Eating a High Fat Diet Enhances Sensitivity of Rats to Serotonin Syndrome

Abstract

Drugs that act on serotonin (5-HT) systems are important for the treatment of many conditions, including anxiety, depression, and obesity. One potential adverse effect of these drugs is the development of 5-HT syndrome. Animal models of 5-HT syndrome include lower lip retraction, flat body posture, and forepaw treading. Diet (e.g., type and amount of food consumed) has been shown to directly impact sensitivity of rats to 5-HT syndrome. For example, eating high fat chow increases sensitivity of rats to 5-HT1A receptor agonist 8-OH-DPAT-induced lower lip retraction; however, it is not known if eating high fat chow also impacts sensitivity of rats to other 5-HT syndrome behaviors, other 5-HT receptor agonists (e.g., 5-HT2C receptor agonists), or if these effects are different among females as compared to males. To test the hypothesis that eating high fat chow enhances the sensitivity of rats to 5-HT syndrome, male and female rats eating high fat (60% kcal from fat) or standard (17% kcal from fat) chow were tested once weekly with cumulative doses of 8-OH-DPAT (0.01-1.0 mg/kg, s.c.), and two different 5-HT2C receptor agonists (lorcaserin [1.0-32.0 mg/kg, i.p.], and WAY 163909 [1.0-32.0 mg/kg, i.p.]). Both lorcaserin and WAY 163909 induced forepaw treading in male and female rats. After 5 weeks, 3-way partially repeated measures ANOVAs and Bonferroni's post hoc multiple comparisons tests revealed that forepaw treading induced by both drugs was enhanced among rats eating high fat chow. Eating high fat chow enhanced sensitivity of male rats to lorcaserin-induced forepaw treading to a greater extent than in females. However, eating high fat chow enhanced sensitivity of females to WAY 163909-induced forepaw treading to a greater extent than in males. 8-OH-DPAT-induced lower lip retraction, flat body posture, and forepaw treading in male and female rats. 8-OH-DPAT induced more lower lip retraction among male rats than female rats, and more lower lip retraction among rats eating high fat chow (in both sexes) than rats eating standard chow. Additionally, 8-OH-DPAT induced more flat body posture among male rats than female rats. These results suggest that sex and dietary history (e.g., patients diagnosed with obesity) could influence sensitivity to therapeutic and adverse effects of serotonergic drugs.