Dopaminergic mechanisms of reinstatement of MDMA‐seeking behaviour in rats

Abstract

BACKGROUND AND PURPOSEAnimal models of drug-seeking suggest that exposure to cues associated with self-administered drugs and drug primes might precipitate relapse via activation of central dopaminergic substrates. EXPERIMENTAL APPROACHThe effects of priming injections of dopamine and 5-HT agonists on drug-seeking and effects of dopamine antagonists on methylenedioxymethamphetamine (MDMA)-produced potentiation of drug-seeking following extinguished MDMA self-administration were examined. KEY RESULTSDrug-seeking was produced by exposure to a light stimulus that had been paired with self-administered MDMA infusions and this effect was potentiated by experimenter-administered injections of the dopamine D2-like receptor agonist, quinpirole, the indirect agonist, amphetamine and the uptake inhibitor, GBR 12909. Drug-seeking was not elicited by the dopamine D1-like receptor agonist, SKF 81297 or the non-selective agonist, apomorphine. The 5-HT receptor agonists DOI or mCPP also failed to elicit drug-seeking. The 5-HT uptake inhibitor, clomipramine, attenuated drug-seeking produced by the MDMA-associated stimulus but failed to alter the potentiated response produced by GBR 12909. The D1 receptor antagonist, SCH 23390 or the D2 receptor antagonist, eticlopride attenuated the potentiation of drug-seeking produced by MDMA. CONCLUSIONS AND IMPLICATIONSThese data provide evidence of dopaminergic mechanisms in drug-seeking following extinction of MDMA self-administration. Because tissue levels of 5-HT were significantly decreased following MDMA self-administration, we suggest that MDMA begins to preferentially activate dopaminergic substrates to potentiate the drug-seeking response.

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

“…Cue-induced reinstatement of MDMA self-administration is blocked by antagonism of DA D 1 and DA D 2 receptors and by inhibition of 5-HT uptake in rats (Schenk et al, 2011) and antagonism of the 5-HT 2A receptor in mice (Orejarena et al, 2011). Moreover, priming-induced reinstatement of CPP is completely blocked in mice treated with a 5-HT 2B antagonist (Doly et al, 2009).…”

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.…”

Involvement of NMDA glutamate receptors in the acquisition and reinstatement of the conditioned place preference induced by MDMA

“…As these effects seem to depend on the activation of DA and 5-HT receptors (Schenk et al, 2011;Vidal-Infer et al, 2012;Roger-Sánchez et al, 2013b, 2013c, it is possible that memantine decreases the levels of these neurotransmitters. Activation of NMDARs stimulates DA release in rat striatal slices, and memantine inhibits this effect (Nankai et al, 1995).…”

“…Although its abuse potential is not as high as that of some other compounds, MDMA dependence has been documented as a result of chronic consumption (Cottler et al, 2001;Degenhardt et al, 2010;Leung et al, 2010). Animal models of reward, such as self-administration (SA) and conditioned place preference (CPP), also point to MDMA as a drug of abuse that induces reinstatement after extinction (Schenk, 2009;Schenk et al, 2011;Roger-Sánchez et al, 2013a), an animal model of relapse to drug seeking after long periods of abstinence Bossert et al, 2013). Several neurotransmitter systems have been implicated in the acquisition and/or reinstatement of the rewarding effects of MDMA in the SA and CPP paradigms: serotonin [5-hydroxytryptamine (5-HT)], dopamine (DA), endogenous opioids, endocannabinoids, neurotensin and adenosine (for a review, see Roger-Sánchez et al, 2013a).…”