Role of the dopamine transporter in mediating the neuroleptic-induced reduction of tyrosine hydroxylase-immunoreactive midbrain neurons

We have previously reported a long-term downregulation of midbrain dopaminergic neurons following treatment with neuroleptic medications. The mechanism of this effect is not clear. The dopamine transporter (DAT) has been shown to play a role in the behavioural and biochemical action of neurotoxins such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). We postulated a role for the DAT in mediating the changes induced by neuroleptic (i.e., antipsychotic) drugs. In the first experiment, Sprague-Dawley rats simultaneously received twice daily sub-cutaneous injections of either saline or the DAT inhibitor GBR 12909 (GBR; 5 mg/kg/day) and haloperidol (HAL; 2 mg/kg/day) or vehicle. In the second experiment, the animals were treated with daily sub-cutaneous injections of saline or the DAT inhibitor GBR 129091 plus oral risperidone (RISP; 1.5 mg/kg/day) or vehicle. In a third experiment, animals were given normal drinking water or water with clozapine (CLZ, 20 mg/kg/day). Animals were sacrificed immediately after the last treatment. Sections of the substantia nigra (SN) and ventral tegmental area (VTA) were processed for tyrosine hydroxylase (TH) immunoreactivity. Cell counts were analyzed by one-way analysis of variance followed by post-hoc Tukey tests, with significance set at p<0.05. Treatment with HAL or RISP resulted in a significant reduction (HAL 27%; RISP 25%) in the number of TH-immunoreactive cells present in the medial SN pars compacta. This effect was in both cases completely blocked by administration of the DAT inhibitor. In the VTA, TH-positive cell counts were significantly decreased with RISP, but not with HAL. Once again, the RISP-induced changes were blocked by co-administration of the DAT inhibitor. CLZ treatment did not significantly affect TH-positive cell counts in the SN. These results indicate a role for the active dopamine transporter in mediating the suppression of TH expression in midbrain dopaminergic neurons by antipsychotic drugs. DAT inhibitors may prove useful in ameliorating the neurological side effects of antipsychotic medication.