Rewarding Effects and Reinstatement of MDMA-Induced CPP in Adolescent Mice

Abstract

Although the rewarding effects of 3,4-methylenedioxy-metamphetamine (MDMA) have been demonstrated in self-administration and conditioned place preference (CPP) procedures, its addictive potential (ie, the vulnerability to relapse, measured by its ability to induce reinstatement of an extinguished response), remains poorly understood. In this study, the effects of MDMA (5, 10, and 20 mg/kg) on the acquisition, extinction and reinstatement of CPP were evaluated in mice, using two different protocols during acquisition of CPP. In the first experiment, animals were trained using a two-session/day schedule (MDMA and saline for 4 consecutive days), whereas in the second experiment, they were trained using an alternating day schedule (MDMA and saline each 48 h). After extinction, the ability of drug priming to reinstate CPP was evaluated. In Experiment 1, MDMA did not significantly increase the time spent in the drug-paired compartment during the post-conditioning (Post-C) test, although the preference was evident a week afterwards, lasting between 2 and 21 weeks. No reinstatement was observed after MDMA priming. In Experiment 2, all doses produced CPP in Post-C, which lasted between 1 and 4 weeks. MDMA induces reinstatement at doses up to 4 times lower than those used in conditioning. The analyses of brain monoamines revealed that the daily schedule of treatment induces a non-dose-dependent decrease in dopamine and serotonin (5-HT) in the striatum, whereas the alternating schedule produces a dose-dependent decrease of 5-HT in the cortex. These results demonstrate that MDMA produces long-lasting rewarding effects and reinstatement after extinction, suggesting the susceptibility of this drug to induce addiction.

Modelos animales de adicción a las drogas

“…La reinstauración se refiere a la recuperación de la respuesta aprendida o condicionada y supone un nuevo aprendizaje de la asociación entre el efecto reforzante de la sustancia y las claves ambientales después de la extinción Do Couto et al, 2006;Do Couto, Aguilar, Lluch, Rodríguez-Arias y Miñarro, 2009;García-Pardo et al, 2014, 2015a, 2015b. La reinstauración puede estar inducida por diferentes factores bien farmacológicos, físi-cos o sociales, como por ejemplo la re-exposición a una dosis baja de la droga con la que se adquirió el condicionamiento, conocida como dosis priming (Cruz, Marín y Planeta, 2008;Daza-Losada et al, 2007), o la exposición a una situación estresante como un shock eléctrico en las patas (Bossert, Marchant, Calu y Shaham, 2013) o como la derrota en un encuentro agonístico (García-Pardo et al, 2014;2015b;Shaham et al, 2003;Shalev, Grimm y Shaham, 2002;Tzschentke, 2007).…”

Effects of ambient temperature on the relative reinforcing strength of MDMA using a choice procedure in monkeys

“…We hypothesized that MDMA choice would be increased by elevating the ambient temperature and decreased by lowering the ambient temperature. Few studies have examined MDMA-induced reinstatement (Morley et al 2004;Daza-Losada et al 2007) and none have examined the ability of MDMA to reinstate responding previously maintained by MDMA. Reinstatement is often used as a model of relapse or craving (for review, see Shaham et al 2003); however, recent studies have suggested that the discriminative stimulus effects of drugs have a prominent role in increasing extinguished responding (Odum and Shahan 2004;Cador et al 2006;Banks et al 2007b).…”

Polydrug Use in Adolescence

“…Since no neurotoxic effects were observed after any of the drug pretreatments measured in the first reinstatement test, our results could be explained by the fact that ethanol increases the concentration of MDMA in the brain. Indeed, we found that the rewarding effects of MDMA produced an inverted U-curve in function of dose, with high doses proving to be devoid of motivational effects (Daza-Losada et al, 2007).…”

“…None of the drugs, whether administered alone or together, induced significant changes in the concentration of these monoamines in the striatum, cortex or hippocampus 3 weeks later, at which time CPP was initiated (Daza-Losada et al 2008b). Moreover, the chosen CPP schedule did not affect the concentration of monoamines (Daza-Losada et al 2007). Fig.…”