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

Abstract

The pharmacokinetics and pharmacodynamics of cocaine and its three metabolites, benzoylecgonine, norcocaine, and cocaethylene, were investigated in awake, freely moving rats. This work was performed to examine the effect of alcohol coadministration on the metabolic profile of cocaine and to determine the contribution of cocaine metabolites to the pharmacological responses observed after cocaine administration. The plasma and brain extracellular fluid concentration-time profiles were characterized after intravenous (iv) administration of cocaine and the three metabolites in a crossover experimental 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 benzoylecgonine. The estimated total body clearances for cocaine, benzoylecgonine, norcocaine, and cocaethylene were 140 +/- 19, 14.7 +/- 1.2, 130 +/- 19, and 111 +/- 16 mL/min/kg, respectively. Alcohol coadministration increased the formation of norcocaine, decreased the formation of benzoylecgonine, and resulted in the formation of the pharmacologically active metabolite cocaethylene. When cocaine was administered with alcohol, 12.9 +/- 3.1% to 15.3 +/- 2.9% of the cocaine dose was converted to cocaethylene. Benzoylecgonine did not have any central nervous system or cardiovascular activities after 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 arterial blood pressure. These results indicate that changes in the cocaine metabolic profile and the formation of the pharmacologically active metabolite cocaethylene are, at least partially, responsible for the more intense and longer lasting effects reported after using this drug in combination with alcohol.

Ethanol consumption reduces the adverse consequences of self-administered intravenous cocaine in rats

“…While subjects avoid an environment associated with the effects of cocaine present 15 min post-injection, the negative properties of CE were not observed until 30 min post-injection. These data indicate that CE is longer acting than cocaine, a finding that is in accordance with the known plasma half-lives of the two compounds (Pan and Hedaya 1999). Thus, the fact that CE is longer-acting and less anxiogenic than cocaine provides a potential explanation for ethanol's effects on cocaine-induced retreat behaviors.…”

“…These results are clearly consistent with opponent-process models of drug action, which propose that the initial affective experience produced by a drug is followed in time by an independent opposing negative experience (Solomon and Corbit 1974;Solomon 1980;Koob et al 1997). Since the plasma half-life of IV cocaine in the rat is 15.8±1.5 min (Pan and Hedaya 1999), the negative effects observed 15 min after drug administration are occurring when the drug plasma levels are falling. It would seem then that the opposing positive and negative consequences of IV cocaine are associated with increasing or decreasing drug plasma levels, respectively.…”

Oral Self-Administration of Ethanol and Cocaine in Rats

“…If the mixtures contained two different concentrations, intakes of ethanol and cocaine were similar because animals adjusted their drinking volumes. Simultaneous consumption of ethanol and cocaine had no specific effect although both drugs can form the active compound cocaethylene [24][25][26]. Most likely, amounts consumed were below concentrations necessary for formation of this active product.…”

Evaluation of anti-cocaine antibodies and a cocaine vaccine in a rat self-administration model

“…Thus, the antibody may equally inhibit the peripheral cardiovascular effects of cocaine as well as its central reinforcing effects across a range of cocaine doses. Recent evidence also indicates that the centrally inactive cocaine metabolites benzoylecgonine and ecgonine methyl ester, which are not recognized by the cocaine vaccine (Fox et al 1996), do not produce cardiovascular effects in unanesthetized rats (Morishima et al 1999;Pan and Hedaya 1999). Consequently, their increased presence in the plasma of immunized animals is unlikely to have caused the flattening of the cocaine dose-response curves due to a change in cardiac function.…”