title: 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.
authors.affiliation: Laboratory of Behavioral and Genomic Neuroscience, National Institute on Alcohol Abuse and Alcoholism (NIAAA), National Institutes of Health (NIH), Bethesda, MD, USA.
authors.forename: Ozge
authors.initials: O
authors.lastname: Gunduz-Cinar
authors.affiliation: Laboratory of Behavioral and Genomic Neuroscience, National Institute on Alcohol Abuse and Alcoholism (NIAAA), National Institutes of Health (NIH), Bethesda, MD, USA.
authors.forename: Shaun
authors.initials: S
authors.lastname: Flynn
authors.affiliation: Laboratory of Behavioral and Genomic Neuroscience, National Institute on Alcohol Abuse and Alcoholism (NIAAA), National Institutes of Health (NIH), Bethesda, MD, USA.
authors.forename: Emma
authors.initials: E
authors.lastname: Brockway
authors.affiliation: Laboratory of Behavioral and Genomic Neuroscience, National Institute on Alcohol Abuse and Alcoholism (NIAAA), National Institutes of Health (NIH), Bethesda, MD, USA.
authors.forename: Katherine
authors.initials: K
authors.lastname: Kaugars
authors.affiliation: Department of Psychiatry and Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Rita
authors.initials: R
authors.lastname: Baldi
authors.affiliation: Department of Psychiatry and Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Teniel S
authors.initials: TS
authors.lastname: Ramikie
authors.affiliation: Laboratory of Physiological Studies, NIAAA, NIH, Bethesda, MD, USA.
authors.forename: Resat
authors.identifier: http://orcid.org/0000-0002-8597-7253
authors.initials: R
authors.lastname: Cinar
authors.affiliation: Laboratory of Physiological Studies, NIAAA, NIH, Bethesda, MD, USA.
authors.forename: George
authors.initials: G
authors.lastname: Kunos
authors.affiliation: Department of Psychiatry and Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Sachin
authors.initials: S
authors.lastname: Patel
authors.affiliation: Laboratory of Behavioral and Genomic Neuroscience, National Institute on Alcohol Abuse and Alcoholism (NIAAA), National Institutes of Health (NIH), Bethesda, MD, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Holmes
mesh_terms: D000581:Amidohydrolases / Q000378:metabolism; D000679:Amygdala / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D001095:Arachidonic Acids / Q000032:analysis / Q000502:physiology; D063388:Endocannabinoids / Q000032:analysis / Q000502:physiology*; D005108:Extinction, Psychological / Q000187:drug effects*; D005239:Fear / Q000187:drug effects*; D005473:Fluoxetine / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D053284:Polyunsaturated Alkamides / Q000032:analysis; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D014151:Anti-Anxiety Agents; D001095:Arachidonic Acids; D063388:Endocannabinoids; D005473:Fluoxetine; D053284:Polyunsaturated Alkamides; D000099252:Fatty Acid Amide Hydrolases; C078814:anandamide