Neuroactive steroids attenuate cocaine-induced sucrose intake in rats, butnot cocaine-induced hyperactivity in mice

Rationale: Neuroactive steroids, including the potent anticonvulsants ganax olone (3 alpha-hydroxy-3 beta-methyl-5 alpha-pregnan-20-one) and Co 2-1068 (3 beta-(4acetyl-phenyl)ethynyl-3 alpha,21 -dihydroxy-5 beta-20-one-21-hemi suc-cinate), have recently been shown to protect against cocaine-induced se izures. Objectives: The purpose of the present experiments was to determine whether ganaxolone and Co 2-1068 attenuate acute behavioral effects of coc aine unrelated to seizures. Methods: In the first experiment, the locomotor effects of Co 2-1068 (10-100 mg/ kg), pentobarbital (10-100 mg/kg) and hal operidol (0.03-0.3 mg/kg), alone or in combination with cocaine (5.6-30 mg/ kg), were determined in mice. In the second experiment, the effects on sucr ose intake of ganaxolone (4-16 mg/kg), Co 2-1068 (8-64 mg/kg), pentobarbita l (4-32 mg/kg), and haloperidol (0.04-0.4 mg/kg), alone or in combination w ith cocaine (4-16 mg/kg), were determined in rats. Results: Cocaine caused a dose-related increase in locomotor activity in mice, whereas Co 2-1068, p entobarbital and haloperidol caused dose-related decreases. The dopamine an tagonist haloperidol, at a dose that had no effect on activity by itself, b ut not Co 2-1068 or pentobarbital, attenuated the cocaine-induced increase in locomotor activity. Cocaine, ganaxolone, Co 2-1068, and haloperidol prod uced dose-related decreases in sucrose intake in rats; the effects of pento barbital on sucrose intake were variable. As with locomotor effects, halope ridol attenuated the cocaine-induced decrease in sucrose intake. In additio n, cocaine-induced decreases in sucrose intake were attenuated by ganaxolon e and Co 2-1068. Pentobarbital had no statistically significant effect on t he cocaine dose-response function. Conclusions: These results suggest that the interaction of neuroactive steroids with cocaine extends to pharmacolog ic actions beyond anticonvulsant efficacy, but that the blockade of behavio ral effects of cocaine by neuroactive steroids does not apply to all acute behaviors.