Exposure to a high-fat diet decreases sensitivity to Δ9-tetrahydrocannabinol-induced motor effects in female rats

Arachidonic acid, a fatty acid component of neuronal cell membranes, forms the backbone of endogenous ligands of the endocannabinoid system. The lipid nature of this system may make it particularly susceptible to changes in fat content of the diet, which may, in turn, affect endocannabinoid tone and subsequent changes in receptor expression or activity. The latter would also be expected to affect responses to exogenous cannabinoids. The purpose of the present study was to determine the effects of a high-fat diet on sensitivity to the pharmacological effects of Δ⁹-tetrahydrocannabinol (Δ⁹-THC). Male and female Long-Evans rats were fed either a diet of standard rodent chow or chow enhanced with corn oil. Subsequently, they were repeatedly assessed for Δ⁹-THC-induced hypomobility, catalepsy and hypothermia. Female rats that received the high-fat diet beginning in adolescence or in adulthood became significantly less sensitive to the effects of Δ⁹-THC on motor behavior, but not its hypothermic effects, with faster development of decreased sensitivity in female rats that began the high-fat diet as adults. In contrast, diet-induced differences either did not occur, or were less pronounced, in male rats of both ages. After acute injection, brain and blood levels of Δ⁹-THC and its two primary metabolites were similar regardless of diet. Combined with the fact that diet differentially affected only some of the measures, these results suggest that pharmacokinetic differences cannot fully account for the effects of the high-fat diet on response to Δ⁹-THC. Further, these results suggest that dietary fat content may represent an important consideration in predicting the effects of marijuana in females.