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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on January 24, 2006; DOI: 10.1124/jpet.105.095760

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Received for publication September 26, 2005.
Revised January 19, 2006.
Accepted for publication January 19, 2006.

Repeated Adolescent MDMA Exposure in Rats Attenuates the Effects of a Subsequent Challenge with MDMA or a 5-HT1A Receptor Agonist

Brian J. Piper 1, Huyen L. Vu 1, Mina G. Safain 1, Andrew J. Oliver 1, Jerrold S. Meyer 1*

1 University of Massachusetts

* Address correspondence to: E-mail: jmeyer{at}psych.umass.edu

Abstract

Adolescent users of 3,4-methylenedioxymethamphetamine (MDMA) may escalate their dose due to the development of tolerance. We examined the influence of intermittent adolescent MDMA exposure on the behavioral, physiological, and neurochemical responses to a subsequent MDMA "binge" or to a 5-HT1A receptor challenge. Male Sprague-Dawley rats were administered MDMA (10 mg/kg b.i.d.), or saline, every fifth day on postnatal days (PD) 35-60. One week later on PD 67, animals were challenged with either multiple doses of MDMA (5 or 10 mg/kg x 4) or a single dose of the 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT; 0.1 or 0.5 mg/kg). Adolescent MDMA exposure partially attenuated the hyperthermic effects of the PD 67 MDMA challenge, completely blocked the locomotor hypoactivity otherwise observed on the day following the challenge, and also prevented MDMA-induced serotonin neurotoxicity assessed on PD 74 by measuring regional [3H]citalopram binding to the serotonin transporter (SERT). Adolescent MDMA-treated animals also showed a partial attenuation of the serotonin syndrome, but not the hypothermic, response to the high dose of 8-OH-DPAT. However, there was no effect of MDMA administration on regional [3H]WAY-100635 binding to 5-HT1A receptors in the brain or spinal cord. These results suggest that chronic, intermittent MDMA exposure during adolescence induces neuroadaptive changes that can protect against the adverse consequences of a subsequent dose escalation. On the other hand, the same exposure pattern appears to produce a partial 5-HT1A receptor desensitization, which may negatively influence the therapeutic responses of chronic MDMA users treated with serotonergic agents for various affective or anxiety disorders.


Key words: MDMA, adolescent, neurotoxicity, rats, serotonin, tolerance




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