggesting a fast action of MET not likely associated with glucocorticoid receptor-mediated transcriptional changes. The most recent observations suggest a role for metyrapone outside the adrenal gland as well [33]. The characteristics of this mechanism have suggested that neurosteroids affecting GABA A receptors may be involved in the actions of metyrapone and the MET/OX combination [36].…”

Dehydroepiandrosterone Attenuates Cocaine‐Seeking Behaviour Independently of Corticosterone Fluctuations

“…Moreover, recent work by Guerin et al . showed that adrenalectomy did not significantly alter the maintenance phase of cocaine self‐administration. Because earlier work found that adrenalectomy blunted the acquisition of cocaine self‐administration , CORT levels may exert a greater influence on drug self‐administration during the acquisition phase, rather than the maintenance phase.…”

“…CORT was shown to be requisite for cocaine self-administration. Acquisition, although not maintenance, was totally blocked by bilateral adrenalectomy, and was dose-dependently decreased by metyrapone, which inhibits CORT synthesis, and was also partly reversed by adding CORT to drinking water in rats (6,7). Goeders and Guerin (8) also found that self-administration does not occur unless plasma CORT is increased above a critical threshold needed for reward.…”