Crucial role of D1 dopamine receptors in mediating the antidepressant effect of imipramine

Although the neurochemical effects of chronic imipramine (IMI) treatment have been related to an increased adrenergic as well as dopaminergic transmission, no clear-cut evidence exists on whether one of these two neuronal systems mediates the behavioral effects of the tricyclic compound. Because a large body of evidence favors the role of dopamine, the interference of a selective inhibition of D1 or D2/D3 dopamine receptors on IMI effect upon the learned helplessness behavior (LH) in rats was studied. A 2-week treatment with SCH 23390, followed by a 24-h washout, showed almost the same efficacy as chronic IMI in preventing LH induction. Moreover, SCH 23390 given acutely before the pretest completely antagonized the effect of chronic IMI. Furthermore, SKF 38393 administered to drug-naive animals prior to the unavoidable shocks completely neutralized its behavioral sequelae. Finally, the inhibition of D2/D3 dopamine receptors by acute sulpiride did not modify IMI efficacy. These results strongly suggest that D1 dopamine receptor function controls the reactivity of animals exposed to a prolonged unavoidable stress, and mediates IMI antidepressant effect.