Antidepressant treatment inhibits fear via brain endocannabinoids

Monday, September 22, 2014 — Poster Session I
12:00 p.m. – 2:00 p.m.	FAES Academic Center	NIAAA	NEURO-8

* FARE Award Winner

Authors

• O. Gunduz-Cinar
• S. Flynn
• R. Cinar
• T. Ramikie
• S. Patel
• G. Kunos
• A. Holmes

Abstract

Endocannabinoids modulate the effects of stress and traumatic experience on brain function and fear behaviors. Augmenting endocannabinoid anandamide, via inhibition of the catabolic enzyme fatty acid amide hydrolase (FAAH), facilitates learned inhibition of fear in mice via CB1 receptors. Interestingly, recent studies demonstrate that chronic treatment with selective serotonin reuptake inhibitor (SSRI) fluoxetine, first-line therapeutic treatment for many anxiety and stress-related neuropsychiatric conditions, facilitates fear extinction and promotes amygdala plasticity in a similar manner to FAAH inhibitors. However, it’s currently unclear whether effects of fluoxetine on fear extinction involve functional interactions with endocannabinoids. To investigate this, we first assessed the effect of chronic fluoxetine treatment on endocannabinoids levels in brain. This revealed a significant elevation in anandamide levels in basolateral amygdala, dorsal striatum and dorsal hippocampus. We next tested whether increased anandamide levels mediated extinction-facilitation effects by blocking CB1 receptors (using the antagonist Rimonabant). Both systemic and intraamygdala microinjections of Rimonabant abolished the extinction-facilitation effects of fluoxetine. Future experiments will examine the effects of fluoxetine on CB1 receptor-mediated synaptic plasticity in basolateral amygdala, and identify key downstream signaling pathways. Altogether, these findings demonstrate a novel, obligatory role for endocannabinoids in fear inhibiting effects of a major pharmacotherapy for anxiety disorders.

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