The International Journal of Neuropsychopharmacology

Research Article

The antidepressant agomelatine blocks the adverse effects of stress on memory and enables spatial learning to rapidly increase neural cell adhesion molecule (NCAM) expression in the hippocampus of rats

Lisa Conboya1 c1, Cihan Tanrikuta1, Phillip R. Zoladza2a4a6, Adam M. Campbella5, Collin R. Parka2a4a6, Cecilia Gabriela7, Elisabeth Mocaera7, Carmen Sandia1 and David M. Diamonda2a3a4a6

a1 Laboratory of Behavioural Genetics, Brain Mind Institute, EPFL, Lausanne, Switzerland

a2 Medical Research, VA Hospital, Tampa, FL, USA

a3 Department of Psychology, University of South Florida, Tampa, FL, USA

a4 Department of Molecular Pharmacology and Physiology, University of South Florida, Tampa, FL, USA

a5 Department of Psychiatry and Behavioral Medicine, University of South Florida, Tampa, FL, USA

a6 Center for Preclinical and Clinical Research on PTSD, University of South Florida, Tampa, FL, USA

a7 IRIS, Courbevoie, France

Abstract

Agomelatine, a novel antidepressant with established clinical efficacy, acts as a melatonin receptor agonist and 5-HT2C receptor antagonist. As stress is a significant risk factor in the development of depression, we sought to determine if chronic agomelatine treatment would block the stress-induced impairment of memory in rats trained in the radial-arm water maze (RAWM), a hippocampus-dependent spatial memory task. Moreover, since neural cell adhesion molecule (NCAM) is known to be critically involved in memory consolidation and synaptic plasticity, we evaluated the effects of agomelatine on NCAM, and polysialylated NCAM (PSA-NCAM) expression in rats given spatial memory training with or without predator stress. Adult male rats were pre-treated with agomelatine (10 mg/kg i.p., daily for 22 d), followed by a single day of RAWM training and memory testing. Rats were given 12 training trials and then they were placed either in their home cages (no stress) or near a cat (predator stress). Thirty minutes later the rats were given a memory test trial followed immediately by brain extraction. We found that: (1) agomelatine blocked the predator stress-induced impairment of spatial memory; (2) agomelatine-treated stressed, as well as non-stressed, rats exhibited a rapid training-induced increase in the expression of synaptic NCAM in the ventral hippocampus; and (3) agomelatine treatment blocked the water-maze training-induced decrease in PSA-NCAM levels in both stressed and non-stressed animals. This work provides novel observations which indicate that agomelatine blocks the adverse effects of stress on hippocampus-dependent memory and activates molecular mechanisms of memory storage in response to a learning experience.

(Received April 25 2008)

(Reviewed June 13 2008)

(Revised June 26 2008)

(Accepted July 10 2008)

(Online publication August 18 2008)

Correspondence:

c1 Address for correspondence: Dr L. Conboy, Laboratory of Behavioural Genetics, Brain Mind Institute, Swiss Federal Institute of Technology, CH-1015 Lausanne, Switzerland. Tel.: +41 21 693 16 75 Fax: +41 21 693 96 37 E-mail: Lisa.Conboy@epfl.ch

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