title: Acquisition of MDMA self-administration: pharmacokinetic factors and MDMA-induced serotonin release.
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.
authors.affiliation: School of Psychology, Victoria University of Wellington, New Zealand.
authors.forename: Sarah
authors.initials: S
authors.lastname: Bradbury
authors.forename: Judith
authors.initials: J
authors.lastname: Bird
authors.forename: Joyce
authors.initials: J
authors.lastname: Colussi-Mas
authors.forename: Melanie
authors.initials: M
authors.lastname: Mueller
authors.forename: George
authors.initials: G
authors.lastname: Ricaurte
authors.forename: Susan
authors.initials: S
authors.lastname: Schenk
mesh_terms: D015116:5,7-Dihydroxytryptamine / Q000494:pharmacology; D000818:Animals; D019540:Area Under Curve; D003042:Cocaine / Q000008:administration & dosage / Q000494:pharmacology; D003216:Conditioning, Operant / Q000187:drug effects; D004298:Dopamine / Q000378:metabolism; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D007262:Infusions, Intravenous; D008297:Male; D017551:Microdialysis / Q000379:methods; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000378:metabolism / Q000493:pharmacokinetics*; D009714:Nucleus Accumbens / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D012646:Self Administration; D012701:Serotonin / Q000378:metabolism*; D018490:Serotonin Agents / Q000494:pharmacology*
chemical_list: D018765:Dopamine Uptake Inhibitors; D018490:Serotonin Agents; D015116:5,7-Dihydroxytryptamine; D012701:Serotonin; D003042:Cocaine; D018817:N-Methyl-3,4-methylenedioxyamphetamine; D004298:Dopamine
keywords: Dopamine; MDMA; microdialysis; pharmacokinetics; self-administration; serotonin