Reboxetine modulates the firing pattern of dopamine cells in the ventral tegmental area and selectively increases dopamine availability in the prefrontal cortex

Central dopaminergic neurons have been suggested to be involved in the path ophysiology of several psychiatric disorders, including depression, and app ear to be modulated by noradrenergic activity both at the nerve terminal le vel and at the somatodendritic level. In recent years reboxetine, a selecti ve noradrenaline reuptake inhibitor that differs from tricyclic antidepress ants by its low affinity for muscarinic, cholinergic and alpha (1)-adrenerg ic receptors, has been introduced clinically. In the present study the effe ct of reboxetine on the function of the mesolimbocortical dopamine system w as investigated by means of single cell recording and microdialysis in rats following administration of reboxetine in doses that appear to yield clini cally relevant plasma concentrations. Reboxetine (0.625-20 mg/kg intravenou sly) induced an increase in burst firing, but not in average firing frequen cy of dopamine (DA) cells in the ventral tegmental area (VTA). Moreover, re boxetine (0.15-13.5 mg/kg intraperitoneally) caused a significantly enhance d DA output in the medial prefrontal cortex, whereas no effect was observed in the nucleus accumbens. Local administration of reboxetine (333 muM, 60 min), by means of reversed microdialysis into these brain regions, caused a significant increase in DA output in both brain regions. However, local ad ministration of reboxetine into the VTA (333 muM, 60 min) did not affect DA availability in these terminal areas. Our results imply that clinical trea tment with reboxetine may result in facilitation of both prefrontal DA outp ut and the excitability of VTA DA neurons, effects that may contribute to i ts antidepressant action, especially on drive and motivation.