5-HT2C receptors in the BNST are necessary for the enhancement of fear learning by selective serotonin reuptake inhibitors

•BNST inactivation does not impair acquisition of cued or context fear conditioning.•SSRI injections enhance cued fear conditioning and Arc expression in the BNST.•The majority of these Arc expressing neurons express 5-HT2C receptors.•BNST infusions of 5-HT2C receptor antagonists block the effects of SSRIs on cued fear.

Selective serotonin reuptake inhibitors (SSRIs) are widely prescribed to treat anxiety and depression, yet they paradoxically increase anxiety during initial treatment. Acute administration of these drugs prior to learning can also enhance Pavlovian cued fear conditioning. This potentiation has been previously reported to depend upon the bed nucleus of the stria terminalis (BNST). Here, using temporary inactivation, we confirmed that the BNST is not necessary for the acquisition of cued or contextual fear memory. Systemic administration of the SSRI citalopram prior to fear conditioning led to an upregulation of the immediate early gene Arc (activity-regulated cytoskeleton-associated protein) in the oval nucleus of the BNST, and a majority of these neurons expressed the 5-HT2C receptor. Finally, local infusions of a 5-HT2C receptor antagonist directly into the oval nucleus of the BNST prevented the fear memory-enhancing effects of citalopram. These findings highlight the ability of the BNST circuitry to be recruited into gating fear and anxiety-like behaviors.