Evidence for opponent-process actions of intravenous cocaine and cocaethylene.

The affective response to cocaine (COC) has been suggested to follow a time-course and pattern that adheres to the prediction of opponent-process models of drug actions. While the initial impact of the drug is positive, within a few minutes that effect wanes and is replaced by an aversive state characterized by anxiety and drug craving. We have demonstrated this phenomenon in animals by showing that rats prefer distinctive environments associated with the immediate effects of intravenous COC (1.0 mg/kg) but avoid environments associated with the state present 15-min postinjection. Human addicts have reported taking ethanol with their COC as a means of attenuating the negative aftereffects of COC administration. The combination of ethanol and COC results in the production of cocaethylene (CE), a metabolite of COC having psychostimulant properties. The current study was devised to assess whether the immediate and delayed affective responses to CE might account for the self-medication strategy of COC addicts pretreating themselves with ethanol. Rats developed conditioned place preferences for environments paired with the immediate effects of a 1.44-mg/kg intravenous dose of CE (equimolar to a 1.0-mg/kg dose of COC). While no aversive effects were observed at 0, 5, or 15 min postinjection, reliable place avoidance was detected for an environment paired with the internal state present 30-min post-CE. These data are consistent with the view that the development of CE may account for efficacy of ethanol to delay and weaken the aversive aftereffects of COC.