Prospect of a Dopamine Contribution in the Next Generation of Antidepressant Drugs: The Triple Reuptake Inhibitors

Biogenic amine transporters for serotonin and norepinephrine (5-HT and NE respectively), are major targets for currently available antidepressant drugs, particularly those inhibiting the reuptake of 5-HT and/or NE. Compelling evidence suggests that dopamine (DA) is also involved in the pathophysiology and treatment of depression, leading to the development of a new class of antidepressants: the triple reuptake inhibitors that simultaneously inhibit 5-HT, NE and DA reuptake thereby prolonging their duration of action at postsynaptic levels. Although preclinical studies strongly suggest that triple reuptake inhibitors display antidepressant-like activity in various behavioural paradigms, including the forced swimming and the tail suspension tests, it has yet to be demonstrated that the addition of the dopaminergic component produces more robust effects than single-or dual-acting compounds. Several arguments favour this hypothesis and particularly the observation that DA may promote neurotrophic processes in the adult hippocampus, as 5-HT and NE do. It is thus possible that the stimulation of multiple signalling pathways resulting from the elevation of all three monoamines may account, in part, for an accelerated and/or greater antidepressant response. To predict the efficacy of triple reuptake inhibitors, it is important to take into consideration the existence of dense connections between monoaminergic neurons. Indeed, it is well established that the increase in central dopaminergic transmission regulates the neuronal activity of 5-HT and NE in the dorsal raphe (DR) and locus coeruleus (LC), respectively, while in turn, the ventral tegmental area (VTA), is sensitive to changes in 5-HT and NE release. This review synthetizes the pertinent litterature, focusing on the contribution of DA, to illustrate the rationale for designing improved antidepressants.