Pharmacological reversal of behavioral and cellular indices of cocaine sensitization in the rat

Rationale and objectives: Behavioral sensitization has been proposed as an animal model for the intensification of drug craving in cocaine addiction. Interactions between dopamine and glutamate systems are important for the i nduction and maintenance of sensitization. The goal of this study was to de termine if established cocaine sensitization could be reversed by pharmacol ogical manipulation of these transmitter systems. Methods: Rats received 15 mg/kg cocaine (IP) on days 1-10 and were challenged with cocaine (10 mg/kg :) on day 13 to verify that sensitization had occurred. On days 14-20, sepa rate groups of sensitized rats received daily injections of dopamine D-1- o r D-2-class agonists, an NMDA receptor antagonist, or a dopamine agonist wi th an NMDA antagonist. Three days or 2 weeks later, all rats were again tes ted for their response to cocaine to determine if sensitization had been re versed. Results: Reversal of sensitization was produced by repeated adminis tration of either a D-1-class agonist (SKF 81297) or the combination of an NMDA receptor antagonist and a D-2-class agonist. Effective combinations we re cocaine+MK-801, quinpirole+MK-801, quinpirole+CGS 19755, and pergolide+m emantine. The latter drugs are approved for human use. Reversal of sensitiz ation persisted for at least 2 weeks after cessation of drug treatment. Ele ctrophysiological studies revealed that these drug treatments also reversed dopamine D-1 receptor supersensitivity in the nucleus accumbens, a cellula r correlate of sensitization. Conclusions: These results demonstrate that p harmacotherapy can reverse behavioral and cellular adaptations associated w ith repeated cocaine administration, and may do so without the need for con tinued medication.