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Fluoxetine Facilitates Fear Extinction Through Amygdala Endocannabinoids
#MMPMID26514583
Gunduz-Cinar O
; Flynn S
; Brockway E
; Kaugars K
; Baldi R
; Ramikie TS
; Cinar R
; Kunos G
; Patel S
; Holmes A
Neuropsychopharmacology
2016[May]; 41
(6
): 1598-609
PMID26514583
show ga
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 the eCB and serotonin systems and preliminary
evidence that antidepressants cause alterations in brain eCBs. However, the
potential role of eCBs in mediating the facilitatory effects of fluoxetine on
fear extinction has not been established. Here, to test for a possible
mechanistic contribution of eCBs to fluoxetine's proextinction effects, we
integrated biochemical, electrophysiological, pharmacological, and behavioral
techniques, using the extinction-impaired 129S1/Sv1mJ mouse strain. Chronic
fluoxetine treatment produced a significant and selective increase in levels of
anandamide in the BLA, and an associated decrease in activity of the
anandamide-catabolizing enzyme, fatty acid amide hydrolase. Slice
electrophysiological recordings showed that fluoxetine-induced increases in
anandamide were associated with the amplification of eCB-mediated tonic
constraint of inhibitory, but not excitatory, transmission in the BLA.
Behaviorally, chronic fluoxetine facilitated extinction retrieval in a manner
that was prevented by systemic or BLA-specific blockade of CB1 receptors. In
contrast to fluoxetine, citalopram treatment did not increase BLA eCBs or
facilitate extinction. Taken together, these findings reveal a novel, obligatory
role for amygdala eCBs in the proextinction effects of a major pharmacotherapy
for trauma- and stressor-related disorders and anxiety disorders.
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