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NEUROPHARMACOLOGY

In Vivo Effect of Venlafaxine on Locus Coeruleus Neurons: Role of Opioid, ₂-Adrenergic, and 5-Hydroxytryptamine_1A Receptors

Pharmacology and Neuroscience Research Group, Department of Neuroscience (Pharmacology and Psychiatry), School of Medicine, University of Cádiz, Cádiz, Spain

The locus coeruleus (LC) is involved in several neural pathways responsible for some somatic and emotional processes, such as pain and depression; its activity is regulated by several receptors, such as opioid, ₂-adrenergic, and 5-hydroxytryptamine (5-HT)_1A receptors. The present study investigates the in vivo effects of venlafaxine, an antidepressant with analgesic properties, on locus coeruleus neurons, and its modulation by opioid, ₂-adrenergic, and 5-HT_1A receptors. The results show that acute administration of venlafaxine produced a dose-dependent, complete inhibition of LC activity. This inhibitory effect was not reversed by the opioid receptor antagonist naloxone, but subsequent administration of idazoxan, an ₂-adrenoceptor antagonist, did reverse it. The preadministration of the 5-HT_1A receptor agonist 8-hydroxy-2-dipropylaminotetralin (8-OH-DPAT) (1 and 40 µg/kg) significantly enhanced the venlafaxine inhibitory effect, decreasing the ED₅₀ by 56 and 44%, respectively. A 14-day treatment with venlafaxine (40 mg/kg/day) induced a suppression of the firing activity of LC neurons. In these treated animals, venlafaxine produced an inhibitory effect similar to that in nontreated animals. This inhibitory effect was not reversed by naloxone, but it was reversed by idazoxan. In addition, the preadministration of 8-OH-DPAT (40 µg/kg) significantly enhanced the venlafaxine effect, decreasing the ED₅₀ by 60%. These results suggest that the effect of venlafaxine on LC neurons is modulated by ₂-adrenergic and 5-HT_1A receptors, and not by opioid receptors. These data could contribute to the further understanding of the antidepressant and analgesic mechanism of action of venlafaxine.

Address correspondence to: Dr. Juan A. Mico, Pharmacology and Neuroscience Research Group, Department of Neuroscience (Pharmacology and Psychiatry), School of Medicine, University of Cádiz, Plaza Fragela 9, 11003 Cádiz, Spain. E-mail: juanantonio.mico{at}uca.es