Repeated exposure to MDMA provides neuroprotection against subsequent MDMA-induced serotonin depletion in brain.
Repeated exposure to sub-lethal insults has been reported to result in neuroprotection against a subsequent deleterious insult. The purpose of this study was to evaluate whether repeated exposure (preconditioning) to a non-5-HT depleting dose of MDMA in adult rats provides neuroprotection against subsequent MDMA-induced 5-HT depletion. Treatment of rats with MDMA (10 mg/kg, ip every 2 h for 4 injections) resulted in a 50-65% depletion of 5-HT in the striatum, hippocampus and cortex, and these depletions were significantly attenuated in rats that received a preconditioning regimen of MDMA (10 mg/kg, ip daily for 4 days). The 5-HT depleting regimen of MDMA also resulted in a 40-80% reduction in 5-HT transporter immunoreactivity (SERT(ir)), and the reduction in SERT(ir) also was completely attenuated in MDMA-preconditioned animals. Preconditioning with MDMA (10 mg/kg, ip) daily for 4 days provided neuroprotection against methamphetamine-induced 5-HT depletion, but not dopamine depletion, in the striatum. Additional studies were conducted to exclude the possibility that alterations in MDMA pharmacokinetics or MDMA-induced hyperthermia in rats previously exposed to MDMA contribute towards neuroprotection. During the administration of the 5-HT depleting regimen of MDMA, there was no difference in the extracellular concentration of the drug in the striatum of rats that had received 4 prior, daily injections of vehicle or MDMA. Moreover, there was no difference in the hyperthermic response to the 5-HT depleting regimen of MDMA in rats that had earlier received 4 daily injections of vehicle or MDMA. Furthermore, hyperthermia induced by MDMA during preconditioning appears not to contribute towards neuroprotection, inasmuch as preconditioning with MDMA at a low ambient temperature at which hyperthermia was absent did not alter the neuroprotection provided by the preconditioning regimen. Thus, prior exposure to MDMA affords protection against the long-term depletion of brain 5-HT produced by subsequent MDMA administration. The mechanisms underlying preconditioning-induced neuroprotection for MDMA remain to be determined.
Bhide
Nirmal S
NS
College of Pharmacy, University of Cincinnati, Cincinnati, OH 45267, USA.
Lipton
Jack W
JW
Cunningham
Jacobi I
JI
Yamamoto
Bryan K
BK
Gudelsky
Gary A
GA
D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology; D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D004361:Drug Tolerance / Q000502:physiology*; D005334:Fever / Q000139:chemically induced; D008694:Methamphetamine / Q000494:pharmacology; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000494:pharmacology*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D016601:RNA-Binding Proteins / Q000096:biosynthesis / Q000187:drug effects; D051381:Rats; D012701:Serotonin / Q000378:metabolism; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*
D018759:Adrenergic Uptake Inhibitors; D004298:Dopamine; D008694:Methamphetamine; D018817:N-Methyl-3,4-methylenedioxyamphetamine; D018696:Neuroprotective Agents; D016601:RNA-Binding Proteins; D012701:Serotonin; D017367:Selective Serotonin Reuptake Inhibitors; C482440:Sert1 protein, rat