Eating a high fat diet enhances sensitivity of rats to serotonin syndrome

Abstract

Eating a high fat diet can lead to obesity, type 2 diabetes, and dysfunction to neurotransmitter systems. For example, eating high fat chow enhances sensitivity of rats to unconditioned behavioral effects (e.g., lower lip retraction) induced by 8‐OH‐DPAT, a serotonin (5‐HT)1A receptor agonist. It is not known if eating high fat chow also impacts sensitivity of rats to other types of 5‐HT receptor agonists, or other behaviors induced by these drugs, collectively referred to as animal models of 5‐HT syndrome (e.g., flat body posture and forepaw treading). Recently, the FDA approved lorcaserin, a 5‐HT2C receptor agonist for the treatment of obesity. Lorcaserin induces some 5‐HT syndrome behaviors in rats including forepaw treading; however, it is not known if diet impacts sensitivity of rats to these lorcaserin‐induced behaviors. Further, previous research suggests that females might be more sensitive to the effects of 5‐HT receptor agonists, and to the effects of eating a high fat diet. To test the hypothesis that eating high fat chow will enhance the sensitivity of rats to the behavioral effects of 5‐HT2C and 5‐HT1A receptor agonists, 16 male and 16 female rats eating high fat chow (60% kcal from fat) or standard chow (17% kcal from fat) were tested once weekly with cumulative doses of 8‐OH‐DPAT (0.01–1.0 mg/kg, s.c.), WAY 163909 (1.0–32.0 mg/kg, i.p.), or lorcaserin (1.0–32.0 mg/kg, i.p.). 8‐OH‐DPAT induced lower lip retraction, flat body posture, and forepaw treading, while WAY 163909 and lorcaserin only induced forepaw treading. Rats eating high fat chow were more sensitive to lower lip retraction (induced by 8‐OH‐DPAT) and forepaw treading (induced by all three serotonergic drugs), as compared to male rats eating standard chow. These experiments are still ongoing; however, preliminary data and previous reports suggest that female rats will be more sensitive than males to diet‐induced enhancements in 5‐HT syndrome behaviors. Future directions will use selective 5‐HT receptor antagonists to examine the specific receptor subtypes mediating these behavioral effects in male and female rats eating different diets.Support or Funding InformationThe authors have no conflicts to disclose. N.M.B. was awarded summer funding through the American Society for Pharmacology and Experimental Therapeutics (ASPET) Summer Undergraduate Research Fellowship (SURF). N.M.B is also supported by the National Institute of General Medical Sciences of the National Institutes of Health (NIH) under R25GM069621.