MDMA pretreatment leads to mild chronic unpredictable stress-induced impairments in spatial learning.

Prior exposure to MDMA makes rats vulnerable to stress-induced learning impairments that do not occur with stress alone. Rats pretreated with MDMA and then exposed to mild chronic unpredictable stress seven days later showed impaired learning in the Morris water maze, whereas stress alone did not cause this deficit. MDMA alone increased anxiety-like behavior on the elevated plus maze, but chronic stress alone or combined with MDMA pretreatment did not increase anxiety. The learning impairment was not accompanied by enhanced depletion of the serotonin transporter in the hippocampus, suggesting the effect involves mechanisms beyond serotonin transporter loss.

Study at a glance

Abstract

3,4-Methylenedioxymethamphetamine (MDMA) is a drug of abuse worldwide and a selective serotonin (5-HT) neurotoxin. An important factor in the risk of drug abuse and relapse is stress. Although multiple parallels exist between MDMA abuse and stress, including effects on 5-HTergic neurotransmission, few studies have investigated the consequences of combined exposure to MDMA and chronic stress. Therefore, rats were pretreated with MDMA and exposed 7 days later to 10 days of mild chronic unpredictable stress (CUS). MDMA pretreatment was hypothesized to enhance the effects of CUS leading to enhanced 5-HT transporter (SERT) depletion in the hippocampus and increased anxiety and cognitive impairment. Whereas MDMA alone increased anxiety-like behavior on the elevated plus maze, CUS alone or in combination with MDMA pretreatment did not increase anxiety-like behavior. In contrast, MDMA pretreatment led to CUS-induced learning impairment in the Morris water maze but not an enhanced depletion of hippocampal SERT protein. These results show that prior exposure to MDMA leads to stress-induced impairments in learning behavior that is not otherwise observed with stress alone and appear unrelated to an enhanced depletion of SERT.