Effects of Lorcaserin on Cocaine and Methamphetamine Self-Administration and Reinstatement of Responding Previously Maintained by Cocaine in Rhesus Monkeys

Abstract

Stimulant abuse is a serious public health issue for which there is no effective pharmacotherapy. The serotonin [5-hydroxytryptamine (5-HT)] receptor agonist lorcaserin decreases some abuse-related effects of cocaine in monkeys and might be useful for treating stimulant abuse. The current study investigated the effectiveness of lorcaserin to reduce self-administration of either cocaine or methamphetamine and cocaine-induced reinstatement of extinguished responding. Four rhesus monkeys responded under a progressive-ratio (PR) schedule in which the response requirement increased after each cocaine infusion (32-320 μg/kg/infusion). A separate group of four monkeys responded under a fixed-ratio (FR) schedule for cocaine (32 μg/kg/infusion) and reinstatement of extinguished responding was examined following administration of noncontingent infusions of cocaine (0.1-1 mg/kg) that were combined with response-contingent presentations of the drug-associated stimuli. Finally, three monkeys responded under a FR schedule for methamphetamine (0.32-100 μg/kg/infusion). Lorcaserin (3.2 mg/kg) significantly decreased the final ratio completed (i.e., decreased break point) in monkeys responding under the PR schedule and reduced the reinstatement of responding for drug-associated stimuli following a noncontingent infusion of cocaine; these effects did not appear to change when lorcaserin was administered daily. The same dose of lorcaserin decreased responding for methamphetamine in two of the three monkeys, and the effect was maintained during daily lorcaserin administration; larger doses given acutely (10-17.8 mg/kg) significantly decreased responding for methamphetamine, although that effect was not sustained during daily lorcaserin administration. Together, these results indicate that lorcaserin might be effective in reducing cocaine and methamphetamine abuse and cocaine relapse at least in some individuals.

Inhibition of Cocaine and 3,4-Methylenedioxypyrovalerone (MDPV) Self-Administration by Lorcaserin Is Mediated by 5-HT2C Receptors in Rats

“…Accordingly, the current study sought to characterize the relative contribution of actions at 5-HT 2C , 5-HT 2A , and 5-HT 1A receptors to the effectiveness of lorcaserin to decrease stimulant self-administration. In addition, the current study extended recent reports of the effects of lorcaserin on stimulants such as cocaine and methamphetamine ( Collins et al, 2016b ; Gerak et al, 2016 ; Harvey-Lewis et al, 2016 ) to MDPV, a synthetic cathinone commonly found in abused “bath salt” preparations that has been reported to be a more effective reinforcer than cocaine or methamphetamine in rats ( Gannon et al, 2017c ). There were three main findings: 1) lorcaserin was equipotent and equally effective at decreasing self-administration of cocaine and MDPV; 2) the capacity of lorcaserin to decrease cocaine and MDPV self-administration was surmounted by larger unit doses of cocaine and MDPV; and 3) the dose-response curves for lorcaserin to decrease self-administration of cocaine and MDPV were shifted to the right by a 5-HT 2C receptor antagonist, but not antagonists selective for 5-HT 2A or 5-HT 1A receptors.…”

“…To test whether the effects of lorcaserin (dose X ) were related to changes in the reinforcing effects of cocaine and MDPV or due to a more general disruption of behavior, this dose of lorcaserin was also evaluated against larger, more reinforcing doses of cocaine (1.78 mg/kg per infusion) and MDPV (0.178 mg/kg per infusion). Importantly, when these larger doses of cocaine and MDPV were available for self-administration, each of the rats increased responding, indicating that the effects of lorcaserin could be surmounted as has been reported in rhesus monkeys ( Gerak et al, 2016 ). Although these findings suggest that the decreases in stimulant self-administration produced by lorcaserin are related to changes in the reinforcing effectiveness of cocaine and MDPV, it is important to note that these doses of lorcaserin (1.0–5.6 mg/kg) are well within the range of doses that have reported to produce behavioral effects mediated by 5-HT 2A (head twitch) and 5-HT 1A (fore-paw treading) receptors ( Serafine et al, 2015 ), raising the possibility that actions at 5-HT 2A and/or 5-HT 1A receptors contribute to the effectiveness of lorcaserin to decrease stimulant self-administration.…”

“…In addition to providing a novel treatment of obesity, the approval of lorcaserin for use in humans provides a translational opportunity to evaluate the effects of a 5-HT 2C receptor agonist in both preclinical and clinical settings. Indeed, when evaluated in rats and monkeys, lorcaserin has also produced dose-dependent reductions in the self-administration of stimulants, such as cocaine and methamphetamine ( Collins et al, 2016b ; Gerak et al, 2016 ; Harvey-Lewis et al, 2016 ). Similarly, lorcaserin has been reported to decrease the self-administration of other drug reinforcers, including nicotine, alcohol, and oxycodone ( Levin et al, 2011 ; Higgins et al, 2012 ; Rezvani et al, 2014 ; Neelakantan et al, 2017 ), suggesting that lorcaserin might have a more general effect on decreasing drug-maintained behavior.…”

Pharmacological Modulation of 5-HT2C Receptor Activity Produces Bidirectional Changes in Locomotor Activity, Responding for a Conditioned Reinforcer, and Mesolimbic DA Release in C57BL/6 Mice

“…5-HT 2C receptor agonists, including Ro60-1075, CP809101, WAY161503, and lorcaserin, reduce food intake (Clifton et al, 2000;Fletcher et al, 2009) and operant responding for food reinforcement (Grottick et al, 2000;Wolff and Leander, 2000). 5-HT 2C receptor agonists also reduce the efficacy of brain stimulation reward (Hayes et al, 2009;Zeeb et al, 2015) and the reinforcing efficacy of self-administration of several abused drugs, including cocaine (Grottick et al, 2000;Manvich et al, 2012b), nicotine (Higgins et al, 2012), oxycodone (Neelakantan et al, 2017), and methamphetamine (Gerak et al, 2016). In mice, a conditioned place preference produced by cocaine, nicotine, or THC is also blocked by 5-HT 2C agonists (Craige and Unterwald, 2013;Ji et al, 2006).…”

Choice between delayed food and immediate opioids in rats: treatment effects and individual differences

“…Third, we tested the effects of the serotonin 5-HT 2C receptor agonist lorcaserin (Smith et al 2008), which is prescribed as a treatment for obesity, but might have anti-addiction effects since it can decrease self-administration of nicotine (Briggs et al 2016; Cousins et al 2014; Higgins et al 2013; Higgins et al 2012; Levin et al 2011), cocaine (Collins et al 2016; Harvey-Lewis et al 2016), methamphetamine (Gerak et al 2016) and oxycodone (Neelakantan et al 2017) in rats. With respect to choice behavior and opioid self-administration, agonists of 5-HT 2C are also interesting because they decrease premature operant responding that is considered a form of impulsivity (Higgins et al 2012; Navarra et al 2008), and they block some effects of opioid administration and withdrawal (Wu et al 2015; Zhang et al 2016).…”