Relevance of MDMA ("ecstasy")-induced neurotoxicity to long-lasting psychomotor stimulation in mice.
BACKGROUND
Although many studies have focused on the mechanisms underlying MDMA-induced neurotoxicity, little is known about the subsequent long-term response to psychostimulants following exposure to a neurotoxic dose of MDMA.


OBJECTIVE
We investigated the effect of pre-exposure to neurotoxic and non-neurotoxic doses of MDMA on the response of mice to the psychomotor stimulating effects of MDMA and cocaine.


METHODS
To investigate MDMA-induced neurotoxicity, male Swiss Webster mice were subjected to three regimens of MDMA: i) 40 mg/kg x 2, ii) 30 mg/kg x 2, and iii) 15 mg/kg x 2 for 2 days. On day 5 following the last exposure to MDMA, the levels of dopaminergic and serotonergic markers were determined. For the behavioral experiments, mice received either a single injection of 10 mg/kg MDMA [MDMA(L)] or one of the following doses of MDMA: 30 mg/kg x 2 or 15 mg/kg x 2 for 2 days [MDMA (H)]. A third group received saline as a control. On day 5 after the last pretreatment injection, the first MDMA (10 mg/kg) challenge was given, and on day 12, cocaine (20 mg/kg) was administered. Subsequently, mice were re-challenged with MDMA on days 35, 50 and 80, after which locomotor activity was monitored by infrared beam-interrupts. On day 83, mice were killed to detect the levels of dopaminergic and serotonergic markers.


RESULTS
MDMA-induced mortality and depletion of dopaminergic and serotonergic markers were dose-dependent. MDMA (H) mice endured a sensitized response to MDMA challenge from days 5 through 80, e.g. a persistent 3-fold increase in locomotor activity compared to the response of mice that were not pretreated with a neurotoxic dose of MDMA. The depletion of DAT and 5-HTT binding sites was sustained throughout this time period (64-68% of control). The MDMA (L) mice showed a sensitized response to MDMA only on day 5. Both MDMA (L) and MDMA (H) mice were sensitized to the cocaine challenge.


CONCLUSIONS
The induction of sensitization to the locomotor stimulating effects of MDMA and cocaine was independent of MDMA-induced neurotoxicity. However, the long-lasting maintenance of the sensitized response to MDMA may be related to the enduring neurotoxicity caused by MDMA.
Itzhak
Yossef
Y
Department of Psychiatry & Behavioral Sciences (R-629), Gautier Building Room # 503, University of Miami School of Medicine, 1011 NW 15th Street, Miami, FL 33136, USA. yitzhak@med.miami.edu
Ali
Syed F
SF
Achat
Cindy N
CN
Anderson
Karen L
KL
D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects; D002352:Carrier Proteins / Q000378:metabolism; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D003042:Cocaine / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins; D004305:Dose-Response Relationship, Drug; D006213:Hallucinogens / Q000633:toxicity*; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000378:metabolism; D051379:Mice; D009043:Motor Activity / Q000187:drug effects*; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000633:toxicity*; D009419:Nerve Tissue Proteins; D020258:Neurotoxicity Syndromes / Q000523:psychology*; D011985:Receptors, Serotonin / Q000187:drug effects; D012701:Serotonin / Q000378:metabolism; D050486:Serotonin Plasma Membrane Transport Proteins; D013997:Time Factors
D002352:Carrier Proteins; D000697:Central Nervous System Stimulants; D050483:Dopamine Plasma Membrane Transport Proteins; D006213:Hallucinogens; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D011985:Receptors, Serotonin; D050486:Serotonin Plasma Membrane Transport Proteins; C493215:Slc6a3 protein, mouse; C493231:Slc6a4 protein, mouse; D012701:Serotonin; D003042:Cocaine; D018817:N-Methyl-3,4-methylenedioxyamphetamine; D004298:Dopamine