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Cross-Talk between Dopaminergic and Noradrenergic Systems in the Rat Ventral Tegmental Area, Locus Ceruleus, and Dorsal Hippocampus

University of Ottawa Institute of Mental Health Research, Ottawa, Ontario, Canada (B.P.G, M.E.M., P.B.); and Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada (P.B.)

A decreased central dopaminergic and/or noradrenergic transmission is believed to be involved in the pathophysiology of depression. It is known that dopamine (DA) neurons in the ventral tegmental area (VTA) and norepinephrine (NE) neurons in the locus ceruleus (LC) are autoregulated by somatodendritic D₂-like and ₂-adrenoceptors, respectively. Complementing these autoreceptor-mediated inhibitory feedbacks, anatomical and functional studies have established a role for noradrenergic inputs in regulating dopaminergic activity, and reciprocally. In the present study, a microiontophoretic approach was used to characterize the postsynaptic catecholamine heteroreceptors involved in such regulations. In the VTA, the application of DA and NE significantly reduced the firing activity of DA neurons. In addition to a role for D₂-like receptors in the inhibitory effects of both catecholamines, it was demonstrated that the ₂-adrenoceptor antagonist idazoxan dampened the DA- and NE-induced attenuations of DA neuronal activity, indicating that both of these receptors are involved in the responsiveness of VTA DA neurons to catecholamines. In the LC, the effectiveness of iontophoretically applied NE and DA to suppress NE neuronal firing was blocked by idazoxan but not by the D₂-like receptor antagonist raclopride, which suggested that only ₂-adrenoceptors were involved. In the dorsal hippocampus, a forebrain region having a sparse dopaminergic innervation but receiving a dense noradrenergic input, the suppressant effects of DA and NE on pyramidal neurons were attenuated by idazoxan but not by raclopride. The suppressant effect of DA was prolonged by administration of the selective NE reuptake inhibitor desipramine and, to lesser extent, of the selective DA reuptake inhibitor 1-(2-[bis(4-fluorophenyl)methoxy]ethyl)-4-(3-phenylpropyl)-piperazine (GBR12909), suggesting that both the NE and DA transporters were involved in DA uptake in the hippocampus. These findings might help in designing new antidepressant strategies aimed at enhancing DA and NE neurotransmission.

Received for publication April 18, 2008.

Accepted for publication August 14, 2008.

Address correspondence to: Dr. Pierre Blier, University of Ottawa Institute of Mental Health Research, 1145 Carling Avenue, Ottawa, K1Z 7K4, Ontario, Canada. E-mail: pblier{at}rohcg.on.ca

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