Pimavanserin and Lorcaserin Attenuate Measures of Binge Eating in Male Sprague-Dawley Rats

Abstract

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.

Lisdexamfetamine and binge-eating disorder: A systematic review and meta-analysis of the preclinical and clinical data with a focus on mechanism of drug action in treating the disorder

“…In this study mCPP also decreased BOLD fMRI responses to the sight of food pictures in areas of reward-associated circuitry which is consistent with preclinical evidence for a role of 5-HT2C receptors in drug reward (Fletcher et al, 2010;Higgins & Fletcher, 2003. Interestingly, lorcaserin was reported to decrease binge eating of high-fat food in rats and mice, an action which has been proposed to be mediated by a serotonin and dopamine neural reward circuit in the midbrain (Price et al, 2018;Xu et al, 2017). It has been proposed that patients with BED may consume excessive food at least in part due to disrupted satiety signals (Sysko et al, 2007), suggesting that a 5-HT2C receptor agonist could decrease food intake during a binge-eating episode by enhancing satiety.…”

“…5-HT2C receptor activation attenuates reward-related behaviours such as drug-seeking and drug-taking (Fletcher et al, 2010;Higgins & Fletcher, 2003 and may therefore decrease palatable food intake by restoring normal reward-related behaviour (Thomas et al, 2018). Thus, it has been suggested (Price et al, 2018) that selective 5-HT2C receptor agonists could be effective in treating BED but to date no clinical trials have been reported. Similarly, to the best of our knowledge, there have been no 5-HT receptor antagonist studies conducted to investigate the potential contribution of LDX-induced serotonin release to the therapeutic actions of the drug in BED.…”

“…Additionally, the effects of 5-HT receptor antagonists on the action of LDX in delay discounting measures of inhibition has yet to be investigated. Similarly, although it has been suggested on the basis of results from preclinical studies (Price et al, 2018) that selective 5-HT2C receptor agonists could be effective in treating BED no experimental medicine studies or clinical trials have been conducted.…”

5-HT2C Receptor Stimulation in Obesity Treatment: Orthosteric Agonists vs. Allosteric Modulators

“…The effect of lorcaserin on food intake has been examined in different animal models of obesity. Some authors used a regular diet [ 60 , 61 ], and other investigators evaluated lorcaserin in rats maintained on a high-fat diet [ 36 , 62 , 63 ]. Lorcaserin treatment rats (1–2 mg/kg) reduced the percentage of body weight by selective reduction of body fat mass [ 36 , 60 ].…”

Prospects for new drugs to treat binge-eating disorder: Insights from psychopathology and neuropharmacology

“…The 5-HT 2C agonist, lorcaserin, has shown efficacy in various substance use disorder models. Lorcaserin and the 5-HT 2A antagonist/inverse agonist, pimavanserin, were evaluated in a rat model of bingeing ( Price et al, 2018 ). Both drugs produced small reductions in palatable food intake, but not binge-frequency.…”