Lorcaserin maintenance fails to attenuate heroin vs. food choice in rhesus monkeys

Abstract

Background:The current opioid crisis has reinvigorated preclinical research in the evaluation of non-opioid candidate treatments for opioid use disorder (OUD). Emerging evidence suggests 5-HT 2C receptor agonists may attenuate the abuse-related effects of opioids. This study evaluated effectiveness of 7-day treatment with the clinically available 5-HT 2C agonist lorcaserin on heroin-vs.-food choice in rhesus monkeys. Lorcaserin effects were compared to effects produced by saline substitution and by 7-day treatment with the opioid antagonist naltrexone. (1) and female (6) rhesus monkeys were trained to respond under a concurrent schedule of food delivery (1g pellets, fixed-ratio 100 schedule) and intravenous heroin injections (0-0.032 mg/kg/injection, fixed-ratio 10 schedule) during daily 2h sessions. Methods: Adult maleHeroin choice dose-effect functions were determined daily before and following 7-day saline substitution or 7-day continuous treatment with naltrexone (0.0032-0.032 mg/kg/h, IV) or lorcaserin (0.032-0.32 mg/kg/h, IV).Results: Under baseline conditions, increasing heroin doses maintained a dose-dependent increase in heroin choice. Both saline substitution and 7-day naltrexone treatment significantly attenuated heroin choice and produced a reciprocal increase in food choice. Continuous lorcaserin treatment significantly increased heroin choice. Conclusions:In contrast to saline substitution and naltrexone, lorcaserin treatment was ineffective to reduce heroin-vs.-food choice. These preclinical results do not support the therapeutic potential of lorcaserin as a candidate OUD treatment.

Effects of naltrexone on amphetamine choice in rhesus monkeys and rats.

“…This extends the range of conditions under which we have observed dose-dependent increases in choice of a drug in comparison to a nondrug alternative reinforcer in a concurrent-choice procedure of drug availability. Second, continuous naltrexone maintenance for 7 days (monkeys) or 5 days (rats) failed to significantly alter amphetamine choice in either species despite assessment of naltrexone doses sufficient to produce >10-fold rightward shifts in opioid choice dose-effect curves in similar choice procedures (Townsend et al, 2019(Townsend et al, , 2020. This finding contrasts with previous evidence to suggest a role for mu opioid receptor (MOR) activation in mediating misuse-related effects of amphetamine.…”

“…First, naltrexone was administered by continuous infusion to mimic maintenance conditions used clinically with substance use disorder treatment medications. Naltrexone was delivered by continuous intravenous infusion for 7 days in monkeys and by continuous subcutaneous minipump delivery for 5 days in rats, as we have reported previously in models of treatment for opioid use disorder (Townsend et al, 2019(Townsend et al, , 2020. We hypothesized that naltrexone maintenance would reduce amphetamine choice and increase food choice.…”

Medications Development for Treatment of Opioid Use Disorder

“…Previous preclinical studies using non-choice schedules of reinforcement have demonstrated that opioid self-administration can be attenuated by either selective MOR antagonists (Negus et al 1993;Zernig et al 1997) or genetic MOR deletion (Becker et al 2000;Sora et al 2001). For example, Figure 5 shows effects of the opioid antagonist naltrexone on heroin-vs.-food choice in nondependent rhesus monkeys and fentanyl-vs.-food choice in nondependent rats (Townsend et al 2019a(Townsend et al , 2019c. Specifically, continuous naltrexone infusion produced dose-dependent rightward shifts in the opioid choice dose-effect function (i.e., decreased opioid choice) in both species, and these doses of naltrexone did not reduce the total number of choices completed.…”

“…For example, G q /G 11 -protein-coupled 5-HT 2C receptors are also located on VTA GABA-ergic neurons, and acute pretreatment with the 5-HT 2C agonist MK-212 blunts morphine-induced increase in nucleus accumbens dopamine levels (Willins and Meltzer 1998). However, chronic treatment with the clinically available 5-HT 2C agonist lorcaserin (Belviq) failed to attenuate heroin-vs.food choice in rhesus monkeys (Townsend et al 2019c). Furthermore, these preclinical results were consistent with lorcaserin effects on oxycodone vs. money choice in humans (Brandt, Jones, Martinez, Manubay, Mogali, Ramey, Levin, and Comer, pers.…”

“…Given that saline does not activate brain reward pathways and function as a reinforcer, saline substitution decreases operant responding previously maintained by the opioid (i.e., extinction; de Wit and Stewart 1983). Under opioid-vs.-food choice conditions, substitution of saline for a previously self-administered opioid results in not only a decrease in operant responding maintained by the opioid, but also a corresponding increase in behavior emitted toward the nonopioid alternative reinforcer (Townsend et al 2019c). Although these preclinical results demonstrate that efforts to reduce opioid availability result in decreased opioid-taking behavior and behavioral reallocation to an alternative nondrug reinforcer, the practical application of this approach outside of a controlled laboratory environment is much more difficult to achieve.…”