1. ¹Abbott Laboratories, Neuroscience Research, Global Pharmaceutical Research & Development, Abbott Park, IL, USA
2. ²Abbott Laboratories, Neuroscience Discovery Research, Ludwigshafen, Germany

Correspondence: Dr AM Basso, Abbott Laboratories, Neuroscience Research Department, R4N5, Bldg. AP-9A LL, 100 Abbott Park Road, Abbott Park, IL 60064, USA. Tel: +1 847 935 1061; Fax: +1 847 938 0072; E-mail: Ana.basso@abbott.com

Received 11 June 2004; Revised 10 December 2004; Accepted 15 December 2004; Published online 26 January 2005.

Abstract

Dopamine plays a role in the pathophysiology of depression and therapeutic effects of antidepressants but the contribution of individual D₂-like receptor subtypes (D₂, D₃, D₄) to depression is not known. We present evidence that activation of D₂/D₃, but not D₄ receptors, can affect the outcome in the rat forced swim test (FST). Nomifensine, a dopamine uptake inhibitor (7, 14, and 28 mol/kg); quinpirole, a D₂-like receptor and agonist (0.4, 1.0, and 2.0 mol/kg); PD 12,8907, a preferential D₃ receptor agonist (0.17, 0.35, and 0.7 mol/kg); PD 168077 (0.1, 0.3, and 1.0 mol/kg) and CP 226269 (0.3, 1.0, and 3.0 mol/kg), both selective D₄ receptor agonists, were administered s.c. 24, 5, and 0.5/1 h before testing. Nomifensine, quinpirole at all doses and PD 128907 at the highest dose decreased immobility time in FST. PD 168077 and CP 226269 had no effect on the model. To further clarify what type of dopamine receptors were involved in the anti-immobility effect of quinpirole, we tested different antagonists. Haloperidol, a D₂-like receptor antagonist (0.27 mol/kg), completely blocked the effect of quinpirole; A-437203 (LU-201640), a selective D₃ receptor antagonist (17.46 mol/kg), showed a nonsignificant trend to attenuate the effect of the low dose of quinpirole, and L-745,870, a selective D₄ receptor antagonist (1.15 mol/kg), had no effect. The pharmacological selectivity of the compounds tested suggests that the antidepressant-like effects of quinpirole are most likely mediated mainly by D₂ and to a lesser extent by D₃ but not D₄ receptors.