Eating a high fat diet enhances sensitivity of rats to serotonin receptor agonists

Rationale: Serotonergic medications are used for treating anxiety, depression, and obesity. Serotonin (5-HT) receptor agonists (e.g., 8-OH-DPAT, lorcaserin, and WAY 163909) induce unconditioned effects in rodents (e.g., lower lip retraction, flat body posture, penile erections, and forepaw treading), which can be used to measure drug sensitivity. Objective: The unconditioned effects of serotonergic drugs are hypothesized to be enhanced by eating a high fat diet. Methods: Male (n = 32) and female (n = 16) Sprague-Dawley 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 (8-OH-DPAT [0.01–1.0 mg/kg, (subcutaneously, s.c.)], lorcaserin [1.0–32.0 mg/kg, (intraperitoneally, i.p.)], or WAY 163909 [1.0–32.0 mg/kg, i.p.] alone and in combination with antagonists selective for 5-HT_1A (WAY 100635; 0.178 mg/kg, s.c.), or 5-HT_2C (SB 242084; 1.0 mg/kg; i.p.) receptors. Results: 8-OH-DPAT induced lower lip retraction, flat body posture, and forepaw treading, while WAY 163909 and lorcaserin induced forepaw treading, penile erections, and weight loss. Rats eating high fat chow were more sensitive to 8-OH-DPAT-induced lower lip retraction and forepaw treading induced by 8-OH-DPAT, lorcaserin, and WAY 163909 as compared to rats eating standard chow. Lorcaserin and WAY 163909-induced penile erections were not different between rats eating high fat or standard chow. Forepaw treading, lower lip retraction, and flat body posture were attenuated by WAY 100635. In contrast, penile erections were attenuated by SB 242084. Conclusions: These results suggest that nutritional factors impact drug sensitivity in ways that might be relevant for the therapeutic effectiveness and side effect severity of serotonergic drugs.