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Vol. 297, Issue 2, 540-546, May 2001

Reboxetine Modulates the Firing Pattern of Dopamine Cells in the Ventral Tegmental Area and Selectively Increases Dopamine Availability in the Prefrontal Cortex

Love Linnér, Hanna Endersz, Daniel Öhman, Finn Bengtsson, Martin Schalling and Torgny H. Svensson

Section of Neuropsychopharmacology, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden (L.L., T.H.S.); Division of Clinical Pharmacology, Department of Medicine and Care, University Hospital, Linköping, Sweden (D.Ö., F.B.); and Neurogenetics Unit, Department of Molecular Medicine, Karolinska Hospital, Stockholm, Sweden (M.S.)

Central dopaminergic neurons have been suggested to be involved in the pathophysiology of several psychiatric disorders, including depression, and appear to be modulated by noradrenergic activity both at the nerve terminal level and at the somatodendritic level. In recent years reboxetine, a selective noradrenaline reuptake inhibitor that differs from tricyclic antidepressants by its low affinity for muscarinic, cholinergic and alpha 1-adrenergic receptors, has been introduced clinically. In the present study the effect of reboxetine on the function of the mesolimbocortical dopamine system was investigated by means of single cell recording and microdialysis in rats following administration of reboxetine in doses that appear to yield clinically relevant plasma concentrations. Reboxetine (0.625-20 mg/kg intravenously) induced an increase in burst firing, but not in average firing frequency of dopamine (DA) cells in the ventral tegmental area (VTA). Moreover, reboxetine (0.15-13.5 mg/kg intraperitoneally) caused a significantly enhanced DA output in the medial prefrontal cortex, whereas no effect was observed in the nucleus accumbens. Local administration of reboxetine (333 µM, 60 min), by means of reversed microdialysis into these brain regions, caused a significant increase in DA output in both brain regions. However, local administration of reboxetine into the VTA (333 µM, 60 min) did not affect DA availability in these terminal areas. Our results imply that clinical treatment with reboxetine may result in facilitation of both prefrontal DA output and the excitability of VTA DA neurons, effects that may contribute to its antidepressant action, especially on drive and motivation.

0022-3565/01/2972-0540$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2001 by The American Society for Pharmacology and Experimental Therapeutics


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