Increased iNOS and Nitrosative Stress in Dopaminergic Neurons of MDMA-Exposed Rats

Stefania Schiavone; Margherita Neri; Angela Bruna Maffione; Paolo Frisoni; Maria Grazia Morgese; Luigia Trabace; Emanuela Turillazzi

doi:10.3390/ijms20051242

Increased iNOS and Nitrosative Stress in Dopaminergic Neurons of MDMA-Exposed Rats

Stefania Schiavone, Margherita Neri, Angela Bruna Maffione, Paolo Frisoni, Maria Grazia Morgese, Luigia Trabace, Emanuela Turillazzi

International Journal of Molecular Sciences March 12, 2019 DOI: 10.3390/ijms20051242 (opens in new tab)

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Study at a glance

AI-extracted from the abstract

Characteristics	Observational cohort Peer reviewed
Population	Rats
Intervention	MDMA
Duration	6 h, 16 h, or 24 h after administration
Topics	MDMA
Keywords	Dopaminergic Pharmacology Oxidative stress
Citations	22
Key findings	iNOS-derived nitrosative stress, but not NOX enzymes, may play a crucial role in MDMA-induced neurotoxicity in the rat frontal cortex.

Abstract

Several mechanisms underlying 3,4-Methylenedioxy-N-methylamphetamine (MDMA) neurotoxicity have been proposed, including neurochemical alterations and excitotoxicity mediated by reactive oxygen species (ROS), nitric oxide (NO), and reactive nitrogen species (RNS). However, ROS, NO, and RNS sources in the brain are not fully known. We aimed to investigate possible alterations in the expression of the ROS producer NOX enzymes (NOX2, NOX1, and NOX4), NO generators (iNOS, eNOS, and nNOS), markers of oxidative (8-hydroxy-2′-deoxyguanosine, 8OHdG), and nitrosative (3-nitrotyrosine, NT) stress, as well as the colocalization between cells positive for the dopamine transporter (DT1) and cells expressing the neuronal nuclei (NeuN) marker, in the frontal cortex of rats receiving saline or MDMA, sacrificed 6 h, 16 h, or 24 h after its administration. MDMA did not affect NOX2, NOX1, and NOX4 immunoreactivity, whereas iNOS expression was enhanced. The number of NT-positive cells was increased in MDMA-exposed animals, whereas no differences were detected in 8OHdG expression among experimental groups. MDMA and NT markers colocalized with DT1 positive cells. DT1 immunostaining was found in NeuN-positive stained cells. Virtually no colocalization was observed with microglia and astrocytes. Moreover, MDMA immunostaining was not found in NOX2-positive cells. Our results suggest that iNOS-derived nitrosative stress, but not NOX enzymes, may have a crucial role in the pathogenesis of MDMA-induced neurotoxicity, highlighting the specificity of different enzymatic systems in the development of neuropathological alterations induced by the abuse of this psychoactive compound.

Comparable studies

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

Study	Year	Design
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

Citations in the library

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