Electrophysiological effects of cocaine in the mesoaccumbens dopamine system: repeated administration.

Behavioral evidence indicates that the potent rewarding effects of cocaine are mediated, in part, by the mesoaccumbens dopamine (DA) system projecting from A10 DA cells in the ventral tegmental area (VTA) to the nucleus accumbens (NAc). Previous electrophysiological studies from our laboratory have indicated that cocaine (i.v.) exerts inhibitory effects on A10 DA neurons, due to enhanced stimulation by DA at DA autoreceptors are well as by activation of NAc-VTA feedback pathways. In the present experiments, extracellular single-unit recording and microiontophoretic techniques were used to determine the possible alterations in the mesoaccumbens DA system after repeated cocaine administration. Twice daily injections of cocaine (10 mg/kg i.p., 14 days) caused significant subsensitivity to the inhibitory effects of low i.v. doses of the DA agonist apomorphine in comparison to rats receiving similar treatments with saline or procaine. Iontophoretic application of DA to A10 DA neurons in rats treated repeatedly with cocaine (2X10 mg/kg, 14 days) also produced significantly less inhibition as compared to control rats. Cell population analysis of the VTA revealed that autoreceptor subsensitivity in cocaine-treated rats resulted in a significantly greater number of spontaneously active A10 DA neurons, and a significantly higher firing rate as compared to A10 DA neurons in control rats. In striking contrast to A10 DA cells, recordings from NAc neurons in cocaine-treated rats (2X10 mg/kg, 14 days) indicated that these cells were supersensitive to the inhibitory effects of iontophoretic DA. Although the mechanism underlying such supersensitivity remains unclear, the increased sensitivity of postsynaptic NAc DA receptors combined with the subsensitivity of A10 DA autoreceptors could lead to greatly enhanced DA transmission and may help to explain some aspects of cocaine-induced behavioral sensitization.