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Differential Response of nNOS Knockout Mice to MDMA (“Ecstasy”)‐ and Methamphetamine‐Induced Psychomotor Sensitization and Neurotoxicity

Yossef Itzhak, Karen L. Anderson, Syed F. Ali

Annals of the New York Academy of Sciences October 1, 2004 DOI: 10.1196/annals.1316.015 (opens in new tab)

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Study at a glance

AI-extracted from the abstract
Characteristics Experimental study Peer reviewed
Population Mice (nNOS knockout and wild-type)
Interventions MDMA Methamphetamine
Duration 5-day repeated administration, 40-day persistence test
Topics MDMA
Keywords Sensitization Methamphetamine Meth- Neurotoxicity Pharmacology Dopaminergic
Citations 31
Key findings The nNOS gene is required for dopamine-mediated behavioral and neurotoxic effects of methamphetamine and MDMA, but not for serotonin-mediated effects of MDMA.

Abstract

A bstract : It has been shown that mice deficient in neuronal nitric oxide synthase (nNOS) gene are resistant to cocaine‐induced psychomotor sensitization and methamphetamine (METH)‐induced dopaminergic neurotoxicity. The present study was undertaken to investigate the hypothesis that nNOS has a major role in dopamine (DA)‐ but not serotonin (5‐hydroxytryptamine; 5‐HT)‐mediated effects of psychostimulants. The response of nNOS knockout (KO) and wild‐type (WT) mice to the psychomotor‐stimulating and neurotoxic effects of 3,4‐methylenedioxymethamphetamine (MDMA; “Ecstasy”) and METH were investigated. Repeated administration of MDMA for 5 days resulted in psychomotor sensitization in both WT and nNOS KO mice, while repeated administration of METH caused psychomotor sensitization in WT but not in KO mice. Sensitization to both MDMA and METH was persistent for 40 days in WT mice, but not in nNOS KO mice. These findings suggest that the induction of psychomotor sensitization to MDMA and METH is NO independent and NO dependent, respectively, while the persistence of sensitization to both drugs is NO dependent. For the neurochemical studies, a high dose of MDMA caused marked depletion of 5‐HT in several brain regions of both WT and KO mice, suggesting that the absence of the nNOS gene did not afford protection against MDMA‐induced depletion of 5‐HT. Striatal dopaminergic neurotoxicity caused by high doses of MDMA and METH in WT mice was partially prevented in KO mice administered with MDMA, but it was fully precluded in KO mice administered with METH. The differential response of nNOS KO mice to the behavioral and neurotoxic effects of MDMA and METH suggests that the nNOS gene is required for the expression and persistence of DA‐mediated effects of METH and MDMA, while 5‐HT‐mediated effects of MDMA (induction of sensitization and 5‐HT depletion) are not dependent on nNOS.

Comparable studies

Other preclinical and animal studies on MDMA, most cited first.

Study Year Design Participants
Neurotoxicity of the psychedelic amphetamine, methylenedioxymethamphetamine. Rats (implied by typical neurochemical study context) 1987 Experimental study
3,4-Methylenedioxymethamphetamine and 3,4-methylenedioxyamphetamine destroy serotonin terminals in rat brain: quantification of neurodegeneration by measurement of [3H]paroxetine-labeled serotonin uptake sites. Rat brain 1987 Animal experiment
Comparison of the monoamine transporters from human and mouse in their sensitivities to psychostimulant drugs Human and mouse dopamine, norepinephrine, and serotonin transporters expressed in cells 2006 In vitro laboratory study
Small Changes in Ambient Temperature Cause Large Changes in 3,4-Methylenedioxymethamphetamine (MDMA)-Induced Serotonin Neurotoxicity and Core Body Temperature in the Rat Rats 1998 Experimental study
Altered Serotonin Innervation Patterns in the Forebrain of Monkeys Treated with (±)3,4-Methylenedioxymethamphetamine Seven Years Previously: Factors Influencing Abnormal Recovery Squirrel monkeys treated with MDMA 1999 Observational cohort

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