One year of continuous treatment with haloperidol or clozapine fails to induce a hypersensitive response of caudate putamen neurons to dopamine D1 and D2 receptor agonists.

In a "blind" experimental design, the sensitivity of caudate-putamen (CPu) cells to the selective dopamine (DA) D1 receptor agonist SKF-38393 and D2 receptor agonist LY171555 (quinpirole) in rats treated with either haloperidol (HAL), clozapine or tap water for 1 year was compared using the techniques of single cell recording and microiontophoresis. Although the maximum binding value for D2 receptors was elevated in chronic HAL-treated rats, there was no sign of electrophysiological supersensitivity of CPu neurons to the selective DA D1 and D2 receptor agonists. CPu cells were subsensitive to LY-171555 in HAL-treated rats without a drug withdrawal period. This suggests that residual HAL in the rat brain actively blocked the D2 DA receptors. In contrast, in clozapine-treated rats with or without a drug withdrawal period, the sensitivity of CPu cells to either the D1 or D2 agonists was not altered. Coadministration of SKF-38393 and LY-171555 onto the CPu neurons primarily produced an additive effect and only two cells both from the HAL group showed a synergistic action. The majority of CPu cells failed to respond to iontophoretic application of CCK-8S in either the control or antipsychotic drug-treated rats. If these findings can be extended to humans, they do not support the view that tardive dyskinesia is the result of CPu DA receptor supersensitivity.