Cholesterol 24-hydroxylase overexpression in the dorsal striatum reduces relapse to cocaine-seeking

Sparse but converging evidence suggests that drug addiction is associated with alterations in the metabolism of cerebral cholesterol. Furthermore, in rats, administration of statins, inhibitors of cholesterol synthesis, reduces risks of relapse to cocaine. However, the direct involvement of brain cholesterol in addiction-related processes remains to be demonstrated. In this study, we investigated whether manipulation of cholesterol metabolism in the dorsal striatum during abstinence could reduce drug-seeking in rats that had self-administered cocaine. To this end, we used a viral approach to overexpress the CYP46A1 gene, that encodes cholesterol 24-hydroxylase, the main enzyme responsible for brain cholesterol catabolism, in the dorsal striatum and after 6 weeks we measured drug-seeking behavior. We found that striatal CYP46A1 overexpression reduces cocaine-seeking but does not affect seeking for natural rewards or the direct reinforcing effects of cocaine. Interestingly, we found that CYP46A1 overexpression increases cholesterol turnover without altering cholesterol levels whereas cocaine exposure did not alter either of these measures. These results suggest that cholesterol metabolism in the dorsal striatum might represent a novel therapeutic target to prevent relapse to cocaine addiction.