The recreational use of 3,4-methylenedioxymethamphetamine (MDMA; Ecstasy) is often characterized by a repeated pattern of frequent drug administrations (binge) followed by a period of abstinence. Radiotelemetry was used to characterize the cardiovascular responses elicited during three MDMA binges (3 or 9 mg/kg b.i.d. for 4 days), each of which was separated by a 10-day MDMA-free period. The heart rate and mean arterial pressure (MAP) responses elicited by 3-mg/kg doses of MDMA were consistent within and between the three binges. In the first binge the 9-mg/kg doses of MDMA increased MAP and produced a biphasic (decrease/increase) heart rate response. The bradycardia elicited by MDMA in the first binge (Ϫ75 bpm) was enhanced in the second and third binges (Ϫ186 and Ϫ287 bpm, respectively). Significant hypotension accompanied the increased bradycardic responses. Atropine abolished the hypotension and significantly attenuated the bradycardic responses. The MAP and heart rate responses elicited by sodium nitroprusside, acetylcholine, phenylephrine, and serotonin (5-HT) were evaluated before each binge and 10 days after the last binge. The hypotension, but not the tachycardia elicited by sodium nitroprusside was attenuated by the repeated administration of MDMA. The responses to phenylephrine, acetylcholine, and 5-HT were unaltered after MDMA. The hearts of treated rats contained foci of inflammatory infiltrates (lymphocytes and macrophages), some of which contained necrotic cells and/or disrupted cytoarchitecture. MDMA produced cardiac arrhythmias in some rats. These results indicate that the binge administration of MDMA can significantly alter cardiovascular and cardiovascular reflex function and produce cardiac toxicity.

The mechanism of the pressor response to ephedrine is controversial. In the present study. i.v. injections of ephedrine increased systemic and pulmonary arterial pressure, and i.a. injections decreased hindlimb blood flow in a dose-related manner. Responses to ephedrine were inhibited by ␣-receptor blocking agents and were not attenuated by blockade of the norepinephrine reuptake transporter (NET) or by catecholamine depletion using reserpine or a combination of reserpine and ␣-methyl-p-tyrosine, whereas responses to tyramine and amphetamine were inhibited by these treatments. The magnitude of the pressor response to ephedrine was similar in anesthetized and conscious rats. Tachyphylaxis developed to pressor responses to ephedrine and amphetamine with sequential injections; however, ephedrine tachyphylaxis differed in that subsequent responses to ␣-receptor agonists were attenuated. These results suggest that the systemic and pulmonary pressor and hindlimb vasoconstrictor responses to ephedrine are mediated by direct action on ␣-adrenergic receptors and that the release of norepinephrine from adrenergic terminals plays no significant role. These results provide support for the hypothesis that responses to ephedrine are directly mediated in the intact rat, whereas responses to amphetamine are mediated in a large part by the release of norepinephrine from adrenergic terminals.

Gamma-hydroxybutyrate (GHB) is generally thought to be a central nervous system depressant; however, GHB also has sympathomimetic cardiovascular actions. Radio telemetry was used to record the cardiovascular responses elicited by GHB (180-1000 mg/kg IV) in conscious rats. GHB elicited increases in mean arterial pressure (MAP) (24 +/- 3 to 60 +/- 5 mm Hg) lasting from 28 +/- 8 to 227 +/- 37 minutes. GHB (560 and 1000 mg/kg IV) also elicited a prolonged tachycardic response (85 +/- 23 and 95 +/- 22 bpm). The hypertension and tachycardia elicited by GHB (560 mg/kg) were reversed by the intravenous and intracerebroventricular administration of the GABAb receptor antagonist CGP 35348. CGP 35348 also reversed GHB-mediated increases in renal sympathetic nerve activity (RSNA). Administration of the purported GHB receptor antagonist NCS-382 reversed the increase in heart rate but not the pressor response elicited by GHB in telemetered rats. These data indicate that the intravenous administration of GHB markedly increases MAP, heart rate, and RSNA in conscious rats via activation of central GABAb receptors. In addition, GHB receptors appear to selectively mediate the increase in heart rate elicited by large doses of GHB.

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Gamma-hydroxybutyrate (GHB) and its metabolic precursor, 1,4-butanediol (BDL) are widely used recreational drugs. Although most commonly described as CNS depressants, GHB and BDL elicit significant sympathomimetic cardiovascular responses (increases in mean arterial pressure (MAP) and heart rate) when administered parenterally. Given that humans most commonly ingest both drugs orally, we examined the dose-response relationships for intragastrically administered GHB and BDL on MAP and heart rate in conscious rats using radiotelemetry. The intragastric administration of GHB increased MAP. BDL increased both MAP and heart rate, and was approximately 10-fold more potent as a cardiovascular stimulant than GHB when administered intragastrically. Pretreatment with ethanol prevented the lethality of BDL. These data indicate that 1) both GHB and BDL produce cardiovascular responses when administered intragastrically, and 2) BDL is more potent and potentially more dangerous than GHB when administered via this route.