Serotoninergic and noradrenergic systems : their involvement in the mechanism of action of antidepressants

There is an historical debate in which the role and importance of the serotoninergic (5-HT) and noradrenergic (NE) systems as being the key components in the antidepressant response is disputed. Alternatively, this contentious debate has directly led to the hypothesis which posits that a combined pharmacological action on both these systems might result in an enhanced antidepressant efficacy. The development of the dual 5-HT/NE reuptake inhibitor venlafaxine has allowed to put to the test this hypothesis. Hence, clinical insight into this problem was provided by studies that documented a greater efficacy of venlafaxine in major depression when used at high doses. The present research endeavour, undertaken in parallel at the Neurobiological Psychiatry Unit with clinical studies, sought to determine the effects of acute and prolonged treatments with venlafaxine on the rat 5-HT and NE systems such as to suggest a biological substratum for its clinical features. Using in vivo electrophysiological paradigms in the rat dorsal hippocampus, dorsal raphe and locus coeruleus, we have shown that: (1) venlafaxine blocks the reuptake of 5-HT more potently than that of NE; (2) venlafaxine and the SSRI paroxetine are equipotent in blocking the reuptake of 5-HT; (3) the NE reuptake inhibitor desipramine is more potent than venlafaxine in blocking the reuptake of NE. We have documented an important discrepancy between the affinity of venlafaxine for both the 5-HT and NE transporters binding sites and its in vivo reuptake inhibition potencies: the in vivo 5-HT and NE reuptake inhibition potencies of venlafaxine are much greater than could have been predicted from its affinities for the 5-HT and NE transporters. The disclosure of this peculiarity sheds doubt on the exact nature of the mechanism by which venlafaxine blocks both reuptake processes and, ultimately, exerts its antidepressant effect. The complementary use of in vivo electrophysiological and in vitro superfusion paradig