Oral Presentation The International Congress of Neuroendocrinology 2014

The glutamatergic basis of anxious/depressive-like behavior in prenatally stressed rats (#85)

Jordan Marrocco 1 , Marie-Line Reynaert 1 , Eleonora Gatta 1 , Cecilia Gabriel 2 , Elisabeth Mocaër 2 , Anna Pittaluga 3 , Ferdinando Nicoletti 4 , Stefania Maccari 1 , Sara Morley-Fletcher 1 , Jérôme Mairesse 1
  1. Université Lille 1/CNRS, Villeneuve D'Ascq, France
  2. Insitutes de Recherches Internationales Servier, Suresnes, France
  3. Dept. of Pharmacy, University of Genoa, Genoa, Italy
  4. Dep. of Physiology and Pharmacology, Sapienza University of Rome, Rome, Italy

Abnormalities of synaptic transmission in the hippocampus represent an integral part of the altered programming triggered by early life stress, which enhances the vulnerability to stress-related disorders in the adult life. Prenatally restraint stressed (PRS) rats develop long-lasting biochemical and behavioral changes, which are the expression of an anxious/depressive-like phenotype. Most neurochemical abnormalities in PRS rats are found in the ventral hippocampus, a region that encodes memories related to stress and emotions.

We report that PRS rats showed a selective impairment of depolarization-stimulated glutamate release in the ventral hippocampus (VH), associated with large reductions in the levels of synaptic vesicle-related proteins, such as VAMP (synaptobrevin), syntaxin-1, synaptophysin, synapsin Ia/b and IIa, munc-18, and Rab3A. Interestingly, anxiety-like behavior in male PRS (and control) rats was inversely related to the extent of depolarization-evoked glutamate release in the VH. We were able to show that intracerebral injections in the VH of drugs aimed at enhancing glutamate release (i.e. a cocktail containing the mGlu2/3 receptor antagonist, LY341495, and the GABAB receptor antagonist, CGP52432) have strong anxiolytic activity in PRS rats. Also, chronic treatment with two antidepressants (agomelatine 40 mg/kg; fluoxetine 5 mg/kg; 21 days i.p.) could correct the defect in glutamate release and associated behavioral and synaptic abnormalities in the VH of PRS rats. Remarkably, the effect of antidepressants on glutamate release was strongly correlated with the improvement of anxiety-like behavior in PRS rats.

These data confer pharmacological validity to the glutamatergic hypothesis of stress-related disorders and lay the groundwork to novel attractive pharmacological strategies to treat anxiety and depression.