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Ethanol–MDMA interactions in rats: the importance of interval between repeated treatments in biobehavioral tolerance and sensitization to the combination

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Abstract

Rationale

In our previous work, we showed that ethanol (EtOH) potentiates 3,4-methylenedioxymethamphetamine (MDMA)-induced hyperlocomotion while protecting against its hyperthermic effects. Whereas the effect on activity were found on all days (although declining over the three first days), the protection against hyperthermia completely disappeared on the second day. The latter effect was previously thought to reflect tolerance to ethanol or the combination, per se.

Objective

In the present study, we changed the treatment regimen to irregular and longer intervals between treatments (48, 120, and again 48 h) to check if tolerance was still observed.

Results

We found progressive sensitization of locomotor activity to EtOH (1.5 g/kg, i.p.)+MDMA (6.6 mg/kg, i.p.), and a partial EtOH protection against MDMA-induced hyperthermia that persisted after the first drug challenge day. When the monoamine neurotransmitters, dopamine, and serotonin were assessed 2 weeks after treatment, we found no consistent effect on the concentration of any of these neurotransmitters, whatever the treatment. Similarly, we found that regional brain concentrations of MDMA were not significantly affected by EtOH at a 45-min post-treatment delay; however, the overall ratio of the metabolite 3,4-methylenedioxyamphetamine (MDA) to MDMA was lower (overall, −16%) in animals treated with the combination compared to MDMA alone, indicating possible contribution of pharmacokinetic factors. This difference was especially marked in the striatum (−25%).

Conclusions

These findings shed new light on the consequences of EtOH–MDMA, taken together at a nearly normal ambient temperature, both in terms of motivation and potential risks for recreational drug users.

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Authors and Affiliations

  1. LINC-UMR 7191, Université Louis Pasteur–CNRS, Institut Fédérératif de Recherche 37, GDR CNRS 2905, 12 rue Goethe, 67000, Strasbourg, France

    Sami Ben Hamida, Erin Plute, Sonia Bach, Christine Lazarus, Christian Kelche, Anne Pereira de Vasconcelos & Jean-Christophe Cassel

  2. Institut Médico-légal de Strasbourg, Université Louis Pasteur, Faculté de Médecine, 11 rue Humann, 67085, Strasbourg, France

    Antoine Tracqui

  3. Biobehavioral Health, 315 E. HHD Building, The Pennsylvania State University, University Park, PA, 16802, USA

    Byron C. Jones

  4. LINC UMR 7191, Université Louis Pasteur-CNRS, Institut Fédératif de Recherche 37, 12 rue Goethe, 67000, Strasbourg, France

    Jean-Christophe Cassel

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  1. Sami Ben Hamida
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Correspondence to Jean-Christophe Cassel.

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Fig. 6

In a very recent preliminary experiment, adult male Long–Evans rats that were naive to MDMA, but not to ethanol (they had received daily ethanol treatments over a 2-week period), were injected with MDMA (6.6 mg/kg, i.p.) combined with 0.75 or 1.5 g/kg ethanol. Their locomotor activity was recorded in exactly the same way as in the related manuscript, except that sampling was performed in 15-min intervals. Figure 6, which is provided as supplementary material, shows that the magnitude of ethanol-enhanced MDMA hyperactivity is dependent upon the dose of ethanol. The difference between both groups was significant during the first 2 h (p < 0.05) (DOC 104 kb)

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Ben Hamida, S., Plute, E., Bach, S. et al. Ethanol–MDMA interactions in rats: the importance of interval between repeated treatments in biobehavioral tolerance and sensitization to the combination. Psychopharmacology 192, 555–569 (2007). https://doi.org/10.1007/s00213-007-0752-9

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