The role of dopamine D1 receptors in MDMA-induced memory impairments

(±) 3,4-methylenedioxymethamphetamine (MDMA) is a recreationally abused psychostimulant that impairs memory performance. This effect is often attributed to a working memory impairment resulting from compromised serotonin systems. However, recent evidence from non-human animal experimental studies suggests that acute MDMA may indirectly impair memory performance through overstimulation of dopamine (DA) D1 receptors, which increases perseverative responding during memory tasks. This hypothesis was explored using DA D1 mutant (DAD1-/-) rats which possess a selective down-regulation in functional D1 receptors. Adult male Wistar DAD1-/- rats and wild type controls were trained over 25 sessions on a spatial working memory T-maze task, delayed non-matching to position (DNMTP). Once trained, the rats were administered MDMA (1.5, 2.25 and 3 mg/kg) or saline fifteen minutes prior to testing on DNMTP with all subjects experiencing all drug doses and saline three times. We predicted that controls would demonstrate decreased task accuracy following MDMA, driven by an increase in perseverative errors. In contrast, we predicted that DAD1-/- rats would be protected from MDMA-induced perseverative errors due to their reduced D1 receptor function. As predicted, during the third block of MDMA administration, control rats demonstrated decreased task accuracy following 2.25 and 3 mg/kg doses, driven by an increase in perseverative errors. In addition, DAD1-/- rats were protected from MDMA-induced task deficits. These findings challenge the assumption that MDMA’s acute effects on memory performance are predominantly due to serotonergic mechanisms and provide support for the hypothesis that acute MDMA impairs memory performance in rats via overstimulation of D1 receptors by increasing perseverative behaviour.