The mesolimbic dopamine system as a target for rapid antidepressant action

Chronic treatment with antidepressant drugs produces a variety of changes in dopaminergic neurotransmission. most notably a sensitization of behavioural responses to agonists acting at dopamine D2/D3 receptors within the nucleus accumbens. Evidence from animal models of depression (the forced swim test and the chronic mild stress procedure) indicates that these effects are crucial for the therapeutic effect of antidepressants in these models. Antidepressant-like effects in animal models are also seen with drugs that act directly on the dopaminergic system. Because of its prolonged time-course, the chronic mild stress procedure can be used to examine onset latencies. Some dopamine-active drugs (e.g. the catechol-O-methyltransferase inhihitor tolcapone; D2/D3 agonists administered intermittently) are active in this procedure but have a time-course comparable to that of conventional antidepressants. Other dopamine-active drugs may have a more rapid onset; the evidence to date suggests this possibility for the D2/D3, agonist pramipexole and the preferential presynaplic antagonist amisulpride. In clinical studies, rapid onset latencies have been claimed for the D2/D3 agonist roxindole, the preferential presynaptic antagonist sulphide and the relatively selective dopamine-uptake inhibitor amineptine. The mechanisms that might give rise to a rapid onset of dopamine-mediated antidepressant effects are discussed.