LeDoux Lab 2010 SfN Abstracts
 
Program#/Poster#: 914.24/MMM40
Title: Agomelatine reduces long term memory but not acquisition or short term expression of fear memories
Location: Halls B-H
Presentation Time: Wednesday, Nov 17, 2010, 4:00 PM - 5:00 PM
Authors: *L. DIAZ-MATAIX1, E. MOCAËR2, L. SEGUIN2, J. E. LEDOUX1,3;
1Ctr. for Neural Sci., New York Univ., NEW YORK, NY; 2Inst. de Recherches Internationales Servier, Courbevoie, France; 3Emotional Brain Inst., Nathan S. Kline Inst. for Psychiatric Res., Orangeburg, NY
Abstract: Affective disorders may arise as a consequence of alterations in fear learning processes. Fear learning has been investigated with Pavlovian classical fear conditioning paradigms, which consist of pairing a neutral conditioned stimulus (CS), such as a tone, with an aversive unconditioned stimulus, such as a footshock. Upon subsequent exposure, the CS is then perceived as aversive and provokes a fear response. Considerable evidence indicates that circuits involving the amygdala play an important role in fear conditioning, and this brain region that has also been implicated in a variety of anxiety disorders. Fear conditioning may therefore be a useful paradigm for studying the mechanism of action of psychiatric drugs that affect emotional processing.
Agomelatine induces antidepressant-like effects in several animal models and clinical studies demonstrated its efficacy in major depressive disorder. This antidepressant acts through a unique mechanism of action, that is, it functions as a melatonergic receptor agonist and a 5-HT2C receptor antagonist, and has anxiolytic properties. 5-HT2C and melatonin receptors, known to be highly expressed in the supraschiasmatic nucleus, are also highly expressed in the amygdala, an area implicated in fear circuitry. These facts suggest that studies of the effects of agomelatine on fear conditioning may be relevant to understanding the mechanisms of action in relieving emotional distress. The aim of this study was thus to determine how acute agomelatine treatment might differentially alter fear circuits by using auditory fear conditioning as a means of accessing this circuitry in the rat.
A single pre-training injection of agomelatine (40 mg/kg intraperitoneally) significantly reduced freezing to the fear arousing CS 24 hours after training but not during training or 3 hours after training. This pattern of results (unimpaired acquisition and STM, and impaired LTM) is consistent with an effect on the consolidation of the fear memory. A single pre-testing injection of agomelatine had no effect on conditioned fear expression. Agomelatine thus appears to disrupt the formation of LTM about fear arousing situations.
These effects on fear conditioning should be considered in relation to the antidepressant action of agomelatine. When compared to other antidepressants, agomelatine achieved a reduction of fear conditioning in a single dose by acting especially on fear memory consolidation, while the classical SSRI citalopram only reduced fear conditioning after chronic treatment. This finding is somewhat consistent with clinical studies that suggest a faster onset of action of agomelatine than classical SSRI treatment.