Acute blockade of CB1 receptor leads to reinstatement of MDMA-induced conditioned place preference.

Cannabis is one of the drugs most commonly consumed in combination with ecstasy (3,4-methylenedioxymethamphetamine, MDMA). Although numerous studies have attempted to further our understanding of the role of the cannabinoid system in drug abuse, few have focused on how it influences the rewarding effects of MDMA. The aim of the present study was to evaluate the role of the CB1 cannabinoid receptor in vulnerability to reinstatement of a MDMA-induced conditioned place preference (CPP). Mice were first conditioned with 5mg/kg of MDMA. Once the preference had been extinguished, a priming dose of MDMA, alone or plus the CB1 cannabinoid agonist WIN 55,212-2 (0.1 and 0.5mg/kg) or the CB1 cannabinoid antagonist SR 141716A (0.3mg/kg), was administered on alternate days. The CB1 receptor antagonist, alone or with any of the priming doses of MDMA, induced reinstatement of the preference. In contrast, WIN 55,212-2 had no effect on reinstatement of the MDMA-induced CPP when administered alone, but potentiated the effects of subthreshold priming doses of MDMA. These results highlight the important role of the CB1 receptor in vulnerability to reinstatement of drug-seeking behavior and point to the importance of the endocannabinoid system in the addictive potential of MDMA.

Potencial adictivo del éxtasis: una visión desde los modelos animales / The addictive potential of ecstasy: an overview of animal models

La 3,4-metilendioximetanfetamina (MDMA) es el principio activo del "éxtasis", un psicoestimulante de gran popularidad entre los adolescentes y los adultos jóvenes. La actividad farmacológica del éxtasis está mediada por la serotonina (5-HT) y la dopamina (DA), esta última fuertemente implicada en la modulación de los efectos reforzantes de las drogas de abuso. Aunque escasos, los estudios realizados en consumidores de éxtasis indican que un porcentaje de ellos cumplirían los criterios de dependencia a esta sustancia. La presente revisión analiza los resultados más relevantes obtenidos hasta el momento sobre los efectos reforzantes de la MDMA, principalmente aquellos obtenidos a partir de modelos animales como la autoadministración intravenosa (AAI) y el condicionamiento de la preferencia de lugar (CPL), así como también los hallazgos derivados a partir del uso de estos paradigmas como modelos de recaída. La MDMA presenta efectos reforzantes y es capaz de reinstaurar una conducta una vez esta se ha extinguido (modelo de recaída), por lo cual podemos concluir que esta droga presenta potencial adictivo y además es capaz de inducir modificaciones en el sistema de refuerzo cerebral que alteran la respuesta ante otras drogas de abuso (AU)

3,4-methylenedioxymetamphetamine (MDMA) is the active compound of the recreational drug "ecstasy", a popular psychostimulant among adolescent and young adults. The pharmacological action of ecstasy is mediated by serotonin (5-HT) and dopamine (DA), the latter of which is strongly implicated in the modulation of the reinforcing effects of drugs of abuse. The few studies performed in human users of ecstasy indicate that a percentage of these subjects fulfill the criteria of dependence to this drug. The present review analyzes the most relevant results published until now regarding the reinforcing effects of MDMA, giving special attention to those obtained with animal models employing intravenous self-administration or conditioned place preference, and those using these paradigms as models of relapse. MDMA produces reinforcing effects and is capable of reinstating an extinguished behavior (relapse model); thus, we can conclude that this drug possesses addictive potential and, in addition, is capable of inducing modifications in the brain reward system that alter the response to other drugs of abuse (AU)

Acute behavioural and neurotoxic effects of MDMA plus cocaine in adolescent mice.

The poly-drug pattern is the most common among those observed in MDMA users, with cocaine being a frequently associated drug. This study evaluates the acute effects of MDMA (5, 10 and 20 mg/kg), alone or in combination with cocaine (25 mg/kg), on motor activity, anxiety (elevated plus maze and social interaction test), memory and brain monoamines in adolescent mice. Both drugs, administered alone or concurrently, produced hyperactivity and a decrease in social contacts. However, an anxiolytic effect, studied by means of the elevated plus maze and expressed as an increase in the time spent on the open arms, was observed only in those animals treated with cocaine and MDMA. The passive avoidance task was affected only with the highest MDMA dose (20 mg/kg). Mice treated with MDMA did not present significant changes in brain monoamines, while those receiving MDMA and cocaine showed a decrease in DA in the striatum, which was accompanied by an increase in the serotonin concentration in the striatum and cortex 30 min after acute administration. In conclusion, the combined use of MDMA and cocaine produces a predominance of serotonin over DA, which is associated with an anxiolytic profile, defensive behaviours and fewer social contacts.

Behavioural and neurotoxic long-lasting effects of MDMA plus cocaine in adolescent mice.

The poly-drug pattern is the most common among MDMA users, with cocaine being a frequently associated drug. The aim of the present work was to evaluate the behavioural and neurotoxic long-term effects of exposure during adolescence to MDMA alone or plus cocaine. Mice of 28 to 30 days of age received a treatment of two daily injections of an identical dose of MDMA (5, 10 or 20 mg/kg), alone or plus cocaine (25 mg/kg), for 3 days (6 administrations). Three weeks after receiving MDMA, an increase in the time dedicated by the animals to social contacts with their conspecifics was observed, whilst their behaviour in the elevated plus maze showed no differences from that of non-treated mice. After being exposed to MDMA plus cocaine, mice spent more time in social contacts during the interaction test, as well as exhibiting an anxiolytic profile in the elevated plus maze, with an increase in the time and number of entries in the open arms. The activity of mice treated with cocaine alone or plus MDMA remained constant; the decrease observed among the rest of the animals after the second hour was absent in their case. The level of dopamine in the striatum was diminished in mice treated with 20 mg/kg of MDMA, but this neurotransmitter was not affected in animals exposed to the same dose plus cocaine. The present results highlight pronounced alterations in the behaviour of adult mice after exposure to MDMA and cocaine during adolescence, and demonstrate that these long-term effects can occur without the dopaminergic system becoming affected.

Effect of adolescent exposure to MDMA and cocaine on acquisition and reinstatement of morphine-induce CPP.

It is well known that an elevated percentage of ecstasy users also consume cocaine. Recently, it has been reported that a high frequency of heroin smokers first consumed heroin under the effects of ecstasy with the hope of reducing the stimulant effects of the latter drug. The aim of the present study was to evaluate the effect of exposure to MDMA and cocaine during adolescence on morphine-induced conditioned place preference (CPP) and reinstatement in adulthood. In the first experiment, adolescent mice were exposed to six injections of MDMA and three weeks later their response to the reinforcing properties of 40 mg/kg of morphine was evaluated using the CPP paradigm. All the treatment groups developed the same magnitude of morphine-induced preference and, after CPP was extinguished, it was restored in all the groups with a priming dose of 10 mg/kg of morphine. Only mice that had been treated with 10 or 20 mg/kg of MDMA had their morphine-induced preference reinstated after receiving only 5 mg/kg of morphine. In the second experiment, adolescent mice were similarly treated with six administrations of cocaine (25 mg/kg) or cocaine plus MDMA (5, 10 or 20 mg/kg), and their response to morphine-induce CPP was evaluated three weeks later. Similarly to the first experiment, all the groups developed a preference for the morphine-paired compartment, but this preference was not reinstated with a priming dose of 10 mg/kg of morphine following extinction, as was the case among the control animals. These results lead us to hypothesize that periadolescent MDMA exposure alters responsiveness to the rewarding properties of morphine, highlighting MDMA as a gateway drug whose use may increase the likelihood of dependence on other drugs.