Fluoxetine Facilitates Fear Extinction Through Amygdala Endocannabinoids

摘要: Pharmacologically elevating brain endocannabinoids (eCBs) share anxiolytic and fear extinction-facilitating properties with classical therapeutics, including the selective serotonin reuptake inhibitor, fluoxetine. There are also known functional interactions between eCB systems preliminary evidence that antidepressants cause alterations in eCBs. However, potential role of eCBs mediating facilitatory effects fluoxetine on extinction has not been established. Here, to test for a possible mechanistic contribution fluoxetine's proextinction effects, we integrated biochemical, electrophysiological, pharmacological, behavioral techniques, using extinction-impaired 129S1/Sv1mJ mouse strain. Chronic treatment produced significant increase levels anandamide BLA, an associated decrease activity anandamide-catabolizing enzyme, fatty acid amide hydrolase. Slice electrophysiological recordings showed fluoxetine-induced increases were amplification eCB-mediated tonic constraint inhibitory, but excitatory, transmission BLA. Behaviorally, chronic facilitated retrieval manner was prevented by systemic or BLA-specific blockade CB1 receptors. In contrast fluoxetine, citalopram did BLA facilitate extinction. Taken together, these findings reveal novel, obligatory amygdala major pharmacotherapy trauma- stressor-related disorders anxiety disorders.