Dopamine D2-receptor knockout mice are protected against dopaminergic neurotoxicity induced by methamphetamine or MDMA
Noelia Granado, Sara Ares-Santos, Idaira Oliva, Esther O’shea, Eduardo D. Martin, María Isabel Colado, Rosario Moratalla
Neurobiology of Disease March 22, 2021 DOI: 10.1016/j.nbd.2011.01.033 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study using knockout mice Peer reviewed |
|---|---|
| Population | Dopamine D2 receptor knock-out mice (D2R−/−) and wild-type mice |
| Interventions | Methamphetamine MDMA reserpine |
| Duration | 1 and 7 days after drug exposure |
| Topics | MDMA |
| Keywords | Th Dat Dopamine Neurotoxicity Neurodegeneration |
| Citations | 117 |
| Key findings | Inactivation of the dopamine D2 receptor prevents methamphetamine- and MDMA-induced neurotoxicity, including hyperthermia, loss of dopamine markers, inflammation, and dopaminergic cell loss, independently of body temperature. |
Abstract
Methamphetamine (METH) and 3,4-methylenedioxymethamphetamine (MDMA), amphetamine derivatives widely used as recreational drugs, induce similar neurotoxic effects in mice, including a marked loss of tyrosine hydroxylase (TH) and dopamine transporter (DAT) in the striatum. Although the role of dopamine in these neurotoxic effects is well established and pharmacological studies suggest involvement of a dopamine D2-like receptor, the specific dopamine receptor subtype involved has not been determined. In this study, we used dopamine D2 receptor knock-out mice (D2R−/−) to determine whether D2R is involved in METH- and MDMA-induced hyperthermia and neurotoxicity. In wild type animals, both drugs induced marked hyperthermia, decreased striatal dopamine content and TH- and DAT-immunoreactivity and increased striatal GFAP and Mac-1 expression as well as iNOS and interleukin 15 at 1 and 7 days after drug exposure. They also caused dopaminergic cell loss in the SNpc. Inactivation of D2R blocked all these effects. Remarkably, D2R inactivation prevented METH-induced loss of dopaminergic neurons in the SNpc. In addition, striatal dopamine overflow, measured by fast scan cyclic voltammetry in the presence of METH, was significantly reduced in D2R−/− mice. Pre-treatment with reserpine indicated that the neuroprotective effect of D2R inactivation cannot be explained solely by its ability to prevent METH-induced hyperthermia: reserpine lowered body temperature in both genotypes, and potentiated METH toxicity in WT, but not D2R−/− mice. Our results demonstrate that the D2R is necessary for METH and MDMA neurotoxicity and that the neuroprotective effect of D2R inactivation is independent of its effect on body temperature.
Comparable studies
Other preclinical and animal studies on MDMA, most cited first.
Citations in the library
Cited by 15
- Psychedelics in Psychiatry: Neuroplastic, Immunomodulatory, and Neurotransmitter Mechanisms Pharmacological Reviews December 16, 2020
- MPTP‐induced dopamine neuron degeneration and glia activation is potentiated in MDMA‐pretreated mice Movement Disorders September 20, 2013
- Pharmacokinetics and pharmacodynamics of 3,4-methylenedioxymethamphetamine (MDMA): interindividual differences due to polymorphisms and drug–drug interactions Critical Reviews in Toxicology October 3, 2012
- Brain dysfunctions and neurotoxicity induced by psychostimulants in experimental models and humans: an overview of recent findings Neural Regeneration Research February 22, 2024
- A study on the mechanism by which MDMA protects against dopaminergic dysfunction after minimal traumatic brain injury (mTBI) in mice. Journal of Molecular Neuroscience December 1, 2014
and 10 more in the library
Cites 6
- A study of the mechanisms involved in the neurotoxic action of 3,4‐methylenedioxymethamphetamine (MDMA, ‘ecstasy’) on dopamine neurones in mouse brain British Journal of Pharmacology December 1, 2001
- Persistent MDMA‐induced dopaminergic neurotoxicity in the striatum and substantia nigra of mice Journal of Neurochemistry September 24, 2008
- A comparative study on the acute and long‐term effects of MDMA and 3,4‐dihydroxymethamphetamine (HHMA) on brain monoamine levels after i.p. or striatal administration in mice British Journal of Pharmacology 2005
- Early loss of dopaminergic terminals in striosomes after MDMA administration to mice Synapse October 25, 2007
- Differential toxic effects of methamphetamine (METH) and methylenedioxymethamphetamine (MDMA) in multidrug-resistant (mdr1a) knockout mice Brain Research September 1, 1997
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