Effects of the serotonin 2C receptor agonist WAY163909 on the abuse-related effects and mesolimbic dopamine neurochemistry induced by abused stimulants in rhesus monkeys

Abstract

Rationale Accumulating evidence shows that the serotonergic system plays a major role in psychostimulant abuse through its interactions with the dopaminergic system. Studies indicate that serotonin 5-HT2C receptors are one of the main classes of receptors involved in mediating the influence of serotonin in drug abuse. Objective The aim of the present study was to evaluate the effects of the selective serotonin 5-HT2C receptor agonist WAY163909 on the behavioral neuropharmacology of cocaine and methamphetamine in adult rhesus macaques. Methods Cocaine or methamphetamine self-administration and reinstatement were evaluated under second-order and fixed-ratio schedules of reinforcement, respectively. Cocaine- and methamphetamine-induced increases in dopamine were assessed through in vivo microdialysis targeting the nucleus accumbens. Results Pretreatment with WAY163909 dose-dependently attenuated cocaine and methamphetamine self-administration and drug-induced reinstatement of extinguished behavior previously maintained by cocaine or methamphetamine delivery. In an additional experiment, WAY163909 induced a dose-dependent attenuation of cocaine- or methamphetamine-induced dopamine overflow in the nucleus accumbens. Conclusions Our data indicate that selective 5-HT2C receptor activation decreases drug intake and drug-seeking behavior in nonhuman primate models of psychostimulant abuse through neurochemical mechanisms involved in the modulation of mesolimbic dopamine.

Effects of long-term high-fat food or methamphetamine intake and serotonin 2C receptors on reversal learning in female rhesus macaques

“…The 5-HT 2C R agonist Ro 60-0175 reduced cocaine intake in squirrel monkeys [19], and lorcaserin reduced nicotine [25] and alcohol [26] intake in rats. In a previous study, the same doses of WAY163909 used here reduced drug intake and drug seeking of METH and cocaine [21] in rhesus monkeys. One study reported that 7-day treatment with lorcaserin, which is less selective for the 5-HT 2C R and exhibits more 5-HT 2A R agonist activity than WAY163909 [40], did not attenuate cocaine vs food choice [48].…”

“…One study reported that 7-day treatment with lorcaserin, which is less selective for the 5-HT 2C R and exhibits more 5-HT 2A R agonist activity than WAY163909 [40], did not attenuate cocaine vs food choice [48]. This study evaluated only male rhesus monkeys; whereas, the study using WAY163909 [21] used males and females. Moreover, the drug self-administration paradigms and actual compounds used were different, which may also account for the opposing results.…”

“…Activation of 5-HT 2C Rs should inhibit mesolimbic DA signaling, attenuating the abuse-related effects of reinforcers. Electrophysiological and microdialysis studies [16,[19][20][21], and receptor knockout studies [22], provide support for this hypothesis. Moreover, 5-HT 2C R agonists decrease psychostimulant selfadministration and reinstatement [21] in non-human primates (NHPs), food intake in humans [23,24], and nicotine [25] and alcohol [26] self-administration in rats.…”

“…WAY163909 pretreatments (vehicle, 0.1, 0.3, and 1.0 mg/kg) were randomized across subjects in each group. Doses were chosen based on psychostimulant self-administration and reinstatement studies, and microdialysis studies on psychostimulant-induced DA overflow in the NAcc [21]. For one subject (Iv8) in the HCD group, the dose range was reduced because the highest dose of WAY163909 produced behavioral suppression during the task.…”

“…Briefly, subjects responded under a fixed-ratio (FR) 20 schedule of drug delivery during 60-min daily sessions in the morning (starting between 0700 and 1000 h) Monday-Friday. The effects of WAY163909 on METH SA were not tested here because they have been previously described [21].…”