Research article summary (published 3 Feb 2008):

Inhibition of uptake 2 (or extraneuronal monoamine transporter) by normetanephrine potentiates the neurochemical effects of venlafaxine.

Full Abstract

Two distinct norepinephrine (NE) transporter mechanisms (uptake 1 and uptake 2) regulate extracellular NE concentrations. An association has been observed between the gradual improvement in patients treated with antidepressants that inhibit the NE transporter (NET/uptake 1) and increases in urinary normetanephrine, the O-methylated NE metabolite and potent inhibitor of uptake 2. These observations led to the hypothesis that increased levels of normetanephrine, and consequently inhibition of uptake 2, may partly be responsible for the clinical efficacy of some antidepressants. To investigate this hypothesis, we employed microdialysis techniques in the rat frontal cortex to monitor extracellular changes in normetanephrine following chronic administration of the clinically effective antidepressant, venlafaxine (a serotonin (5-HT) and NE reuptake inhibitor). We evaluated the neurochemical effects of inhibiting uptake 2 alone, or in conjunction with venlafaxine, on extracellular levels of NE and 5-HT. Chronic venlafaxine administration (14 days, 10 mg/kg, s.c.) elicited significant increases in cortical NE and 5-HT while producing a non-significant trend to increase cortical levels of normetanephrine. Additional studies revealed that combining normetanephrine with venlafaxine (10 mg/kg, i.p.), at a dose of normetanephrine (10 mg/kg, i.p.) that did not produce changes in extracellular levels of NE on its own, potentiated antidepressant-induced increases in extracellular NE. We also report mouse behavioral data involving the tail suspension test that complement the neurochemical observations. These preclinical findings, taken together, suggest that inhibiting both uptake 1 and uptake 2 via venlafaxine and normetanephrine, respectively, elicits a greater increase in cortical levels of NE than inhibiting either transporter alone.

Author information

Author/s: Rahman, Zia (Z); Ring, Robert H (RH); Young, Kimberly (K); Platt, Brian (B); Lin, Qian (Q); Schechter, Lee E (LE); Rosenzweig-Lipson, Sharon (S); Beyer, Chad E (CE);

Affiliation: Wyeth Research, Discovery Neuroscience, Depression and Anxiety Disorders, CN 8000, Princeton, NJ 08543-8000, USA. rahmanz(-atsign-)wyeth.com

Journal and publication information

Publication Type: Journal Article

Journal: Brain research (Brain Res), published in Netherlands. (Language: eng)

Reference: 2008-Apr; vol 1203 (issue ) : pp 68-78

Dates: Created 2008/03/31; Completed 2008/08/01;

PMID: 18321472, status: MEDLINE (last retrieval date: 2/18/2009, IMS Date: )

Sourced from the National Library of Medicine. Abstract text and other information may be subject to copyright.

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MeSH headings (categories)

This article was linked to the MESH Headings shown below.

Animals Behavior, Animal - drug effects Brain Chemistry - drug effects Cyclohexanols - pharmacology Dose-Response Relationship, Drug Drug Administration Schedule Extracellular Fluid - drug effects; metabolism Frontal Lobe - drug effects; metabolism Hindlimb Suspension - methods

Immobility Response, Tonic - drug effects Male Microdialysis Norepinephrine - metabolism Normetanephrine - metabolism; pharmacology Rats Rats, Sprague-Dawley Serotonin - metabolism Serotonin Uptake Inhibitors - pharmacology

Associated Chemicals: Cyclohexanols (0) ; Serotonin Uptake Inhibitors (0) ; Serotonin (50-67-9) ; Norepinephrine (51-41-2) ; venlafaxine (93413-69-5) ; Normetanephrine (97-31-4)

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