Role of the Dopaminergic System in the Acquisition, Expression and Reinstatement of MDMA-Induced Conditioned Place Preference in Adolescent Mice

Abstract

BackgroundThe rewarding effects of 3,4-methylenedioxy-metamphetamine (MDMA) have been demonstrated in conditioned place preference (CPP) procedures, but the involvement of the dopaminergic system in MDMA-induced CPP and reinstatement is poorly understood.Methodology/Principal FindingsIn this study, the effects of the DA D1 antagonist SCH 23390 (0.125 and 0.250 mg/kg), the DA D2 antagonist Haloperidol (0.1 and 0.2 mg/kg), the D2 antagonist Raclopride (0.3 and 0.6 mg/kg) and the dopamine release inhibitor CGS 10746B (3 and 10 mg/kg) on the acquisition, expression and reinstatement of a CPP induced by 10 mg/kg of MDMA were evaluated in adolescent mice. As expected, MDMA significantly increased the time spent in the drug-paired compartment during the post-conditioning (Post-C) test, and a priming dose of 5 mg/kg reinstated the extinguished preference. The higher doses of Haloperidol, Raclopride and CGS 10746B and both doses of SCH 23390 blocked acquisition of the MDMA-induced CPP. However, only Haloperidol blocked expression of the CPP. Reinstatement of the extinguished preference was not affected by any of the drugs studied. Analysis of brain monoamines revealed that the blockade of CPP acquisition was accompanied by an increase in DA concentration in the striatum, with a concomitant decrease in DOPAC and HVA levels. Administration of haloperidol during the Post-C test produced increases in striatal serotonin, DOPAC and HVA concentrations. In mice treated with the higher doses of haloperidol and CGS an increase in SERT concentration in the striatum was detected during acquisition of the CPP, but no changes in DAT were observed.Conclusions/SignificanceThese results demonstrate that, in adolescent mice, the dopaminergic system is involved in the acquisition and expression of MDMA-induced CPP, but not in its reinstatement.

Effects of risperidone on the acquisition and reinstatement of the conditioned place preference induced by MDMA

“…Given that the low dose of risperidone had no effects, our results suggest that the higher dose acted by blocking DA D 2 receptors, although blockade of 5-HT 2 receptors could also have contributed to the effects observed. A recent study in our laboratory has demonstrated that DA D 2 receptors are involved in the rewarding effects of MDMA, since raclopride and haloperidol blocked the development of CPP (Vidal-Infer et al, 2012). Furthermore, a study using mice without 5-HT 2B receptors highlighted the role of said receptors in the rewarding effects induced by low (but not high) doses of MDMA, since 30 (but not 10) mg/kg induced CPP (Doly et al, 2009).…”

“…Evaluation of the effects of an experimental compound such as risperidone in animal models of drug reward is an initial step in the study of its therapeutic efficacy in humans. We have recently demonstrated that different DA antagonists block the rewarding effects of MDMA in the CPP paradigm but not reinstatement after extinction, which suggests that their efficacy for treating MDMA dependence in humans is limited (Vidal-Infer et al, 2012). On the other hand, risperidone blocks both DA and 5-HT 2 receptors, a pharmacological profile that suggests therapeutic efficacy with respect to MDMA abuse, since both DA and 5-HT systems have been implicated in the rewarding effects of this drug.…”

“…Moreover, priming-induced reinstatement of CPP is completely blocked in mice treated with a 5-HT 2B antagonist (Doly et al, 2009). Conversely, it has been shown that the DA release inhibitor CGS 10746B and different DA antagonists have no effects on priming-induced reinstatement of MDMA CPP in mice (Vidal-Infer et al, 2012). Such results suggest that acquisition and reinstatement of CPP depend on different neurochemical substrates, and that the effects of drugs on the reinstatement of self-administration and reinstatement of CPP vary.…”

“…Moreover, 5-HT 2 receptors are involved in the modulation of mesolimbic DA release (Gudelsky et al, 1994). Both DA D 1 and DA D 2 receptors are known to be involved in the maintenance of MDMA self-administration (Brennan et al, 2009;Daniela et al, 2004) and in the acquisition of MDMA-induced CPP (Vidal-Infer et al, 2012). Self-administration of MDMA is also attenuated in rhesus monkeys treated with serotonin 5-HT 2A antagonists (Fantegrossi et al, 2002) and in 5-HT 2A receptor KO mice (Orejarena et al, 2011).…”

Abuse potential of methylenedioxymethamphetamine (MDMA) and its derivatives in zebrafish: role of serotonin 5HT2-type receptors

“…Moreover, MDMA increases DA in the nucleus accumbens primarily through serotonergic stimulation (Kankaanpää et al 1998;Robledo et al 2004;O'Shea et al 2005;Cadoni et al 2005). Thus, dopaminergic (Bilsky et al 1998;Daniela et al 2004;Brennan et al 2009;Schenk et al 2011;Vidal-Infer et al 2012) and serotonergic (Roger-Sánchez et al 2013a, b, c;Müller and Homberg 2015) mechanisms contribute to the rewarding effects of MDMA. On the other hand, in vivo microdialysis experiments have found that PMA markedly influences DA and 5-HT release in rat brain (Gołembiowska et al 2016), while for DOB, no data are available on dopamine activity.…”