Amygdala endocannabinoids are essential for the extinction facilitating actions of chronic fluoxetine

Authors

• O Gunduz-Cinar
• S Flynn
• K Kaugars
• R Cinar
• TS Ramikie
• S Patel
• G Kunos
• A Holmes

Abstract

Endocannabinoids are neuromodulators crucial for protection and recovery from stress and traumatic experiences. Augmenting endocannabinoid anandamide, via inhibition of the catabolic enzyme fatty acid amide hydrolase (FAAH), facilitates the learned inhibition of fear (i.e. extinction) in mice. This effect is mediated via CB1 receptors in basolateral amygdala and is associated with facilitation of synaptic plasticity (long-term depression of inhibitory transmission). Similarly chronic treatment with the selective serotonin reuptake inhibitor (SSRI) fluoxetine, facilitates fear extinction and promotes amygdala. It’s currently unclear whether fluoxetine’s effects on fear extinction involve functional interactions with endocannabinoids. To investigate this, we first evaluated changes in endocannabinoids in basolateral amygdala and other extinction-mediating brain regions following chronic fluoxetine. This revealed a significant elevation in levels of the endocannabinoid anandamide in the basolateral amygdala as well as dorsal striatum and dorsal hippocampus. We next tested whether the increased endocannabinoid tone after fluoxetine mediated the drug’s extinction-facilitation effects by blocking CB1 receptors, via rimonabant, either systemically or only in the basolateral amygdala. Both systemic and intra-amygdala rimonabant blocked the extinction-facilitation effects of fluoxetine. Subsequent electrophysiological studies revealed that CB1 receptor-dependent tonic suppression of inhibitory transmission after chronic fluoxetine treatment is significantly augmented. Interestingly, chronic treatment with a more selective SSRI, citalopram, was not able to alter the endocannabinoids neither in the basolateral amygdala nor in any other region moreover citalopram treatment did not facilitate extinction. Altogether these findings demonstrate a novel, obligatory role for endocannabinoids in the fear inhibiting effects of a major pharmacotherapy for anxiety disorders.

Scientific Focus Area: Neuroscience

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