MDMA alters the response of the mammalian circadian clock in hamsters: Effects on re-entrainment and triazolam-induced phase shifts

Serotonin (5-hydroxytryptamine or 5-HT) is a neurotransmitter that is involved in a wide range of behavioural and physiological processes. Previous work has indicated that serotonin is important in the regulation of the circadian clock, which is located in the suprachiasmatic nuclei (SCN) of the hypothalamus. 3,4-methylenedioxymethamphetamine (MDMA or ‘Ecstasy’), which is widely used as a recreational drug of abuse, is a serotonin neurotoxin in animals and non-human primates. Previous work has shown that MDMA exposure can alter circadian clock function both in vitro and in vivo. Evidence shows that 5-HT may have a modulatory role in the regulation of the circadian clock by non-photic stimuli, such as the benzodiazepine triazolam (TRZ). Triazolam is a short-acting benzodiazepine that results in phase advances of the wheel running activity in hamsters when administered during the mid-subjective day. In the present study, male Syrian hamsters treated with TRZ (5 mg/kg) at ZT6 significantly phase advanced their clock. Treatment with MDMA significantly diminished the TRZ induced phase shift in hamsters. Previous evidence shows the involvement of 5-HT in the re-synchronisation of the endogenous clock to a new shifted light–dark cycle. Untreated animals were successfully entrained to a new, 6 h advanced light–dark cycle within an average of 4.5 ± 0.1 days. Following treatment with MDMA, these animals took an average of 8.3 ± 0.1 days to re-entrain to a shifted environmental cycle. Immunohistochemical analysis revealed that animals treated with MDMA showed reduced serotonin staining, as evidenced by a decrease in innervation density in the SCN. No significant differences were found in cell counts within the raphe nuclei. These results demonstrate the importance of the serotonergic system in the modulation of photic and non-photic responses of the circadian pacemaker