Effects of Cocaine and MDMA Self-Administration on Serotonin Transporter Availability in Monkeys

Abstract

Although serotonin (5-HT) can interact with dopamine (DA) systems to modulate the subjective and reinforcing effects of psychostimulants such as cocaine and 3,4-methyldioxymethamphetamine (MDMA, ecstasy), the long-term effects of exposure to psychostimulants on brain 5-HT systems are not well characterized. The present study assessed 5-HT transporter (SERT) availability using positron emission tomography (PET) in rhesus monkeys with the SERT-specific radioligand [11 C]3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)-benzonitrile (DASB). SERT availability was assessed in regions of interest including the caudate nucleus, putamen, anterior cingulate cortex, and cerebellum. [ 11 C]DASB distribution volume ratios (DVRs) were calculated using the cerebellum as the reference region. DVRs were calculated in control monkeys and in cocaine or MDMA self-administering monkeys approximately 24 h after the last self-administration (SA) session. SERT availability did not differ between monkeys with a history of MDMA SA and control monkeys in any region examined. In contrast, monkeys with a history of cocaine SA showed significantly higher levels of SERT availability in the caudate nucleus and putamen compared to control subjects. These results suggest that chronic SA of cocaine, but not MDMA, leads to alterations in serotonergic function in brain areas relevant to drug abuse. The higher level of SERT availability in cocaineexperienced monkeys may lead to a reduced inhibitory tone of 5-HT on the DA system, which may explain, in part, differences in the abuse liability between cocaine and MDMA.

Differential changes in mesolimbic dopamine following contingent and non-contingent MDMA self-administration in mice

“…In contrast, experimenter-administered low doses of MDMA (1.5 mg/kg×3) did not significantly modify basal or drugstimulated levels of DA or 5-HT in the striatum of rats (Baumann et al 2008). Similarly, using operant protocols, two studies in monkeys show no deficits in SERT following a prolonged self-administration of small amounts of MDMA (0.33 mg/kg/day; Fantegrossi et al 2004;Banks et al 2008). However, with respect to mice, no evidence relating alterations in DA markers with repeated selfadministration of MDMA has been put forward.…”

Serotonin 5-HT2Receptor Interactions with Dopamine Function: Implications for Therapeutics in Cocaine Use Disorder

“…Increases in the SERT after chronic cocaine have been reported in cells (Kittler et al, 2010), rodents (Cunningham et al, 1992), nonhuman primates (Banks et al, 2008;Gould et al, 2011), and humans (Jacobsen et al, 2000;Mash et al, 2000). Chronic self-administration of cocaine in rhesus monkeys also resulted in an upregulation of 5-HT 2A R in the frontal cortex (Sawyer et al, 2012) as determined in vivo with PET imaging and the selective 5-HT 2A R ligand [ 11 C]M100907 (Fig.…”

MDMA Self-Administration in Laboratory Animals: A Summary of the Literature and Proposal for Future Research

“…Two studies in monkeys have examined the effects of self-administered MDMA on indices of central 5-HT function [30,34] . Neither of these, however, found that self-administered MDMA produced significant decreases in 5-HT, although a trend was observed in 1 study [30] .…”