The Role of Serotonin in MDMA Self-administration in Rats

Rationale: The profile of acquisition for MDMA self-administration differs from that of amphetamine and cocaine self-administration in that fewer rats meet an acquisition criterion and the latency to acquisition is longer. These characteristics of MDMA self-administration may be because it preferentially stimulates serotonin (5HT) release whereas self-administration has generally been attributed to enhanced dopamine (DA) neurotransmission. Because 5HTergic agonists are not self-administered and increased synaptic 5HT decreased self-administration of other drugs, MDMA self-administration may be initially inhibited by the pronounced 5HT response. Accordingly, the acquisition of MDMA self-administration might proceed as a result of deficits in 5HT neurotransmission and a corresponding disinhibition of DA neurotransmission. Objective: The primary objective was to determine the role of 5HT in the acquisition and maintenance of MDMA self-administration. Methods: MDMA-induced increases of extracellular 5HT and DA and their primary metabolites were measured in the DA terminal regions of the nucleus accumbens (NAc) using in vivo microdialysis, prior to the commencement of MDMA self-administration. The relationship between MDMA-induced increases of neurotransmitter levels and the acquisition of MDMA self-administration was assessed. A subsequent study depleted brain 5HT by administering the neurotoxin, 5,7 – DHT, or vehicle into the lateral ventricle of the left hemisphere, prior to the commencement of MDMA self-administration. The proportion of subjects that acquired MDMA self-administration and the latency to acquire MDMA self-administration was compared for the two groups. In order to determine effects of MDMA self-administration on 5HT and DA responses, behaviours that reflect 5HT and/or DA neurotransmission were measured 5 or 14 days after self-administration of 165 mg/kg MDMA, or 14 days after vehicle self-administration. These time periods were chosen because they reflect a period of 5HT deficits (5 days) and recovery (14 days). Finally, the effect of abstinence on MDMA self-administration was measured. Results: The MDMA-induced increase of extracellular 5HT was significantly lower for the group that subsequently acquired MDMA self-administration but the MDMA-induced increase in DA was not different from the group that failed to acquire self-administration. 5, 7-DHT administration significantly decreased tissue levels of 5HT, but not DA. MDMA self-administration was facilitated by the lesion; 100% of the lesion group acquired MDMA self-administration, whereas only 50% of the control group acquired self-administration. Five days following the last MDMA self-administration session, DAergic behaviours were enhanced and 5HTergic behaviours were reduced relative to the control group. These differences in 5HTergic mediated behaviours were not apparent 14 days after self-administration but the DAergic behaviours remained elevated. The pattern of self-administration did not differ as a function of the length of the abstinence period. Conclusions: The variability in acquisition of MDMA self-administration was related to the magnitude of the 5HT response evoked by initial exposure to MDMA. These findings suggested that predisposing differences in the 5HT response might explain differences in the variability in acquisition of MDMA self-administration. The negative impact of 5HT on the acquisition of MDMA self-administration was clearly demonstrated following a 5, 7-DHT lesion. Thus, 5HT limits the development of MDMA self-administration. With repeated exposure to self-administered MDMA, behavioural responses indicative of 5HT activation were reduced whereas behavioural indices of DA activation were increased. The maintenance of MDMA self-administration was comparable regardless of whether there was a forced abstinence period or not. These data are consistent with the hypotheses that 5HT is inhibitory to the acquisition, but not the maintenance, of MDMA self-administration. Rather, the maintenance of self-administration might reflect sensitised DA responses that became apparent following repeated exposure.