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

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.

Ethanol-ecstasy (MDMA) interactions in rats: preserved attenuation of hyperthermia and potentiation of hyperactivity by ethanol despite prior ethanol treatment.

Recreational use of ecstasy, or (+/-)-3,4-methylenedioxymethamphetamine (MDMA), is often associated with other drugs, among which ethanol is one of the most common. Little is known, however, about the interaction between these two drugs. Using a daily ethanol and/or MDMA administration regimen, we recently showed that ethanol potentiated the hyperactivity (in the home cage), but attenuated the hyperthermia induced by MDMA. The prevention of hyperthermia occurred only on the first of four daily ethanol-MDMA treatments, indicating possible tolerance to ethanol. In order to test the tolerance hypothesis, we treated Long-Evans adult male rats with ethanol on 4 consecutive days prior to their first treatment with MDMA-ethanol. Our results first confirmed that ethanol (1.5 g/kg, i.p.) potentiates the psychomotor effects of MDMA (10 mg/kg, i.p.), while attenuating its pyretic effects (6.6 mg/kg, i.p.). The results also showed that both the potentiation of locomotor activity and the attenuation of hyperthermia by ethanol are not at all altered by prior ethanol treatment. This indicates that tolerance to ethanol per se does not account for what appears to be tolerance to the ethanol-MDMA combination, thus indicating that ethanol-MDMA combination likely has unique pharmacological effects.