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

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

Charles W Schindler  1 , Eric B Thorndike, Bruce E Blough, Srihari R Tella, Steven R Goldberg, Michael H Baumann
Affiliations

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

Charles W Schindler et al. Br J Pharmacol. 2014 Jan.

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.

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Figures

Figure 1
Figure 1
Metabolism of MDMA in humans and rats. Abbreviations for drug names are found in the text. The main cytochrome p450 (CYP) isoforms responsible for specific biotransformation reactions are given for humans (H) and rats (R). Catechol-O-methyltransferase is abbreviated as COMT. Thick arrows represent major pathways of metabolism, whereas thin arrows represent minor pathways.
Figure 2
Figure 2
Effects of MDMA, HHMA, HMMA and saline on BP (A, B), HR (C, D) and activity (E, F). Left-hand panels (A, C and E) depict time course data for a selected dose of MDMA (10 mg·kg−1) and HHMA (10 mg·kg−1) compared with saline. Each point represents mean ± SEM during a 5 min period. Right-hand panels (B, D and F) show the mean change scores (Δ) over the entire 120 min session for all doses tested. Change scores are compared with saline control. Filled symbols indicate significant difference (P < 0.05) with respect to saline-treated rats. Number of rats per dose is given for MDMA in (B) and for HHMA and HMMA in (D). Number of rats for saline for each drug is given in Table 1. Both MDMA and HHMA significantly increased HR. Only MDMA significantly increased BP and activity.
Figure 3
Figure 3
Effects of MDA, HHA, HMA and saline on BP (A, B), HR (C, D) and activity (E, F). Left-hand panels (A, C and E) depict time course data for a selected dose of MDA (10 mg·kg−1) and HHA (10 mg·kg−1) compared with saline. Each point represents mean ± SEM during a 5 min period. Right-hand panels (B, D and F) show the mean change scores (Δ) over the entire 120 min session for all drugs tested. Change scores are compared with saline control. Filled symbols indicate significant difference (P < 0.05) with respect to saline-treated rats. Number of rats per dose is given for MDA in (B) and for HHA and HMA in (D). Number of rats for saline for each drug is given in Table 1. Both MDA and HHA significantly increased BP. HHA also increased HR and MDA significantly increased activity.
Figure 4
Figure 4
Effects of MDMA (3 mg·kg−1) and HHMA (3 mg·kg−1) alone and in combination with propranolol (1 mg·kg−1) on HR. The filled bars indicate that both MDMA and HHMA significantly (P < 0.05) increased HR compared with saline-treated controls. Significant increases in HR were not observed for MDMA and HHMA following pretreatment with propranolol. Propranolol alone did not significantly affect HR. n = 4 for every condition.
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