Antidepressant-like effect of D2/3 receptor-, but not D 4 receptor-activation in the rat forced swim test

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/D 3, but not D4 receptors, can affect the outcome in the rat forced swim test (FST). Nomifensine, a dopamine uptake inhibitor (7, 14, and 28 μmol/kg); quinpirole, a D2-like receptor and agonist (0.4, 1.0, and 2.0 μmol/kg); PD 12,8907, a preferential D3 receptor agonist (0.17, 0.35, and 0.7 μmol/kg); PD 168077 (0.1, 0.3, and 1.0 μmol/kg) and CP 226269 (0.3, 1.0, and 3.0 μmol/kg), both selective D4 receptor agonists, were administered s.c. 24, 5, and 0.5/1 h before testing. Nomifensine, quinpirole at ail 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 D 2-like receptor antagonist (0.27 μmol/kg), completely blocked the effect of quinpirole; A-437203 (LU-201640), a selective D3 receptor antagonist (17,46 μmol/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 μmol/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. © 2005 Nature Publishing Group All rights reserved.