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Effects of repeated treatment with MDMA on working memory and behavioural flexibility in mice
Xavier Viñals1, Rafael Maldonado, Patricia Robledo
1Laboratory of Neuropharmacology, Pompeu Fabra University (UPF), Spain.
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.
Insights
Repeated high doses of 3,4-methylenedioxymethamphetamine (MDMA) cause lasting cognitive deficits in mice, including impaired working memory and reduced cognitive flexibility, by affecting dopamine transporter function.
Area of Science:
- Neuroscience
- Psychopharmacology
- Cognitive Science
Background:
- Repeated 3,4-methylenedioxymethamphetamine (MDMA) administration is known to cause dopaminergic neurotoxicity.
- The impact of MDMA-induced neurotoxicity on specific executive functions remains unclear.
Purpose of the Study:
- To investigate the effects of neurotoxic and non-neurotoxic doses of MDMA on working memory and attentional set-shifting in mice.
- To assess changes in extracellular dopamine (DA) levels in the striatum following MDMA treatment.
Main Methods:
- Mice received MDMA (0, 3, or 30 mg/kg) twice daily for 4 days.
- Cognitive functions were assessed using operant alternation and attentional set-shifting tasks.
- Extracellular DA levels were measured via microdialysis, with acute MDMA challenges used to assess DA transporter functionality.
Main Results:
- High-dose MDMA (30 mg/kg) impaired working memory (operant alternation) and attentional set-shifting, evidenced by increased perseveration errors.
- Impairments in alternation persisted for at least 5 days post-treatment.
- While basal striatal DA levels were unchanged, acute MDMA challenge revealed reduced DA outflow, indicating impaired DA transporter function, which recovered by 7 days post-treatment.
Conclusions:
- Repeated neurotoxic MDMA doses induce persistent deficits in recall of alternation behavior and cognitive flexibility in mice.
- These cognitive impairments are linked to a temporary decrease in dopamine transporter functionality.
- The study highlights the long-term cognitive consequences of MDMA neurotoxicity.
