(±) 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 delayed non-matching to position (DNMTP) task. 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.

(±) 3,4-亚甲二氧基甲基苯丙胺 (MDMA) 是一种消遣性滥用的精神兴奋剂，会损害记忆力。这种影响通常归因于血清素系统受损导致的工作记忆障碍。然而，来自非人类动物实验研究的最新证据表明，急性 MDMA 可能通过过度刺激多巴胺 (DA) D1 受体间接损害记忆力，这会增加记忆任务期间的持续反应。使用在功能性 D1 受体中具有选择性下调的DA D1 突变体 (DAD1 ^-/- ) 大鼠探索了该假设。成年男性 Wistar DAD1 ^-/-大鼠和野生型对照接受了 25 次空间工作记忆 T 迷宫延迟不匹配位置 (DNMTP) 任务的训练。训练后，在 DNMTP 测试前 15 分钟给大鼠注射 MDMA（1.5、2.25 和 3 mg/kg）或生理盐水，所有受试者均接受所有药物剂量和生理盐水三次。我们预测，在 MDMA 之后，由于持续性错误的增加，控制会表现出任务准确性的降低。相比之下，我们预测，由于 D1 受体功能降低，DAD1 ^-/-大鼠将免受 MDMA 诱导的持续性错误的影响。正如预测的那样，在第三组 MDMA 给药期间，对照组大鼠在 2.25 和 3 mg/kg 剂量后表现出任务准确性降低，这是由持续错误的增加驱动的。此外，DAD1^-/-大鼠免受 MDMA 诱导的任务缺陷的影响。这些发现挑战了 MDMA 对记忆能力的急性影响主要是由于血清素能机制的假设，并为急性 MDMA 通过增加持续行为对 D1 受体的过度刺激而损害大鼠的记忆能力的假设提供了支持。