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

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. 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. 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. 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. 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.