Effects of repeated treatment with MDMA on working memory and behavioural flexibility in mice

Repeated high doses of MDMA (30 mg/kg) given to mice impaired working memory and cognitive flexibility, with deficits in recalling learned alternation behavior persisting five days after the last dose. The high dose also increased perseveration errors in an attentional set-shifting task, indicating reduced cognitive flexibility. These behavioral effects were not due to anhedonia, as saccharin preference remained unchanged. Although baseline dopamine levels in the striatum were unaffected, an acute MDMA challenge failed to increase dopamine outflow in mice that had received the high dose, suggesting reduced dopamine transporter function. Dopamine outflow recovered seven days later. The findings suggest that neurotoxic MDMA doses cause lasting impairments in recall and cognitive flexibility in mice.

Study at a glance

Abstract

ABSTRACT 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.