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

Mice lacking the neuronal nitric oxide synthase (nNOS) gene are resistant to methamphetamine-induced psychomotor sensitization and dopaminergic neurotoxicity, but not to serotonin-mediated effects of MDMA (Ecstasy). Repeated MDMA administration caused psychomotor sensitization in both normal and nNOS knockout mice, while methamphetamine caused sensitization only in normal mice. Sensitization to both drugs persisted for 40 days in normal mice but not in knockouts. High-dose MDMA depleted serotonin in several brain regions of both types, indicating nNOS absence does not protect against serotonin loss. Striatal dopamine neurotoxicity from high-dose MDMA and methamphetamine was partially prevented in knockouts given MDMA and fully prevented in knockouts given methamphetamine. The nNOS gene is required for dopamine-mediated effects of both drugs but not for serotonin-mediated effects of MDMA.

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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.