Eating a High Fat Diet Enhances Sensitivity of Rats to 5‐HT1A Receptor‐Mediated Behavioral Effects of Serotonergic Drugs

Abstract

Diet (e.g., type and amount of food consumed) has been shown to impact drug sensitivity, in ways that might be relevant for the therapeutic effects and side effects of medications. For example, previous studies have demonstrated that rats eating a high fat diet are more sensitive to some of the effects of dopaminergic drugs. Considerably less is known about how eating a high fat diet might impact sensitivity to drugs that act on serotonin (5‐HT) systems, many of which might be beneficial for the treatment of obesity, since they can decrease feeding. Drugs with agonist effects at 5‐HT receptors can produce a collection of adverse effects, known as 5‐HT syndrome. Animal models of 5‐HT syndrome include lower lip retraction, flat body posture, penile erections, and forepaw treading. To test the hypothesis that eating a high fat diet enhances sensitivity of rats to 5‐HT syndrome, male (n=16) and female (n=16) rats eating high fat (60% kcal from fat) or standard (17% kcal from fat) laboratory chow were tested once weekly with cumulative doses of 5‐HT receptor agonists, including 8‐OH‐DPAT (0.01‐1.0 mg/kg, s.c.), lorcaserin (1.0‐32.0 mg/kg, i.p.) and WAY 163909 (1.0‐32.0 mg/kg, i.p.). Agonists were also studied in combination with antagonists selective for 5‐HT1A (WAY 100635; 0.178 mg/kg, s.c.), or 5‐HT2C (SB 242084; 1.0 mg/kg; i.p.) receptors. Food consumption and body weight were measured throughout the study. Results were analyzed using either two‐way or three‐way mixed model ANOVAs with diet and dose, diet and day, or diet, sex, and drug as factors, and Bonferroni post hoc comparisons where appropriate. Effects mediated by the 5‐HT2C receptor (e.g, penile erections as well as decreased food consumption), were only observed following injections of lorcaserin and WAY 163909 (but not 8‐OH‐DPAT), and were not different between rats eating standard or high fat chow. Regarding 5‐HT1A receptor‐mediated effects, all three 5‐HT receptor agonists induced forepaw treading in rats; however, flat body posture and lower lip retraction were only induced by 8‐OH‐DPAT. Rats eating high fat chow were more sensitive to forepaw treading, regardless of which drug induced this behavior; however, WAY 163909 induced less forepaw treading as compared to the other two drugs, regardless of diet. Rats eating high fat chow were also more sensitive to 8‐OH‐DPAT‐induced lower lip retraction, but not flat body posture. These results suggest that eating a high fat diet can impact sensitivity of rats to some of the effects of serotonergic drugs. Additionally, these results demonstrate that while both lorcaserin and WAY 163909 decrease feeding, WAY 163909 produces less 5‐HT1A‐mediated forepaw treading than lorcaserin, which might indicate that it will produce fewer side effects in humans as well. Finally, these results suggest that dietary history could influence sensitivity of individuals to the adverse effects of serotonergic drugs, such as 5‐HT syndrome.