Tolerance to 3,4-methylenedioxymethamphetamine in rats exposed to single high-dose binges.
Michael H. Baumann, R D Clark, F H Franken, J J Rutter, Richard B Rothman
Neuroscience March 27, 2008 DOI: 10.1016/j.neuroscience.2008.01.007 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental animal study Peer reviewed |
|---|---|
| Population | Male rats |
| Intervention | MDMA |
| Dose | 1.5 mg/kg x3 (low dose) or 7.5 mg/kg x3 (high dose), i.p.; challenge doses of 1 and 3 mg/kg i.v. |
| Duration | 2 weeks after binges for challenge tests |
| Topics | MDMA |
| Key findings | High-dose MDMA binges caused approximately 50% loss of forebrain serotonin and reduced subsequent MDMA-evoked hormone secretion and serotonin release, while low-dose binges had no such effects. The authors propose that MDMA tolerance in humans may reflect serotonin deficits, potentially leading to dose escalation. |
Abstract
3,4-Methylenedioxymethamphetamine (MDMA or ecstasy) stimulates the transporter-mediated release of monoamines, including 5-HT. High-dose exposure to MDMA causes persistent 5-HT deficits (e.g. depletion of brain 5-HT) in animals, yet the functional and clinical relevance of such deficits are poorly defined. Here we examine functional consequences of MDMA-induced 5-HT depletions in rats. Male rats received binges of three i.p. injections of MDMA or saline, one injection every 2 h; MDMA was given at a threshold pharmacological dose (1.5 mg/kgx3, low dose) or at a fivefold higher amount (7.5 mg/kgx3, high dose). One week later, jugular catheters and intracerebral guide cannulae were implanted. Two weeks after binges, rats received acute i.v. challenge injections of 1 and 3 mg/kg MDMA. Neuroendocrine effects evoked by i.v. MDMA (prolactin and corticosterone secretion) were assessed via serial blood sampling, while neurochemical effects (5-HT and dopamine release) were assessed via microdialysis in brain. MDMA binges elevated core temperatures only in the high-dose group, with these same rats exhibiting approximately 50% loss of forebrain 5-HT 2 weeks later. Prior exposure to MDMA did not alter baseline plasma hormones or dialysate monoamines, and effects of i.v. MDMA were similar in saline and low-dose groups. By contrast, rats pretreated with high-dose MDMA displayed significant reductions in evoked hormone secretion and 5-HT release when challenged with i.v. MDMA. As tolerance developed only in rats exposed to high-dose binges, hyperthermia and 5-HT depletion are implicated in this phenomenon. Our results suggest that MDMA tolerance in humans may reflect 5-HT deficits which could contribute to further dose escalation.
Comparable studies
Other preclinical and animal studies on MDMA, most cited first.
Citations in the library
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- Dopaminergic mechanisms of reinstatement of MDMA‐seeking behaviour in rats British Journal of Pharmacology December 30, 2010
- Acquisition of MDMA self‐administration: pharmacokinetic factors and MDMA‐induced serotonin release Addiction Biology June 14, 2013
- Drug seeking in response to a priming injection of MDMA in rats: relationship to initial sensitivity to self-administered MDMA and dorsal striatal dopamine The International Journal of Neuropsychopharmacology March 25, 2010
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Cites 32
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