Selective dopamine D4 receptor antagonists reverse apomorphine-induced blockade of prepulse inhibition

Recent evidence suggests that the dopamine D-4 receptor may play a role in schizophrenia, and that the atypical properties of the antipsychotic clozapine may be attributable in part to its antagonistic actions at this receptor. In the present study, clozapine and three other compounds having D-4 dopamine receptor antagonist properties were examined for their effectiveness in reducing losses in prepulse inhibition (PPI) induced in rats by the dopamine receptor agonist apomorphine. Previously. activity in the PPI model has been shown to correlate highly with the antipsychotic potency of a number of neuroleptics. As previously 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), also significantly blocked the losses in PPI produced by apomorphine. Taken together, these results suggest that dopamine receptor antagonists with selectivity for the D-4 dopamine receptor subtype may be effective in the treatment of schizophrenia, while being less likely to produce dyskinesias associated with D-2 receptor antagonists.