Cocaethylene: A neuropharmacologically active metabolite assciated with concurrent cocaine-ethanol ingestion

TLDR

High concentrations of cocaethylene (EC), the ethyl ester of benzoylecgonine, were found in the blood of individuals who used cocaine and ethanol together. The study compared the effects of EC on dopamine uptake and behavior with those of cocaine. This comparison was grounded in the hypothesis that cocaine’s reinforcing effects depend on dopamine reuptake inhibition. EC was equipotent to cocaine in inhibiting dopamine reuptake, increasing extracellular dopamine, stimulating locomotor activity, and sustaining self‑administration in rats and primates, indicating that its in vivo formation may contribute to the combined abuse of cocaine and ethanol.

Abstract

High concentrations of cocaethylene (EC), the ethyl ester of benzoylecgonine, were measured in the blood of individuals who had concurrently used cocaine and ethanol. Since the powerful reinforcing effects of cocaine appear to be dependent on inhibition of dopamine reuptake in brain, we compared the effects of EC on the dopamine uptake system and its behavioral effects with those of cocaine. EC was equipotent to cocaine with respect to inhibition of binding of [3H]GBR 12395 to the dopamine reuptake complex, inhibition of [3H]dopamine uptake into synaptosomes and in its ability to increase extracellular dopamine concentration in the nucleus accumbens following its systemic administration to rats. Moreover, in rats, EC and cocaine each increased locomotor activity and rearing to the same extent following i.p. administration. In self-administration studies in primates, EC was approximately equipotent to cocaine in maintaining responding. The in vivo formation of this active, transesterified ethyl homolog of cocaine may contribute to the effects and consequences of combined cocaine and ethanol abuse.