Interaction of cocaine with positive GABAA modulators on the repeated acquisition and performance of response sequences in rats.

RATIONALE

Although positive GABA(A) modulators can attenuate several cocaine-induced behavioral effects, there is a paucity of data on their interaction with cocaine on transition behavior or learning.

OBJECTIVES

The current study examined the effects of cocaine (3.2-32 mg/kg), pregnanolone (3.2-24 mg/kg), and lorazepam (0.1-10 mg/kg) alone and in combination in rats responding under a multiple schedule of repeated acquisition and performance.

METHODS

In the acquisition component, subjects acquired a different three-response sequence each session, whereas in the performance component, they responded on the same three-response sequence each session.

RESULTS

All three drugs produced dose-dependent rate-decreasing and error-increasing effects. Cocaine was the least effective in decreasing rates and the most effective in increasing the percentage of errors. In combination with pregnanolone (3.2 or 10 mg/kg), the rate-decreasing effects of cocaine were relatively unchanged in both components, but 3.2 mg/kg of pregnanolone enhanced its error-increasing effects and the 10-mg/kg dose produced a significant dose-dependent interaction on errors. The combination of cocaine with lorazepam (0.32 mg/kg, 70-min pretreatment) produced significantly greater rate-decreasing and error-increasing effects than cocaine alone. A 15-min pretreatment with the same dose of lorazepam enhanced the error-increasing effects of small doses and attenuated the effects of larger doses of cocaine. Combinations of pregnanolone and lorazepam produced greater rate-decreasing and error-increasing effects in both components than either drug alone.

CONCLUSIONS

The present data show that cocaine is more disruptive to learning in rats than pregnanolone or lorazepam, and that the disruptive effects of cocaine can be enhanced by CNS depressants.