Cocaine and alcohol interactions in the rat: Contribution of cocaine metabolites to the pharmacological effects

The pharmacokinetics and pharmacodynamics of cocaine and its three metaboli tes, benzoylecgonine, norcocaine, and cocaethylene, were investigated in aw ake, freely moving rats. This work was performed to examine the effect of a lcohol coadministration on the metabolic profile of cocaine and to determin e the contribution of cocaine metabolites to the pharmacological responses observed after cocaine administration. The plasma and brain extracellular f luid concentration-time profiles were characterized after intravenous (iv) administration of cocaine and the three metabolites in a crossover experime ntal design. The neurochemical response, measured as the change in dopamine concentration in the nucleus accumbens, and the cardiovascular responses, measured as the change in the mean arterial blood pressure, heart rate, and QRS interval, were monitored simultaneously. Cocaethylene had the highest brain-to-plasma distribution ratio, followed by cocaine, norcocaine, and be nzoylecgonine. The estimated total body clearances for cocaine, benzoylecgo nine, norcocaine, and cocaethylene were 140 +/- 19, 14.7 +/- 1.2, 130 +/- 1 9, and 111 +/- 16 mL/min/kg, respectively. Alcohol coadministration increas ed the formation of norcocaine, decreased the formation of benzoylecgonine, and resulted in the formation of the pharmacologically active metabolite c ocaethylene. When cocaine was administered with alcohol. 12.9 +/- 3.1% to 1 5.3 +/- 2.9% of the cocaine dose was converted to cocaethylene. Benzoylecgo nine did not have any central nervous system or cardiovascular activities a fter iv administration. Compared with cocaine, norcocaine and cocaethylene had more potent and prolonged effects on the neurochemical, heart rate, and QRS interval responses, and were equipotent in increasing the mean arteria l blood pressure. These results indicate that changes in the cocaine metabo lic profile and the formation of the pharmacologically active metabolite co caethylene are, at least partially, responsible for the more intense and lo nger lasting effects reported after using this drug in combination with alc ohol.