Effect of dopamine D3 antagonists on PPI in DBA/2J mice or PPI deficit induced by neonatal ventral hippocampal lesions in rats

Schizophrenic patients typically exhibit impairment of sensorimotor gating, which can be modeled in animal models such as the test of prepulse inhibition of startle response (PPI) in rodents. It has been found that antipsychotics enhanced PPI in DBA mice and reversed the PPI deficit induced by neonatal ventral hippocampal (NVH) lesions in rats. However, the relative involvement of D-3 and D-2 receptors in these effects is unknown since all antipsychotics are D-2/D-3 antagonists with limited binding preference at D-2 receptors. Therefore, in the current study, we investigated the influence of several dopamine antagonists with higher selectivity at D-3 vs D-2 receptors on PPI in DBA/2J mice and in NVH-lesioned rats. The PPI in DBA/2J mice was enhanced by the nonselective D-2/D-3 antagonists, haloperidol at 0.3-3 mg/kg, or risperidone at 0.3-1 mg/kg, while PPI-enhancing effects were observed after the administration of higher doses of the preferential D-3/D-2 antagonist, BP 897 at 8 mg/kg, and the selective D-3 antagonists, SB 277011 at 30 mg/kg and A-437203 at 30 mg/kg. No effect was observed following the treatment with the selective D-3 antagonist, AVE 5997 up to 30 mg/kg. The PPI deficits induced by NVH lesions were reversed by haloperidol but not by the more selective D-3 antagonists, A-437203 and AVE 5997. BP 897 enhanced PPI nonselectivity, that is, in both lesioned and nonlesioned rats. In summary, the present study indicates that PPI-enhancing effects induced by antipsychotics in DBA/2J mice and in NVH-lesioned rats are unlikely to be mediated by D-3 receptors.