The 5-HT2C Receptor Agonist Lorcaserin Reduces Nicotine Self-Administration, Discrimination, and Reinstatement: Relationship to Feeding Behavior and Impulse Control

Abstract

Lorcaserin ((1R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine HCl) is a selective 5-HT 2C receptor agonist with clinical efficacy in phase-III obesity trials. Based on evidence that this drug class also affects behaviors motivated by drug reinforcement, we compared the effect of lorcaserin on behavior maintained by food and nicotine reinforcement, as well as the stimulant and discriminative stimulus properties of nicotine in the rat. Acutely administered lorcaserin (0.3-3 mg/kg, subcutaneous (SC)) dose dependently reduced feeding induced by 22-h food deprivation or palatability. Effects up to 1 mg/kg were consistent with a specific effect on feeding motivation. Lorcaserin (0.6-1 mg/kg, SC) reduced operant responding for food on progressive and fixed ratio schedules of reinforcement. In this dose range lorcaserin also reversed the motor stimulant effect of nicotine, reduced intravenous self-administration of nicotine, and attenuated the nicotine cue in rats trained to discriminate nicotine from saline. Lorcaserin also reduced the reinstatement of nicotine-seeking behavior elicited by a compound cue comprising a nicotine prime and conditioned stimulus previously paired with nicotine reinforcement. Lorcaserin did not reinstate nicotine-seeking behavior or substitute for a nicotine cue. Finally, lorcaserin (0.3-1 mg/kg) reduced nicotine-induced increases in anticipatory responding, a measure of impulsive action, in rats performing the fivechoice serial reaction time task. Importantly, these results indicate that lorcaserin, and likely other selective 5-HT 2C receptor agonists, similarly affect both food-and nicotine-motivated behaviors, and nicotine-induced impulsivity. Collectively, these findings highlight a therapeutic potential for 5-HT 2C agonists such as lorcaserin beyond obesity into addictive behaviors, such as nicotine dependence.

A Novel Aminotetralin-Type Serotonin (5-HT)2CReceptor-Specific Agonist and 5-HT2ACompetitive Antagonist/5-HT2BInverse Agonist with Preclinical Efficacy for Psychoses

“…Drugs that activate 5-HT 2C receptors hold promise for the treatment of psychoses and psychostimulant abuse, in part because of their ability to modulate central dopamine signaling and their effectiveness in preclinical models and at least one clinical study (Di Matteo et al, 2004;Shen et al, 2010;Higgins et al, 2012;Cunningham et al, 2013). Herein is described (2)-MBP, a novel and potent 5-HT 2C receptorspecific agonist with 5-HT 2A and 5-HT 2B competitive antagonist and inverse agonist properties that is effective in preclinical mouse models of psychoses, does not affect locomotion on its own, and reduces palatable food intake, important properties distinguishing it from available antipsychotic drugs that suppress locomotion and increase appetite, leading to obesity (Stip et al, 2012).…”

Serotonin controlling feeding and satiety

“…Experimental evidence exists that 5-HT2C agonists do not only inhibit food intake, e.g. the consummatory component of feeding behaviour, but also the preceding appetitive phase, which is not yet food related [82,359]. Combining the 5-HT2C/1B agonist mCPP with the CB1 antagonist/partial agonist rimonabant synergistically reduced motivated feeding behaviour in an operant paradigm in mice [360].…”

Lorcaserin Reduces the Discriminative Stimulus and Reinforcing Effects of Cocaine in Rhesus Monkeys

“…In clinical studies, lorcaserin is well tolerated and decreases food intake and body weight (Smith et al, 2009(Smith et al, , 2010Chan et al, 2013;Aronne et al, 2014) at doses that have low potential for producing heart valve disease (Weissman et al, 2013) or abuse (Shram et al, 2011), effects commonly associated with 5-HT 2B and 5-HT 2A receptor agonists, respectively (Nichols, 2004;Hutcheson et al, 2011). In addition to preclinical studies demonstrating that lorcaserin decreases food intake and body weight (Smith et al, 2008;Thomsen et al, 2008;Higgins et al, 2013b;Grottick et al, 2015), lorcaserin is also shown to decrease nicotine selfadministration and the reinstatement of responding for nicotine in rats (Levin et al, 2011;Higgins et al, 2012Higgins et al, , 2013b.…”