Electrophysiological effects of cocaine in the rat nucleus accumbens: microiontophoretic studies

The nucleus accumbens (NAc) is intricately involved in maintaining cocaine self-administration. Cocaine inhibits the firing of most NAc cells due to its ability to prevent the reuptake of dopamine (DA) and 5-hydroxytryptamine (5-HT), both of which predominantly inhibit NAc cell discharge in vivo. The present studies investigated the roles of DA and 5-HT in the effects of iontophoretically applied cocaine. Most NAc cells exhibited negative/positive waveforms (Type I cells). These cells were significantly more sensitive to cocaine than Type II cells (positive/negative waveforms), apparently due to differences in the actions of 5-HT. Whereas DA was equipotent at inhibiting Type I and Type II cells, 5-HT inhibited Type I cells but, primarily excited Type II cells. Thus the ability of cocaine to potentiate the effects of both DA and 5-HT resulted in a pronounced inhibition of Type I cells, whereas the 5-HT-mediated excitation of Type II cells appeared to reduce DA-mediated inhibition. Combined administration of selective DA (GBR 12909) and 5-HT (fluoxetine) uptake inhibitors was required to mimic the effects of cocaine on Type I and Type II NAc cells. Acute depletion of DA (86%) produced by alpha-methyl-p-tyrosine (AMPT) significantly reduced the inhibitory effects of cocaine on all NAc cells. Acute depletion of 5-HT (74%) produced by p-chlorophenylalanine (PCPA) significantly reduced the inhibitory effect of cocaine on Type I cells, but it significantly enhanced the inhibition of Type II cells. Simultaneous reduction of DA and 5-HT levels produced a significantly greater reduction of cocaine-induced inhibition of Type I neurons than did AMPT or PCPA alone. These findings are discussed in relation to proposed roles of DA and 5-HT in cocaine self-administration.