Acquisition of MDMA self-administration: Pharmacokinetic factors and MDMA-induced serotonin release

Sarah Bradbury, Judith Bird, Joyce Colussi-Mas, Melanie Mueller, George Ricaurte, Susan Schenk

Research output: Contribution to journalArticle

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. 5,7 DHT lesions that decreased 5HT in a number of brain regions facilitated the acquisition of both MDMA and cocaine self-administration. Only about 50% of the control rats met a criterion for acquisition of MDMA self-administration within 25 days of testing, but all of the lesioned rats met the criterion and did so with a shorter latency than the control rats. These data support the idea that MDMA- and cocaine-produced increases in 5HT delays the acquisition of self-administration.

Original languageEnglish (US)
Pages (from-to)874-884
Number of pages11
JournalAddiction Biology
Volume19
Issue number5
DOIs
StatePublished - Sep 2014

Keywords

  • Dopamine
  • MDMA
  • microdialysis
  • pharmacokinetics
  • self-administration
  • serotonin

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Pharmacology
  • Psychiatry and Mental health

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