Effects of 3,4-methylenedioxymethamphetamine (MDMA) and its main metabolites on cardiovascular function in conscious rats

Br J Pharmacol. 2014 Jan;171(1):83-91. doi: 10.1111/bph.12423.

Abstract

Background and purpose: The cardiovascular effects produced by 3,4-methylenedioxymethamphetamine (MDMA; 'Ecstasy') contribute to its acute toxicity, but the potential role of its metabolites in these cardiovascular effects is not known. Here we examined the effects of MDMA metabolites on cardiovascular function in rats.

Experimental approach: Radiotelemetry was employed to evaluate the effects of s.c. administration of racemic MDMA and its phase I metabolites on BP, heart rate (HR) and locomotor activity in conscious male rats.

Key results: MDMA (1-20 mg·kg(-1)) produced dose-related increases in BP, HR and activity. The peak effects on HR occurred at a lower dose than peak effects on BP or activity. The N-demethylated metabolite, 3,4-methylenedioxyamphetamine (MDA), produced effects that mimicked those of MDMA. The metabolite 3,4-dihydroxymethamphetamine (HHMA; 1-10 mg·kg(-1)) increased HR more potently and to a greater extent than MDMA, whereas 3,4-dihydroxyamphetamine (HHA) increased HR, but to a lesser extent than HHMA. Neither dihydroxy metabolite altered motor activity. The metabolites 4-hydroxy-3-methoxymethamphetamine (HMMA) and 4-hydroxy-3-methoxyamphetamine (HMA) did not affect any of the parameters measured. The tachycardia produced by MDMA and HHMA was blocked by the β-adrenoceptor antagonist propranolol.

Conclusions and implications: Our results demonstrate that HHMA may contribute significantly to the cardiovascular effects of MDMA in vivo. As such, determining the molecular mechanism of action of HHMA and the other hydroxyl metabolites of MDMA warrants further study.

Keywords: BP; MDMA metabolites; heart rate; noradrenergic; telemetry.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • 3,4-Methylenedioxyamphetamine / metabolism
  • 3,4-Methylenedioxyamphetamine / pharmacology
  • Adrenergic beta-Antagonists / pharmacology
  • Animals
  • Blood Pressure / drug effects*
  • Cardiovascular System / drug effects*
  • Consciousness
  • Deoxyepinephrine / analogs & derivatives
  • Deoxyepinephrine / metabolism
  • Deoxyepinephrine / pharmacology
  • Dopamine / analogs & derivatives
  • Dopamine / pharmacology
  • Dose-Response Relationship, Drug
  • Hallucinogens / metabolism
  • Hallucinogens / pharmacology*
  • Heart Rate / drug effects*
  • Male
  • Metabolic Detoxication, Phase I
  • Methamphetamine / analogs & derivatives
  • Methamphetamine / metabolism
  • Methamphetamine / pharmacology
  • Motor Activity / drug effects
  • N-Methyl-3,4-methylenedioxyamphetamine / metabolism
  • N-Methyl-3,4-methylenedioxyamphetamine / pharmacology*
  • Rats
  • Rats, Sprague-Dawley
  • Telemetry
  • Time Factors

Substances

  • Adrenergic beta-Antagonists
  • Hallucinogens
  • 4-hydroxy-3-methoxymethamphetamine
  • 3-O-methyl-alpha-methyldopamine
  • alpha-methylepinine
  • Methamphetamine
  • 3,4-Methylenedioxyamphetamine
  • N-Methyl-3,4-methylenedioxyamphetamine
  • Deoxyepinephrine
  • Dopamine