The Effects of Eating a High Fat Diet on Sensitivity of Male and Female Rats to Methamphetamine and Dopamine D1 Receptor Agonist SKF 82958

Rats eating high fat chow are more sensitive to the behavioral effects of dopaminergic drugs, including methamphetamine and the dopamine D-2/D-3 receptor agonist quinpirole, than rats eating standard chow. However, limited work has explored possible sex differences regarding the impact of diet on drug sensitivity. It is also unknown whether eating high fat chow enhances sensitivity of rats to other dopamine (e.g., D-1) receptor agonists. To explore these possibilities, male and female Sprague-Dawley rats eating standard laboratory chow (17% kcal from fat) or high fat chow (60% kcal from fat) were tested once per week for 6 weeks with dopamine D-1 receptor agonist SKF 82958 (0.013.2 mg/kg) or methamphetamine (0.1-3.2 mg/kg) using cumulative dosing procedures. Eating high fat chow increased sensitivity of male and female rats to methamphetamine-induced locomotion; however, only female rats eating high fat chow were more sensitive to SKF 82958-induced locomotion. SKF 82958-induced eye blinking was also marginally, although not significantly, enhanced among female rats eating high fat chow, but not males. Further, although dopamine D-2 receptor expression was significantly increased for SKF 82958-treated rats eating high fat chow regardless of sex, no differences were observed in dopamine D-1 receptor expression. Taken together, the present study suggests that although eating high fat chow enhances sensitivity of both sexes to dopaminergic drugs, the mechanism driving this effect might be different for males versus females. These data further demonstrate the importance of studying both sexes simultaneously when investigating factors that influence drug sensitivity. SIGNIFICANCE STATEMENT Although it is known that diet can impact sensitivity to some dopaminergic drugs, sex differences regarding this effect are not well characterized. This report demonstrates that eating a high fat diet enhances sensitivity to methamphetamine, regardless of sex; however, sensitivity to dopamine D-1 receptor agonist SKF 82958 is increased only among females eating high fat chow, but not males. This suggests that the mechanism(s) driving diet-induced changes in drug sensitivity might be different between sexes.