HETEROGENEOUS SUBREGIONAL BINDING PATTERNS OF H-3 WIN-35,428 AND H-3 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 trans porter (H-3-WIN 35,428 and H-3-GBR 12,935 binding) and concentration o f monoamine (dopamine, serotonin, noradrenaline and metabolites) neuro transmitters in rat brain. In normal rodent striatum H-3-WIN 35,428 an d H-3-GBR 12,935 binding to the dopamine transporter, although general ly similar, showed different subregional rostrocaudal and mediolateral gradients, suggesting that the two ligands might bind to different su btypes or states of the dopamine transporter. Following chronic, unlim ited access cocaine self-administration, binding of 3H-WIN 35,428 was significantly elevated in whole nucleus accumbens (+69%, p < 0.001) an d 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 0.001) on the last day of cocaine exposure (''on -cocaine group''); whereas in the 3 week withdrawn animals (''cocaine- withdrawn group''), levels were either normal (striatum) or reduced (- 30%, p 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 H-3-GBR 12,935 binding were observed, this dopamine transporter ligand showed a smaller and highly subregionally dependent increase in binding in s triatal subdivisions of the on-cocaine group, but a more marked bindin g reduction in the cocaine withdrawn animals. As compared with the con trols, 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 0.05) of t he cocaine-withdrawn group. These data provide additional support to t he hypothesis that some of the long-term effects of cocaine exposure ( drug craving, depression) could be consequent to reduced nucleus accum bens dopamine function. Our data also suggest that dopamine transporte r concentration, and perhaps function, might undergo up- or downregula tion, either as a direct effect of cocaine, or indirectly as part of a homeostatic response to altered synaptic dopamine levels, and therefo re might participate in the neuronal events underlying cocaine-induced behavioral changes.