Enhanced Hyperthermia Induced by MDMA in Parkin Knockout Mice

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.

Overexpression of parkin in the rat nigrostriatal dopamine system protects against methamphetamine neurotoxicity

“…On the other hand, parkin might play a role in thermoregulation in rodents (Itier, et al, 2003, Takamatsu, et al, 2011). To examine whether parkin overexpression influences basal body temperature or METH-induced hyperthermia, parkin overexpressing rats were treated with saline or METH together with AAV2/6-injected controls.…”

“…Parkin may play a role in temperature regulation in amphetamine-exposed rodents. Firstly, parkin KO mice have decreased body temperature (Itier, et al, 2003), whereas 3,4-Methylenedioxymethamphetamine (MDMA)-exposed parkin KO mice show enhanced hyperthermia (Takamatsu, et al, 2011). Secondly, both temperature and parkin function are regulated by DA D1 receptor (Ares-Santos, et al, 2012, Berthet, et al, 2012) and, therefore, they might be functionally connected.…”

Monoamine Reuptake Inhibitors in Parkinson’s Disease

“…Heterozygous and homozygous parkin knockout mice are more likely to develop MDMA-induced hyperthermia (30 mg/kg i.p.) than wild-type parkin mice [ 742 ].…”