Reinstatement of MDMA (ecstasy) seeking by exposure to discrete drug-conditioned cues

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Abstract

The widely used recreational drug MDMA (ecstasy) supports self-administration in animals, but it is not known whether MDMA-associated cues are able to reinstate drug seeking in a relapse model of drug addiction. To assess this possibility, drug-naïve rats were trained to press a lever for MDMA infusions (0.30 mg/kg/infusion, i.v.) paired with a compound cue (light and tone) in daily 2 h sessions. Responding was reinforced contingent on a modified fixed-ratio 5 schedule of reinforcement. Conditioned cue-induced reinstatement tests were conducted after lever pressing was extinguished in the absence of MDMA and the conditioned cues. Conditioned cues reinstated lever pressing after extinction, and the magnitude of reinstatement was positively correlated with the level of responding during MDMA self-administration. These results show for the first time that conditioned cues can trigger reinstatement of MDMA-seeking behavior in rats, and that individual differences in the pattern of MDMA self-administration can predict the magnitude of reinstatement responding.

Introduction

The widely used amphetamine derivative 3,4-methylenedioxymethamphetamine (MDMA; ecstasy) is a so-called “club” or “designer” drug that has an amphetamine-like action at monoamine transporters (Nash and Brodkin, 1991), resulting in increased synaptic levels of serotonin and dopamine (Gough et al., 1991). Although the neurobehavioral effects of MDMA can be distinguished from those of amphetamine, MDMA appears to share several important properties with other highly addictive psychostimulants. In fact, several animal models of drug reinforcement and addiction, including conditioned place preference (Marona-Lewicka et al., 1996, Meyer et al., 2002), a rat runway procedure (Wakonigg et al., 2003), behavioral sensitization (Ball et al., 2006, Kalivas et al., 1998), and drug self-administration (Beardsley et al., 1986, Ratzenboeck et al., 2001), have provided evidence of MDMA's positive reinforcing properties and potential for abuse.

In contrast, human MDMA use appears to be, for the most part, recreational or casual (Meilman et al., 1990, Solowij et al., 1992). It is not surprising, therefore, that many users believe MDMA is a safe drug with relatively low abuse potential (Murphy et al., 2006). Indeed, progressive-ratio self-administration studies in rhesus monkeys have shown that MDMA is a weaker reinforcer compared to the psychomotor stimulants methamphetamine and cocaine (Lile et al., 2005, Wang and Woolverton, 2007). Nonetheless, there are data to suggest that a minority of individuals find their MDMA use problematic (Topp et al., 1999) or meet the Diagnostic and Statistical Manual of Mental Disorders criteria for dependence (Cottler et al., 2001). Furthermore, recent reports suggest that, for a subgroup of users, MDMA is consumed in large amounts (Gouzoulis-Mayfrank et al., 2005, McCann et al., 2005), sometimes as much as 25 pills in a single session (Parrott, 2005). Taken together, these data suggest that although many MDMA users do not fit the profile of a compulsive user, there is a high degree of individual variability in the pattern of MDMA use and in the drug's potential for abuse (Soar et al., 2006).

To explore further the addictive potential of MDMA, we used an animal model of drug addiction known as the reinstatement model (Stewart and de Wit, 1987). This paradigm models the most challenging problem in clinical drug treatment—the high rate of relapse among addicts (Mendelson and Mello, 1996). In this model, the same stimuli that induce craving and relapse in humans, such as exposure to the drug, drug-associated cues, or a stressor (Jaffe et al., 1989;O'Brien et al., 1992, Sinha et al., 1999), are used to reinstate extinguished drug-seeking behavior in animals with a history of drug self-administration. Although these stimuli have been reported to reinstate responding for several drugs of abuse (Lệ and Shaham, 2002, Shalev et al., 2002), no studies to date have assessed whether this holds true for MDMA. To test this possibility, we used the reinstatement model to assess whether discrete cues previously paired with intravenously self-administered MDMA would reinstate extinguished MDMA-seeking behavior in rats. In addition, we assessed how individual rats' self-administration behavior was related to subsequent relapse vulnerability.

Section snippets

Animals

Data were collected from experimentally naïve adult (3–4 months of age) male Sprague–Dawley rats (n = 14), bred from animals supplied by Harlan Industries (Indianapolis, IN), and housed individually in a colony room maintained on a 12 h light cycle from 7:30 AM to 7:30 PM. Animals were allowed free access to water and were maintained at ∼ 85% of free-feeding body weight via restricted diet throughout experiments with the exception of a period before and after surgery during which animals were

MDMA self-administration

Fig. 1A shows the mean response rates for each of the 14 self-administration sessions. Animals acquired MDMA self-administration as determined by means of a one-tailed repeated measures t-test comparing responses/hour during the last self-administration session with responses during the last extinction session [t(6) = 2.00, p < 0.05]. Nonetheless, there was considerable variability in self-administration behavior both between animals and within individual animals across sessions. Mean (± S.E.M.)

Discussion

These results not only support and extend earlier studies showing that rats will intravenously self-administer MDMA (for review, see De La Garza et al., 2007), but also indicate that discrete MDMA-paired cues can reinstate extinguished MDMA-seeking behavior. Although the majority of previous MDMA self-administration studies in rats used either FR1 or FR2 schedules of reinforcement, the overall drug intake we report is very similar to these studies, which noted average infusion rates between 3

Conclusion

The present results provide the first evidence that discrete MDMA-associated cues reinstate extinguished MDMA-seeking behavior in animals. In addition, these findings show remarkable homology with two important observations in the clinical literature: 1) a minority of individuals are more vulnerable to compulsive drug use than most following recreational exposure to drugs and 2) the longer an individual uses drugs, the more prominent these differences become (Uhl, 2004). In this regard, MDMA

Acknowledgements

This work was supported by the National Institutes of Health grant DA 02451 (G.V.R.) and National Research Service Award DA 020209 (K.T.B.). MDMA was generously provided by the National Institute on Drug Abuse. The authors wish to thank Paul Langley for technical support, and Faye Caylor for editorial assistance.

References (45)

  • L. Topp et al.

    Ecstasy use in Australia: patterns of use and associated harm

    Drug Alcohol Depend

    (1999)
  • G.R. Uhl

    Molecular genetic underpinnings of human substance abuse vulnerability: likely contributions to understanding addiction as a mnemonic process

    Neuropharmacology

    (2004)
  • D.A. Baker et al.

    Influence of individual differences and chronic fluoxetine treatment on cocaine-seeking behavior in rats

    Psychopharmacology

    (2001)
  • K.T. Ball et al.

    Role of 5-HT2A and 5-HT2C/B receptors in the acute effects of 3,4-methylenedioxymethamphetamine (MDMA) on striatal single-unit activity and locomotion in freely moving rats

    Psychopharmacology

    (2005)
  • K.T. Ball et al.

    Context-dependent behavioural and neuronal sensitization in striatum to MDMA (ecstasy) administration in rats

    Eur J Neurosci

    (2006)
  • L.B. Cottler et al.

    Ecstasy abuse and dependence among adolescents and young adults: applicability and reliability of DSM-IV criteria

    Hum Psychopharmacol Clin Exp

    (2001)
  • E. Daniela et al.

    Conditioning following repeated exposure to MDMA in rats: role in the maintenance of MDMA self-administration

    Behav Pharmacol

    (2006)
  • R. De La Garza et al.

    Relevance of rodent models of intravenous MDMA self-administration to human MDMA consumption patterns

    Psychopharmacology

    (2007)
  • V. Deroche-Gamonet et al.

    Evidence of addiction-like behavior in the rat

    Science

    (2004)
  • R.A. Fuchs et al.

    Differential involvement of the core and shell subregions of the nucleus accumbens in conditioned cue-induced reinstatement of cocaine seeking in rats

    Psychopharmacology

    (2004)
  • R.A. Fuchs et al.

    Differential involvement of orbitofrontal cortex subregions in conditioned cue-induced and cocaine-primed reinstatement of cocaine seeking in rats

    J Neurosci

    (2004)
  • R.A. Fuchs et al.

    The role of the dorsomedial prefrontal cortex, basolateral amygdala, and dorsal hippocampus in contextual reinstatement of cocaine seeking in rats

    Neuropsychopharmacology

    (2005)
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