LeDoux Lab 2012 SfN Abstracts |
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Program#/Poster#: | 603.06/EEE9 |
Title: | Agomelatine reduces fear long term memory but not acquisition or short term fear memories. Involvement of melatonergic and 5HT2C receptors |
Location: | Hall F-J |
Presentation Time: | Tuesday, Oct 16, 2012, 9:00 AM -10:00 AM |
Authors: | *L. DIAZ-MATAIX1,
E. MOCAER2, L. SEGUIN2, J. E. LEDOUX1,3;
1Ctr. for Neural Sci., New York Univ., NEW YORK, NY; 2Neuro-psychiatric Dept., I.R.I.S, Suresnes, France; 3Emotional Brain Inst., Nathan Kline Inst. for psychiatric research, Orangeburg, NY |
Abstract: | Alterations in fear learning
processes may be implicated in mood disorders. Fear learning has been investigated with Pavlovian fear conditioning paradigms, it which a conditioned stimulus (CS) is paired with an aversive unconditioned stimulus (US). Afterwards, CS exposure provokes a fear response. The novel antidepressant agomelatine is a melatonergic receptor agonist and a 5-HT2C receptor antagonist (1). Here we evaluate how acute agomelatine treatment might alter fear conditioning by using auditory fear conditioning in the rat as well as its mechanism of action. A single pre-training injection of agomelatine (40 mg/kg) significantly reduced freezing to the CS 24 hours after training but not during training or 3 hours after training. A single post-training or pre-testing injection of agomelatine had no effect on conditioned fear expression. This pattern of results is consistent with an agomelatine effect on the consolidation of the fear memory. Agomelatine did not block reconsolidation of fear memory. In order to characterize the mechanism of action of agomelatine in the consolidation of fear, a pre-training injection of melatonin (40 mg/kg) or the 5-HT2C antagonist, S32006, (10 mg/kg) was administered. Neither of the drugs had any effect in the consolidation of fear suggesting that the synergistic effect of both, melatonergic agonism and 5-HT2C antagonism, is necessary for this effect. In contrast an injection of S22153 (20 mg/kg.), a melatonergic antagonist, before the pre-training administration of agomelatine, prevented the decrease in the consolidation of fear induced by agomelatine showing a role of the melatonin receptors on this effect. Finally, agomelatine infused into the lateral amygdala before training induced a reduction in the consolidation of fear conditioning demonstrating that lateral amygdala is involved in the systemic effect of agomelatine. Globally these results suggest that the effects of agomelatine on fear conditioning should be related to its antidepressant/anxiolytic activity. Agomelatine acutely achieved a reduction of fear conditioning, while classical SSRIs only reduced fear conditioning after chronic treatment (2). A synergy between melatonergic agonist and 5HT2C antagonist properties seems to be involved in the reduction of the consolidation of fear conditioning in agreement with previous reports showing the same mechanism of action of agomelatine in alleviating depression in animal models (3). References (1) de Bodinat et al. Nat Rev Drug Discovery2010;9:628-642. (2) Burghardt et al. Biol Psychiatry 2004;55:1171-1178. (3) Racagni et al. World J Biol Psychiatry 2011;12:574-587. |
Support: | Sevier Laboratories |