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

Abstract

Cocaine abuse and obesity are serious public health problems, and studies suggest that both dopamine and serotonin systems are involved in regulating the consumption of drugs and food. Lorcaserin has serotonin (5-HT) 2C receptor agonist actions, is approved by the U.S. Food and Drug Administration for treating obesity, and might be effective for treating cocaine abuse. These studies characterized the pharmacokinetic and behavioral profiles of lorcaserin (intragastric administration) and determined the effectiveness of lorcaserin to alter discriminative stimulus and reinforcing effects of cocaine (intravenous administration) in rhesus monkeys. Administered acutely, lorcaserin dosedependently increased the occurrence of yawning while decreasing spontaneous activity and operant responding for food. These effects appeared within 30-60 minutes of administration and began to dissipate by 240 minutes, a time course closely matching plasma concentrations of lorcaserin. In monkeys discriminating cocaine from saline, lorcaserin alone did not occasion cocaine-appropriate responding but shifted the cocaine dose-response curve to the right and down in two of three monkeys. When administered acutely, lorcaserin dosedependently decreased the rate at which monkeys responded for infusions of cocaine. When administered chronically, 3.2 mg/kg lorcaserin reduced the rate of cocaine-maintained responding by 50% for the duration of a 14-day treatment period. Together, these results show that lorcaserin attenuates the discriminative stimulus effects of cocaine after acute administration and the reinforcing effects of cocaine after acute and repeated administration, consistent with the view that it might have utility in treating cocaine abuse.

Effects of lorcaserin (Belviq®) on nicotine- and food-maintained responding in non-human primates

“…This finding has clear clinical implications, as it suggests that increased nicotine use appears unlikely to overcome lorcaserin’s treatment effects. Moreover, decreases in nicotine-maintained responding were generally consistent over 3 – 5 days of continuous treatment with lorcaserin and these findings are consistent with previous reports showing that orally-administered lorcaserin reliably decreased cocaine self-administration over a 14-day treatment period in rhesus monkeys (Collins et al, 2016) and suggest that tolerance does not develop rapidly to the desired treatment effects of lorcaserin. However, studies in which high daily dosages of lorcaserin are administered over extended time periods (e.g., months) are necessary for a full evaluation of whether and at what rate tolerance may develop to lorcaserin’s effects.…”

“…It is unclear whether the different effects of lorcaserin on food-maintained behavior in the two experiments were due to differences in dosing regimen (acute bolus dose vs. continuous accumulating dosage) or differences in response requirement (FR5 vs. FR1 in, respectively, acute and continuous dosing studies). Some reduction in food-maintained responding is perhaps not surprising in view of lorcaserin’s FDA-approval as a weight loss medication and, as well, previous reports of decreases in feeding or food-reinforced behavior in rats (Higgins et al, 2012; Thomsen et al, 2008) and monkeys (Collins et al, 2016). Indeed, more pronounced effects of lorcaserin on food-maintained responding might have been expected in the present experiments.…”

“…The time-course of decreased activity is in line with the reported plasma half-life of about 11-hr for lorcaserin in humans (Eisai Inc., 2016). Previous studies in rhesus monkeys and rodents also have demonstrated that doses of lorcaserin that effectively decrease drug self-administration (i.e., cocaine, nicotine) also generally decrease activity (Collins et al, 2016; Higgins et al, 2012; Levin et al, 2011). Such decreased activity does not appear to reflect sedation or non-specific motoric disruption that prevents subjects from engaging in operant behavior.…”

“…With this in mind, the present study was conducted to assess the extent to which acute or continuous lorcaserin treatment may attenuate the reinforcing effects of IV nicotine in rhesus monkeys with an extensive history of IV nicotine self-administration (i.e., >2 years). As lorcaserin has been reported to also alter other types of behavior (e.g., food consumption and activity; Collins et al, 2016; Higgins et al, 2012), we also assessed its effects on food-maintained behavior and daily activity levels. Results indicate that doses of lorcaserin that markedly decreased IV nicotine self-administration produced less pronounced effects on food-maintained responding, providing preclinical support for the continued evaluation of lorcaserin’s pharmacotherapeutic utility in smoking cessation programs.…”

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).…”