MDMA: effects on sleep and the circadian system

Abstract

±3,4-methylenedioxymethamphetamine (MDMA) commonly referred to as ‘ecstasy’ is an illicit drug, often associated with raves and house parties. Ecstasy prinicipally targets the serotonergic (5-HT) system, where it acutely raises levels of this neurotransmitter. Subsequently however, ecstasy use leads to reduced 5-HT availability, possibly due to a functional loss or impairment of the serotonergic transporter (SERT). These marked changes in 5-HT functioning have implications for ecstasy users given that 5-HT is an essential regulator of many behavioural and physiological functions including mood, temperature regulation, sleep, and circadian rhythmicity. Given the paucity of research which has investigated the effects of ecstasy upon sleep and circadian rhythms, the following dissertation aimed to investigate the following: (1) The nature of any functional deficits in sleep in ecstasy users; and (2) Mechanisms of action of MDMA on the circadian timing system, examined in an animal model at both the behavioural and genetic levels. The results of this dissertation demonstrated that in a sample of ecstasy users (n=395), a high proportion (~70%) had clinically significant problems with their sleep quality, with those at greatest risk identified as regularly taking more ecstasy per occasion of use, reporting either harm to themselves or others following their ecstasy use, or reporting being told to cut down on their ecstasy use. Importantly, this subgroup of ecstasy users was also more impaired on a number of sleep domains including sleep latency and use of sleep medication. Based on these findings, we speculated that the circadian system, which is partially responsible for control of sleep initiation and maintenance, may be affected by the drug. Hence, subsequent experiments were conducted to test this hypothesis in a rodent model utilising both behavioural and genetic outcome measures. These experiments demonstrated that a single, moderate dose of MDMA (either 5 or 10 mg/kg) disrupted measures associated with the circadian system. When rats were housed under a 12-12 h light-dark cycle, their activity was substantially altered, such that they did a greater proportion of their wheel running during their normal ‘rest’ phase, without a significant increase in their total activity for the day. In contrast, when MDMA was administered to rats that were subsequently held under constant darkness to monitor its effects on the circadian pacemaker, we found time-of-day dependent effects on their length of activity (alpha), the timing of offset of activity and the circadian period (cycle length) assessed over ten days post administration. Subsequent examination of cfos and Per gene expression determined that a single dose of MDMA (5mg/kg) disrupted the normal cycling of these genes, such that Per1 and Per2 were over expressed at ZT16 (during the dark phase) and cfos was induced at both ZT16 and ZT6. Taken together, these findings represent the first studies to have directly examined circadian involvement in mediating some of the effects of MDMA. The importance of these results corroborates the initial finding that the majority of ecstasy users report sleep disturbance acutely following ecstasy use, which may persist following a period of abstinence. The collective implications of these outcomes and future directions for research within this area are discussed.