Sterol carrier protein 2 loss reduces anxiety and enhances fear extinction.

Brain endocannabinoid (eCB) signaling, which includes CB1 cannabinoid receptors (CB1R) and the eCBs N-arachidonoylethanolamine (AEA) and 2-arachidonoylglycerol (2-AG), modulates behavioral responses to stress and fear extinction. Sterol carrier protein 2 (SCP-2) is an intracellular lipid binding protein expressed in brain that binds AEA and 2-AG at nanomolar concentrations and facilitates their cellular accumulation. SCP-2 mRNA is present in mouse limbic brain regions and is increased in the prefrontal cortex (PFC) and amygdalar complex in mice with impaired (129S1/Sv1mJ) fear extinction compared to mice with normal (C57BL/6J) fear extinction. In this study, we utilized mice with deletion of the gene for SCP-2 and an overlapping gene, SCP-X (SCP-2/X-/-), to examine the hypothesis that SCP-2 regulates behaviors associated with anxiety and fear. Compared to WT mice, SCP-2/X-/- mice exhibit enhanced fear extinction and reduced anxiety-driven behaviors in the elevated plus maze. These differences are abrogated by treatment with a CB1R antagonist and not recapitulated in mice with selective deletion of SCP-X. While baseline brain tissue concentrations of AEA and 2-AG are not different between WT and SCP-2/X-/- mice, amygdalar and PFC 2-AG concentrations are significantly higher in SCP-2/X-/- mice 24 h following foot shock. There are no differences between WT and SCP-2/X-/- mice in rectal temperature; or in tail flick and catalepsy assays. These findings support the hypothesis that as yet unproven functions of the lipid carrier protein SCP-2 regulate behaviors associated with fear memory and anxiety and suggest that pharmacological inhibitors of SCP-2 could reduce acute anxiety and enhance fear extinction.