1. ¹Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL, USA
2. ²Abbott GmbH & Co KG, CNS Pharmacology, Ludwigshafen, Germany

Correspondence: Dr M Zhang, Neuroscience Research, Abbott Laboratories, AP9, R4N5, 100 Abbott Park, Abbott Park, IL 60064-6115, USA. Tel: +1 847 938 1016; Fax: +1 847 938 0072; E-mail: min.zhang@abbott.com

Received 12 May 2005; Revised 30 September 2005; Accepted 4 October 2005; Published online 14 December 2005.

Abstract

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 D₃ and D₂ receptors in these effects is unknown since all antipsychotics are D₂/D₃ antagonists with limited binding preference at D₂ receptors. Therefore, in the current study, we investigated the influence of several dopamine antagonists with higher selectivity at D₃ vs D₂ receptors on PPI in DBA/2J mice and in NVH-lesioned rats. The PPI in DBA/2J mice was enhanced by the nonselective D₂/D₃ 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 D₃/D₂ antagonist, BP 897 at 8 mg/kg, and the selective D₃ antagonists, SB 277011 at 30 mg/kg and A-437203 at 30 mg/kg. No effect was observed following the treatment with the selective D₃ 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 D₃ 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 D₃ receptors.