Acquisition of MDMA self‐administration: pharmacokinetic factors and MDMA‐induced serotonin release

Abstract

Abstract The current study aimed to elucidate the role of pharmacokinetic ( PK ) parameters and neurotransmitter efflux in explaining variability in (±) 3, 4‐methylenedioxymethamphetamine ( MDMA ) self‐administration in rats. PK profiles of MDMA and its major metabolites were determined after the administration of 1.0 mg/kg MDMA (iv) prior to, and following, the acquisition of MDMA self‐administration. Synaptic levels of 5‐hydroxytryptamine ( 5HT ) and dopamine ( DA ) in the nucleus accumbens were measured following administration of MDMA (1.0 and 3.0 mg/kg, iv) using in vivo microdialysis and compared for rats that acquired or failed to acquire MDMA self‐administration. Effects of the 5HT neurotoxin, 5,7 dihydroxytryptamine (5, 7‐ DHT ), on the acquisition of MDMA and cocaine self‐administration were also determined. In keeping with previous findings, approximately 50% of rats failed to meet a criterion for acquisition of MDMA self‐administration. The PK profiles of MDMA and its metabolites did not differ between rats that acquired or failed to acquire MDMA self‐administration. MDMA produced more overflow of 5HT than DA . The MDMA ‐induced 5HT overflow was lower in rats that acquired MDMA self‐administration compared with those that did not acquire self‐administration. In contrast, MDMA ‐induced DA overflow was comparable for the two groups. Prior 5,7‐ DHT lesions reduced tissue levels of 5HT and markedly increased the percentage of rats that acquired MDMA self‐administration and also decreased the latency to acquisition of cocaine self‐administration. These data suggest that 5HT limits the initial sensitivity to the positively reinforcing effects of MDMA and delays the acquisition of reliable self‐administration.