Enhanced Hyperthermia Induced by MDMA in Parkin Knockout Mice

S Kasai,T Iwamura,H Shiotsuki,N Hattori,K Ikeda,Y Takamatsu,S Sato

doi:10.2174/157015911795016985

Abstract

MDMA (3,4-methylenedioxymethamphetamine) is reportedly severely toxic to both dopamine (DA) and serotonin neurons. MDMA significantly reduces the number of DA neurons in the substantia nigra, but not in the nucleus accumbens, indicating that MDMA causes selective destruction of DA neurons in the nigrostriatal pathway, sparing the mesolimbic pathway. Parkinson’s disease (PD) is a neurodegenerative disorder of multifactorial origin. The pathological hallmark of PD is the degeneration of DA neurons in the nigrostriatal pathway. Mutations in the parkin gene are frequently observed in autosomal recessive parkinsonism in humans. Parkin is hypothesized to protect against neurotoxic insult, and we attempted to clarify the role of parkin in MDMA-induced hyperthermia, one of the causal factors of neuronal damage, using parkin knockout mice. Body temperature was measured rectally before and 15, 30, 45, and 60 min after intraperitoneal injection of MDMA (30 mg/kg) at an ambient temperature of 22 ± 2°C. Significantly enhanced hyper-thermia after MDMA injection was observed in heterozygous and homozygous parkin knockout mice compared with wildtype mice, suggesting that parkin plays a protective role in MDMA neurotoxicity.

Highlights

The amphetamine derivative 3,4-methylenedioxymethamphetamine (MDMA) is abused by young adults despite its potentially neurotoxic effects and psychiatric complications
No significant difference in baseline body temperature was observed among wildtype, heterozygous, and homozygous parkin knockout mice (Fig. 1)
MDMA significantly enhanced hyperthermia from 15 to 45 min after injection in parkin knockout mice and from 45 to 60 min after injection in heterozygous mice compared with wildtype mice (Fig. 3A)

Summary

Introduction

The amphetamine derivative 3,4-methylenedioxymethamphetamine (MDMA) is abused by young adults despite its potentially neurotoxic effects and psychiatric complications. MDMA produces a rapid enhancement of serotonin and dopamine (DA) release in the brain [1, 2]. Administration of MDMA in mice is well known to produce acute hyperthermia and degeneration of striatal DA nerve terminals [3]. Granado and colleagues [4] reported that MDMA produces a significant decrease in the number of tyrosine hydroxylase (TH)-immunoreactive neurons in the substantia nigra. This decrease was accompanied by a dosedependent decrease in TH- and DA transporter (DAT)immunoreactivity in the striatum. Attenuation of the hyperthermia alleviates MDMA-induced loss of striatal dopamine [3]

Methods

Results

Conclusion