Effects of venlafaxine on extracellular concentrations of 5-HT and noradrenaline in the rat frontal cortex:: augmentation via 5-HT1A receptor antagonism

Venlafaxine is a novel serotonin/noradrenaline reuptake inhibitor (SNRI) which has been shown clinically to be an effective antidepressant (AD) with a faster onset of action than serotonin specific reuptake inhibitors (SSRI). Preclinically, venlafaxine has been shown to potently inhibit dorsal raphe neuronal (DRN) firing through a 5-HT1A mediated mechanism, in st similar manner to SSRIs. Here we demonstrate the acute neurochemical effects of venlafaxine on extracellular concentrations of 5-HT and noradrenaline (NA) from the rat frontal cortex using in vivo microdialysis. Administration of venlafaxine (3-50 mg/kg s.c.) resulted in a significant dose-dependent increase in extracellular NA, but produced no significant increase in 5-HT concentrations. Combination treatment with the selective 5-HT1A antagonist WAY100635 produced a dose-dependent augmentation of venlafaxine-induced (3-30 mg/kg s.c) extracellular 5-HT concentrations, but had no further effect on NA above that produced by venlafaxine alone. WAY100635, at doses as low as 0.03 mg/kg s.c., maintained this potentiation effect. The beta-adnnergic/5-HT1A,, receptor antagonist (+/-)pindolol and the selective 5-HT1B/D antagonist GR127935 produced no significant augmentation of venlafaxine-induced changes in either 5-HT or NA. Using the alpha(1), and alpha(2)-adrenoceptor antagonists, prazosin and idazoxane, we also demonstrate the role of the cr-adrenoceptors in the augmentation of venlafaxine-induced changes. The possible mechanisms underlying venlafaxines improved clinical AD action and the potential for further enhancement of this SNRIs clinical effects are discussed. (C) 1999 Elsevier Science Ltd. All rights reserved.