title: Effects of venlafaxine on extracellular concentrations of 5-HT and noradrenaline in the rat frontal cortex: augmentation via 5-HT1A receptor antagonism.
abstract: 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 a 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-adrenergic/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 alpha1 and alpha2-adrenoceptor antagonists, prazosin and idazoxane, we also demonstrate the role of the alpha-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.
authors.affiliation: CNS Disorders, Wyeth-Ayerst Research, Princeton, NJ 08543-8000, USA. dawsonl@war.wyeth.com
authors.forename: L A
authors.initials: LA
authors.lastname: Dawson
authors.forename: H Q
authors.initials: HQ
authors.lastname: Nguyen
authors.forename: A
authors.initials: A
authors.lastname: Geiger
mesh_terms: D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D002540:Cerebral Cortex / Q000737:chemistry / Q000187:drug effects*; D003511:Cyclohexanols / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D019329:Idazoxan / Q000494:pharmacology; D008297:Male; D009638:Norepinephrine / Q000378:metabolism*; D010069:Oxadiazoles / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D011224:Prazosin / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000187:drug effects*; D044263:Receptors, Serotonin, 5-HT1; D012701:Serotonin / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000494:pharmacology; D017367:Selective Serotonin Reuptake Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D000069470:Venlafaxine Hydrochloride
chemical_list: D000317:Adrenergic alpha-Antagonists; D003511:Cyclohexanols; D019329:Idazoxan; D009638:Norepinephrine; D010069:Oxadiazoles; D010879:Piperazines; D011224:Prazosin; D011725:Pyridines; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D012701:Serotonin; D012702:Serotonin Antagonists; D017367:Selective Serotonin Reuptake Inhibitors; D000069470:Venlafaxine Hydrochloride; C090701:GR 127935; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide