Binge eating disorder (BED) is characterized by dysregulated feeding and reward-related processes, and treatment is often challenged by limited therapeutic options. The serotonin (5-HT) 5-HT2A receptor (5-HT2AR) and 5-HT2CR are implicated in both feeding-related and reward-related behaviors and are thus poised to regulate BED-related behaviors. The purpose of this study was to assess the efficacy of the FDA-approved medications pimavanserin, a 5-HT2AR antagonist/inverse agonist, and lorcaserin, a 5-HT2CR agonist, in a rodent model of binge eating. The effects of pimavanserin (0.3–3.0 mg/kg), lorcaserin (0.25–1.0 mg/kg), and the lowest effective dose of pimavanserin (0.3 mg/kg) plus lorcaserin (1.0 mg/kg) were tested in a high-fat food (HFF) intermittent access binge eating model in adult male Sprague-Dawley rats (n = 64). We assessed three measures related to binge eating – binge episode occurrence, binge intake, and weight gain associated with HFF access. Pimavanserin decreased binge intake and weight gain associated with HFF access, but did not prevent binge episode occurrence. Lorcaserin decreased binge intake, but did not prevent binge episode occurrence or weight gain associated with HFF access. Combined pimavanserin plus lorcaserin prevented binge episode occurrence in addition to decreasing binge intake and weight gain associated with HFF access. These preclinical findings in male rats suggest that pimavanserin and lorcaserin may be effective in treating patients with BED. Our studies further indicate that administration of one or both drugs may be more effective in certain sub-populations of patients with BED because of the unique profile each treatment elicits. These data support future assessment in clinical populations with BED.

Ghrelin is a 28‐amino acid peptide produced by epithelial cells in the stomach mucosa and is well‐characterized to modulate gastrointestinal function, growth hormone secretion, glucose regulation, and appetite, and is increasingly implicated in substance use disorder (SUD) phenotypes. Ghrelin actions are transduced through the growth hormone secretagogue receptor 1α (GHS1αR) which is noted to exhibit constitutive activity in in vitro recombinant cell lines, and in dispersed pancreas islet cells, studies which support the concept of endogenous ghrelin tone. The small molecule PF5190457 exhibits relatively equipotent actions as a neutral GHS1αR antagonist and inverse agonist without apparent partial agonist actions (Kong et al. Br J Pharmacol 173:1452, 2016). To expand our knowledge of the physiological impact of GHS1αR function in vivo and determine an effective dose of PF5190457 for future studies of SUD phenotypes, we tested the hypotheses that PF5190457 would antagonize GHS1αR agonist‐induced intake of standard chow (SD) or high fat food (HFF) and act as an inverse agonist to inhibit basal HFF intake and weight gain. Methods Male Sprague‐Dawley rats (n=16) maintained on ad libitum SD were pretreated with intraperitoneal injection of PF5190457 (20 mg/kg) or vehicle 60 min prior to subcutaneous (SC) injection of the GHS1αR agonist hexarelin (80 μg/kg) and assay of SD intake over a 6‐hr period. In a second study, rats (n=32) were administered acute or repeated PF5190457 (20 mg/kg) prior to maintenance on ad libitum HFF for three days. On day 3, all rats were treated with PF5190457 or vehicle 60 min prior to hexarelin (80 μg/kg; SC). Food intake and body weight were recorded throughout the study. Results PF5190457 significantly suppressed hexarelin‐induced SD intake vs. vehicle (p < 0.05). Both acute and repeated PF5190457 administration suppressed hexarelin‐induced HFF intake vs. control (p < 0.05). Repeated PF5190457 suppressed basal HFF intake and body weight gain (p < 0.05). Conclusions The novel GHS1αR inverse agonist/antagonist PF5190457 suppressed measures of both hexarelin‐induced SD and HFF intake, demonstrating antagonist activity in vivo. Similar efficacy of acute and repeated PF5190457 to suppress hexarelin‐induced HFF intake suggests that tolerance did not develop. Further, PF5190457 suppressed basal HFF intake and HFF‐associated weight gain, indicating inverse agonist activity in vivo. Together, these data suggest that PF5190457 will be a useful pharmacological tool to study the involvement of GHS1αR in SUD phenotypes. Support or Funding Information Supported by NIDA UG3 DA050317 and F30 DA049501