Fluoxetine Facilitates Fear Extinction Through Amygdala Endocannabinoids

Abstract

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.

Interactions Between Anandamide and Corticotropin-Releasing Factor Signaling Modulate Human Amygdala Function and Risk for Anxiety Disorders: An Imaging Genetics Strategy for Modeling Molecular Interactions

“…We focused on amygdala habituation, as opposed to activity, in light of evidence that reductions in amygdala activation are associated with successful fear extinction (20, 21), and that decreased amygdala habituation is associated with psychopathology characterized by anxiety and excessive fear (22–25). A focus on habituation is further consistent with knockout and pharmacologic manipulation studies in rodents suggesting that eCB signaling is critical for fear extinction, but not conditioning (1, 4, 26), and prior evidence that genetic variation in the eCB system is associated with amygdala habituation in humans (1, 27). …”

Administration of moclobemide facilitates fear extinction and attenuates anxiety‐like behaviors by regulating synaptic‐associated proteins in a rat model of post‐traumatic stress disorder

“…The results of the behavioral test showed that early intervention with Moc could facilitate the extinction of fear induced by SPS. Results that are quite similar have been reported in previous research, which showed that some antidepressant drugs could restore fear memory to control levels and facilitates fear extinction in stressed rats, and vortioxetine (Hatherall, Sanchez, & Morilak, ) and fluoxetine (Gunduz‐Cinar et al, ) included. Fear extinction is a process of creating a new retreating memory by learning.…”

Inhibition of serotonin transporters disrupts the enhancement of fear memory extinction by 3,4-methylenedioxymethamphetamine (MDMA)

“…While citalopram treatment itself selectively increases extracellular 5-HT in the brain (Balu et al 2013), we and others have observed that neither acute nor chronic treatment with citalopram enhances fear memory extinction (Burghardt et al 2013; Gunduz-Cinar et al 2016). Even more strikingly, acute treatment with fenfluramine, which potently releases 5-HT through the 5-HTT (Crespi et al 1997), did not enhance fear memory extinction on its own in our study.…”

“…Even more strikingly, acute treatment with fenfluramine, which potently releases 5-HT through the 5-HTT (Crespi et al 1997), did not enhance fear memory extinction on its own in our study. On the other hand, SSRIs that have significant binding affinity at other monoamine transporters can enhance fear extinction in rodents when chronically administered between fear conditioning and extinction training (Gunduz-Cinar et al 2016; Karpova et al 2011). While disrupting MDMA's access to 5-HTTs with the highly-selective SSRI citalopram (Sanchez and Hyttel 1999) actually blocked MDMA-induced extinction enhancement, the fact that drugs that specifically increase 5-HT do not improve extinction suggest the requirement of pharmacodynamic mechanisms beyond acute 5-HT release are required.…”