Heterogeneous subregional binding patterns of ³H-WIN 35,428 and ³H-GBR 12,935 are differentially regulated by chronic cocaine self-administration

We examined the influence of chronic cocaine exposure, in an unlimited access self-administration paradigm, on density of the dopamine transporter (³H-WIN 35,428 and ³H-GBR 12,935 binding) and concentration of monoamine (dopamine, serotonin, noradrenaline and metabolites) neurotransmitters in rat brain. In normal rodent striatum ³H-WIN 35,428 and ³H-GBR 12,935 binding to the dopamine transporter, although generally similar, showed different subregional rostrocaudal and mediolateral gradients, suggesting that the two ligands might bind to different subtypes or states of the dopamine transporter. Following chronic, unlimited access cocaine self-administration, binding of ³H-WIN 35,428 was significantly elevated in whole nucleus accumbens (+69%, p < 0.001) and striatum (+65%, p < 0.001) on the last day of cocaine exposure ('on-cocaine group'); whereas in the 3 week withdrawn animals ('cocaine-withdrawn group'), levels were either normal (striatum) or reduced (-30%, p < 0.05, nucleus accumbens). Although similar changes in ³H- GBR 12,935 binding were observed, this dopamine transporter ligand showed a smaller and highly subregionally dependent increase in binding in striatal subdivisions of the on-cocaine group, but a more marked binding reduction in the cocaine-withdrawn animals. As compared with the controls, mean dopamine levels were reduced in striatum (-15%, p < 0.05) of the on-cocaine group and in nucleus accumbens (-40%, p < 0.05) of the cocaine-withdrawn group. These data provide additional support to the hypothesis that some of the long-term effects of cocaine exposure (drug craving, depression) could be consequent to reduced nucleus accumbens dopamine function. Our data also suggest that dopamine transporter concentration, and perhaps function, might undergo up- or downregulation, either as a direct effect of cocaine, or indirectly as part of a homeostatic response to altered synaptic dopamine levels, and therefore might participate in the neuronal events underlying cocaine- induced behavioral changes.