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Repeated administration of 3,4-methylenedioxymethamphetamine (MDMA) produces dopaminergic neurotoxicity in mice. However, it is still not clear whether this exposure induces deficits in cognitive processing related to specific subsets of executive functioning. We evaluated the effects of neurotoxic and non-neurotoxic doses of MDMA (0, 3 and 30 mg/kg, twice daily for 4 days) on working memory and attentional set-shifting in mice, and changes in extracellular levels of dopamine (DA) in the striatum. Treatment with MDMA (30 mg/kg) disrupted performance of acquired operant alternation, and this impairment was still apparent 5 days after the last drug administration. Decreased alternation was not related to anhedonia because no differences were observed between groups in the saccharin preference test under similar experimental conditions. Correct responding on delayed alternation was increased 1 day after repeated treatment with MDMA (30 mg/kg), probably because of general behavioural quiescence. Notably, the high dose regimen of MDMA impaired attentional set-shifting related to an increase in total perseveration errors. Finally, basal extracellular levels of DA in the striatum were not modified in mice repeatedly treated with MDMA with respect to controls. However, an acute challenge with MDMA (10 mg/kg) failed to increase DA outflow in mice receiving the highest MDMA dose (30 mg/kg), corroborating a decrease in the functionality of DA transporters. Seven days after this treatment, the effects of MDMA on DA outflow were recovered. These results suggest that repeated neurotoxic doses of MDMA produce lasting impairments in recall of alternation behaviour and reduce cognitive flexibility in mice., (© 2012 The Authors, Addiction Biology © 2012 Society for the Study of Addiction.)

Rationale: Repeated administration of 3,4-methylenedioxymethamphetamine (MDMA) produces mainly dopaminergic neurotoxicity in mice. However, the consequences of this exposure on the behavioural responses related to natural reinforcing stimuli are still largely unknown., Objectives: We examined whether repeated treatment with neurotoxic and non-neurotoxic doses of MDMA could exert acute and long-lasting effects on the motivation of mice to obtain a highly palatable food and on the extinction and reinstatement of food-seeking behaviour. Food-deprived mice were first trained to acquire stable responding on fixed ratio (FR) schedules of reinforcement and then treated twice daily with saline, 3 or 30 mg/kg MDMA during four consecutive days., Results: The high dose of MDMA impaired instrumental responding on the first and third day of treatment, whilst no residual effects were apparent on FR5 responding at any of the doses studied 24 h after treatment withdrawal. Breaking points were decreased in mice treated with both doses of MDMA. This decrease in motivation for palatable food was not due to unspecific locomotor or coordination deficits. A resistance to extinction was observed only with the highest dose of MDMA, whilst all mice showed similar reinstatement of palatable food-seeking behaviour irrespective of previous treatment. Autoradiography of [3H]-mazindol binding revealed a decrease in striatal dopamine transporter binding only in mice treated with the highest dose of MDMA., Conclusions: This study demonstrates that repeated treatment with MDMA decreases the incentive motivation for a palatable food reward and that long-lasting MDMA-induced dopaminergic neurotoxicity increases the resistance to extinction of responding in the absence of reward.