The effects of clomipramine on the excitatory action of ethanol on dopaminergic neurons of the ventral tegmental area in vitro.

Dopaminergic neurons of the ventral tegmental area (VTA) are important in the mediation of the rewarding properties of drugs of abuse such as ethanol. We have demonstrated in electrophysiological experiments in brain slices that serotonin potentiates the excitatory effect of ethanol on putative dopaminergic neurons of the VTA. Inasmuch as serotonin reuptake inhibitors have been shown to reduce ethanol intake in clinical studies, we investigated the effect of two serotonin reuptake inhibitors, clomipramine and zimelidine, on ethanol-induced excitation of VTA neurons recorded in vitro. Although zimelidine did potentiate ethanol-induced excitation in some neurons, on average, the effect of zimelidine was not significant. Significant potentiation of ethanol excitation was seen with 500 nM clomipramine, but not at higher or lower concentrations. In addition, clomipramine also enhanced the potentiation produced by low concentrations of serotonin. The lack of potentiation of ethanol excitation seen with application of higher concentrations of clomipramine could not be explained by inhibition of reuptake of norepinephrine or dopamine, and is probably due to blockade of 5-HT2 receptors by these higher concentrations of clomipramine. These results may have some implications for the development of serotonergic drugs, including serotonin uptake inhibitors, for the treatment of alcoholism.