SELECTIVE DOPAMINE D-4 RECEPTOR ANTAGONISTS REVERSE APOMORPHINE-INDUCED BLOCKADE OF PREPULSE INHIBITION

Recent evidence suggests that the dopamine D-4 receptor may play a rol e in schizophrenia, and that the atypical properties of the antipsycho tic clozapine may be attributable in part to its antagonistic actions at this receptor. In the present study, clozapine and three other comp ounds having D-4 dopamine receptor antagonist properties were examined for their effectiveness in reducing losses in prepulse inhibition (PP I) induced in rats by the dopamine receptor agonist apomorphine. Previ ously. activity in the PPI model has been shown to correlate highly wi th the antipsychotic potency of a number of neuroleptics. As previousl y reported, clozapine (1-5.6 mg/kg) significantly reduced apomorphine- induced PPI deficits. The three D-4-selective compounds, CP-293,019 (5 .6-17.8 mg/kg), U-101,387 (3-30 mg/kg) and L-745,870 (1-10 mg/kg), als o significantly blocked the losses in PPI produced by apomorphine. Tak en together, these results suggest that dopamine receptor antagonists with selectivity for the D-4 dopamine receptor subtype may be effectiv e in the treatment of schizophrenia, while being less likely to produc e dyskinesias associated with D-2 receptor antagonists.