Electrophysiological effects of cocaethylene, cocaine, and ethanol on dopaminergic neurons of the ventral tegmental area.

Coabuse of ethanol and cocaine is one of the most commonly used drug combinations and results in the formation of cocaethylene by the liver. Dopaminergic neurons of the ventral tegmental area (VTA) play a key role in the rewarding properties of drugs of abuse, including ethanol and cocaine. We have previously examined the electrophysiological effects of ethanol and cocaine, and their combined effects on these neurons. The present study investigates the electrophysiological effects of cocaethylene on dopaminergic VTA neurons with extracellular single-unit recording in brain slices from Fischer 344 rats. Cocaethylene (1--10 microM) decreased the firing rate of dopaminergic VTA neurons, similar to the effect of cocaine over this concentration range. This inhibition was blocked by the D(2) dopamine receptor antagonist, sulpiride (2 microM). At a lower concentration, cocaethylene (500 nM) potentiated ethanol-induced excitation of these neurons, similar to the effect of cocaine (500 nM) previously reported. This potentiation of ethanol excitation by cocaethylene was reversed by the 5-HT(2) antagonist ketanserin (5 microM). These data suggest that cocaethylene acts through a serotonergic mechanism at low concentrations to potentiate ethanol excitation of reward neurons and through a dopaminergic mechanism at high concentrations. The potency of cocaethylene in both of these actions is similar to that of cocaine. These effects of cocaethylene are likely to contribute to the synergistic effect on the dopaminergic reward pathway when ethanol and cocaine are used together; this may help to explain the high incidence of coabuse of ethanol and cocaine.