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D1 but not D4 Dopamine Receptors are Critical for MDMA-Induced Neurotoxicity in Mice

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Abstract

MDMA, an addictive psychostimulant-consumed worldwide, has the ability to induce neurotoxic effects and addiction in laboratory animals and in humans through its effects on monoaminergic systems. MDMA-induced neurotoxicity in mice occurs primarily in dopaminergic neurons and does not significantly affect the serotonergic system. As the neurotoxic effects of MDMA in mice involve excessive dopamine (DA) release, DA receptors are highly likely to play a role in MDMA neurotoxicity, but the specific dopamine receptor subtypes involved have not previously been determined definitively. In this study, dopamine D1 and D4 receptor knock-out mice (D1R−/− and D4R−/−) were used to determine whether these receptors are involved in MDMA neurotoxicity. D1R inactivation attenuated MDMA-induced hyperthermia, decreased the reduction of dopamine and dopamine metabolite levels, and protected against dopamine terminal loss and reactive astrogliosis as determined in the striatum, 7 days after MDMA treatment. In sharp contrast, inactivation of D4R did not prevent hyperthermia or the neurotoxic effects of MDMA. Altogether, these results indicate that D1R, but not D4R, plays a significant role in the dopaminergic striatal neurotoxicity observed after exposure to MDMA.

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Abbreviations

D1R:

D1 dopamine receptor

D4R:

D4 dopamine receptor

D1R−/− :

D1 dopamine receptor knockout

D4R−/− :

D4 dopamine receptor knockout

DA:

Dopamine

DAT:

Dopamine transporter

DOPAC:

3,4-Dihidroxyphenylacetic acid

HVA:

Homovanillic acid

5-HT:

Serotonin

5-HIAA:

5-Hydroxyindolacetic acid

MDMA:

3,4-Methylenedioxymethamphetamine

PB:

Phosphate buffer

PBST:

Phosphate sodium buffer with triton

TH:

Tyrosine hydroxylase

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Acknowledgments

This study was supported by Grants from the Spanish Ministry of Ciencia e Innovación: Grant No. BFU2010-20664, Spanish Ministries of Economía y Competitividad and of Sanidad, Servicios Sociales e Igualdad, ISCIII, PNSD nº 2012/071, RedRTA (RD06/0001/1011), CIBERNED ref CB06/05/0055 and Comunidad de Madrid ref S2011/BMD-2336 to RM. NG received a Juan de la Cierva post-doctoral fellowship and a research contract NEUROSTEM-M S2010/BMD-2336 and SAS received a JAE pre-doctoral fellowship from the CSIC. The authors would like to thank Prof. MI Colado and E O’Shea for their assistance with the HPLC experiments and to Mrs Emilia Rubio and Mr Marco de Mesa for their excellent technical assistance and Dr. Andrés Urrutia, for his help technical assistance with HPLC. MDMA hydrochloride was obtained from NIDA (Research Triangle Park, North Carolina, USA).

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Instituto Cajal, Consejo Superior de Investigaciones Científicas, CSIC, Avd. Dr. Arce 37, 28002, Madrid, Spain

    N. Granado, S. Ares-Santos & R. Moratalla

  2. CIBERNED, Instituto de Salud Carlos III, Madrid, Spain

    N. Granado, S. Ares-Santos & R. Moratalla

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  1. N. Granado
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  2. S. Ares-Santos
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  3. R. Moratalla
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Correspondence to R. Moratalla.

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Granado, N., Ares-Santos, S. & Moratalla, R. D1 but not D4 Dopamine Receptors are Critical for MDMA-Induced Neurotoxicity in Mice. Neurotox Res 25, 100–109 (2014). https://doi.org/10.1007/s12640-013-9438-8

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