Genetic Deletion of Sterol Carrier Protein 2 Selectively Enhances Amygdalar Endocannabinoid Signaling

Abstract

Sterol carrier protein 2 (SCP-2) is an intracellular lipid transport protein that transports cholesterol, fatty acids and the endocannabinoids (eCBs). Cellular accumulation of the eCBs contributes to inactivation of endocannabinoid signaling (ECS); and we have shown that SCP-2 can facilitate this process. These data lead to the hypothesis that reduction of SCP-2 enhances ECS through increased ligand availability. SCP-2 is expressed in the amygdala, where CB1 cannabinoid receptor (CB1R) signaling regulates extinction of fear. SCP-2 KO mice indeed exhibit enhanced extinction of fear, and this enhancement is reversed by CB1R blockade. However, concentrations of the eCBs anandamide and 2-arachidonoylglycerol (2-AG) were not greater in SCP-2 KO amygdala; in fact, 2-AG concentrations were significantly less than wild type. On the other hand, amygdalar CB1R mRNA expression and binding site density were both significantly increased in the SCP-2 KO mice compared to wild type, suggesting that the hypercannabinergic phenotype is the result of increased CB1R rather than eCB ligand. CB1R expression and binding site density were not increased in hippocampus, prefrontal cortex and cerebellum. These findings suggest that reduced SCP-2 function results in enhanced CB1R expression in the amygdala through an as-yet unknown mechanism. These data have relevance for discovery of processes by which CB1R function can be selectively enhanced in the CNS. Supported by R01 DA09155 and the Advancing a Healthier Wisconsin Endowment at the Medical College of Wisconsin.