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Abstract
Cocaethylene is a psychoactive metabolite formed during the combined consumption of cocaine and ethanol. In this brief review, we discuss several well-characterized effects of this metabolite with an emphasis on the neurobiological and behavioral correlates of polydrug addiction. Included herein are the descriptions of some of the changes in trans-synaptic transmission and their relationship to pathological behaviors associated with a chronic, drug-dependent state that may be altered by the spatial or temporal dynamics of cocaethylene.
Introduction
One of the most pervasive patterns of substance abuse in our society is the simultaneous ingestion of cocaine and ethanol.l 3 This pattern of drug consumption has serious health implications as seen by the number and frequency of individuals seeking drug abuse treatment. Given the seriousness of this clinical issue, one challenge facing scientists is to unravel the endogenous mechanisms or correlates that underlie polydrug abuse. This is not an easy task, as numerous factors appear to contribute significantly to the use, abuse of, and dependency on drugs such as cocaine and ethanol. Some of these factors include past drug history, psychological stress and genetic vulnerability.4 7 Another potential factor that may contribute to a drug-dependent state is that of the metabolic interaction resulting from the combined ingestion of several psychoactive drugs. In the context of cocaine and ethanol consumption, cocaethylene, an active cocaine metabolite, has been implicated in promoting and sustaining substance dependence by acting on specific brain systems critical for drug-reinforcing phenomena.8-13 Therefore, to illustrate the importance of cocaethylene as a potential variable mediating some of the characteristics of polydrug addiction, this review will focus on recent findings concerning the biological and behavioral indices attributed to this novel metabolite. We will attempt to be selective in our review and to emphasize only the consequences of cocaethylene on dopamine (DA) and serotonin (5-hydroxytryptamine, 5-HT) synaptic release, cellular immediate-early gene (IEG) expression and specific behaviors identified with the pathology of addiction.
Cocaethylene synthesis
In mammals, cocaethylene is synthesized by specific carboxylesterases in hepatic microsomal fractions.89 Carboxylesterases, a class of 3-esterases, are enzymes that have broad substrate specificity for the hydrolysis of heterogeneous esterases.14 The general mechanism(s) of carboxylesterase-mediated catalysis of cocaine is the hydrolysis of the methyl ester of the cocaine molecule into benzoylecgonine species, which...