Effects of the serotonin 2C receptor agonist WAY163909
on the abuse-related effects and mesolimbic dopamine
neurochemistry induced by abused stimulants in rhesus monkeys
Laís F. Berro
Maylen Perez Diaz
Leonard L. Howell
Received: 30 August 2016 /Accepted: 19 May 2017 /Published online: 5 June 2017
Springer-Verlag Berlin Heidelberg 2017
Rationale Accumulating evidence shows that the serotoner-
gic system plays a major role in psychostimulant abuse
through its interactions with the dopaminergic system.
Studies indicate that serotonin 5-HT
receptors are one of
the main classes of receptors involved in mediating the influ-
ence of serotonin in drug abuse.
Objective The aim of the present study was to evaluate the
effects of the selective serotonin 5-HT
WAY163909 on the behavioral neuropharmacology of co-
caine 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 dopa-
mine were assessed through in vivo microdialysis targeting
the nucleus accumbens.
Results Pretreatment with WAY163909 dose-dependently at-
tenuated cocaine and methamphetamine self-administration
and drug-induced reinstatement of extinguished behavior pre-
viously 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-HT
activation decreases drug intake and drug-seeking behavior in
nonhuman primate models of psychostimulant abuse through
neurochemical mechanisms involved in the modulation of
In vivo microdialysis
Psychostimulant abuse is a chronic relapsing disorder charac-
terized by loss of control over drug intake despite harmful
consequences (American Psychiatric Association 2013).
Although psychostimulants differ in their pharmacodynamic
properties, stimulant drugs exhibit abuse liability as a com-
mon feature and exert their reinforcing properties by increas-
ing dopamine levels in the mesolimbic dopaminergic system
(Koob and LeMoal 2006). For instance, the effectiveness of
psychostimulants to increase extracellular dopamine levels in
the nucleus accumbens has been shown to parallel their stim-
ulant, reinforcing and reinstating effects in nonhuman pri-
mates (for review see Howell and Negus 2014). Thus, dopa-
minergic neurotransmission has been a primary target for
medications development for psychostimulant abuse.
Despite decades of research, there are no approved
dopamine-based medications for the treatment of stimulant
abuse. This has prompted researchers to investigate other pos-
sible neural systems that contribute to the development and
maintenance of drug abuse. In this context, the serotonergic
system has gained attention for playing an important role in
Laís F. Berro and Maylen Perez Diaz contributed equally to the study
* Leonard L. Howell
Yerkes National Primate Research Center, Emory University, 954
Gatewood Road N.E, Atlanta, GA 30329, USA
Department of Psychobiology, Universidade Federal de São Paulo,
São Paulo, SP, Brazil
Department of Psychiatry and Behavioral Science, Yerkes National
Primate Research Center, Emory University, 954 Gatewood Road
N.E, Atlanta, GA 30329, USA
Psychopharmacology (2017) 234:2607–2617