COCAINE AND ALCOHOL INTERACTIONS IN NAIVE AND ALCOHOL-PRETREATED RATS

The interaction between cocaine (COC) and ethyl alcohol (ALC) was inve stigated in ALC-naive and ALC-pretreated rats. In each group, COC (30 mg/kg ip) was administered 15 min after administration of ALC (3 g/kg, by gavage) or normal saline (NS), in a balanced cross-over experiment al design. Cocaethylene (CE) was detected only in the rat plasma when ALC was administered with COC. In the ALC-naive rats, COC area under t he plasma concentration-time curve (AUC) and maximum plasma concentrat ion (Cp(max)) were significantly higher after administration of COC+AL C compared with after administration of COC+NS. However, COC half-life (t(1/2)) was not different after the two treatments, indicating that the higher COC Cp(max) and AUC after COC+ALC primarily resulted from e nhanced COC absorption. In the ALC-pretreated rats, COC AUC, Cp(max), and t(1/2) were not different after administration of COC+ALC or COC+N S. However, COC t(1/2) in the ALC-pretreated rats after COC+ALC and CO C+NS were significantly longer than the corresponding COC t(1/2) in th e ALC-naive rats. This indicates that repeated ALC exposure significan tly slows the rate of COC elimination. In the ALC-pretreated rats, CE AUC was significantly larger, and t(1/2) was significantly longer than CE AUC and t(1/2) in the ALC-naive rats. This indicates that previous ALC exposure inhibits CE elimination and may increase the fraction of COC dose metabolized to CE. Benzoylecgonine formation was significant ly reduced, and its t(1/2) was significantly prolonged after administr ation of COC+ALC in the ALC-naive and the ALC-pretreated rats. These r esults suggest that the combined abuse of COC and ALC leads to higher plasma COC concentrations that can lead to augmentation of cocaine eff ects in addition to the COC-like effects of CE. Also, repeated use of ALC slows the rate of COC elimination after administration of COC eith er alone or in combination with ALC, resulting in higher and prolonged COC plasma concentrations that can potentiate COC effects and toxicit ies. This higher COC concentrations in addition to the formation of CE are, at least partially, responsible for the serious consequences ass ociated with the combined abuse of COC and ALC.