Cocaine effects in the ventral tegmental area: evidence for an indirect dopaminergic mechanism of action.

Behavioral studies have implicated central dopaminergic systems, especially the ventral tegmental area of Tsai (VTA), in the mediation of the reinforcing effects of drugs of abuse such as cocaine. A brain slice preparation of the VTA was used to assess the direct effects of cocaine on the spontaneous activity of dopamine-type neurons. When superfused with 1-10 microM cocaine the firing rate of spontaneously active VTA neurons was decreased, with no corresponding change in spike height. While there was a considerable variability in the response to a given concentration of cocaine among the individual units, every cell inhibited by dopamine was also inhibited by cocaine. The local anesthetic lidocaine had variable effects on firing rate, but never potentiated the inhibitory effects of dopamine. Inhibitory responses to either dopamine or cocaine were blocked by the specific D2 dopamine receptor antagonist sulpiride. Small concentrations of cocaine (0.1-0.5 microM), which by themselves had little or no effect on spontaneous activity, potentiated the inhibitory effect of exogenously applied dopamine. Furthermore, the inhibitory action of apomorphine on spontaneous activity in the VTA was not potentiated by cocaine. These observations suggest that in low concentrations, cocaine can act as a dopamine reuptake inhibitor in the VTA, and that the resultant increase in extracellular dopamine acts upon dopamine autoreceptors to inhibit cellular activity.