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Ultrastructural characterization of tryptophan hydroxylase 2-specific cortical serotonergic fibers and dorsal raphe neuronal cell bodies after MDMA treatment in rat

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Abstract

Rationale

3,4-Methylenedioxymethamphetamine (MDMA, “ecstasy”) is a widely used recreational drug known to cause selective long-term serotonergic damage.

Objectives

The aim of this study was to characterize the ultrastructure of serotonergic pericarya and proximal neurites in the dorsal raphe nucleus as well as the ultrastructure of serotonergic axons in the frontal cortex of adolescent Dark Agouti rats 3 days after treatment with 15 mg/kg i.p. MDMA.

Methods

Light microscopic immunohistochemistry and pre-embedding immunoelectron microscopy with a novel tryptophan hydroxylase-2 (Tph2) specific antibody, as a marker of serotonergic structures.

Results

Light microscopic analysis showed reduced serotonergic axon density and aberrant swollen varicosities in the frontal cortex of MDMA-treated animals. According to the electron microscopic analysis, Tph2 exhibited diffuse cytoplasmic immunolocalization in dorsal raphe neuronal cell bodies. The ultrastructural-morphometric analysis of these cell bodies did not indicate pathological changes or significant alteration in the cross-sectional areal density of any examined organelles. Proximal serotonergic neurites in the dorsal raphe exhibited no ultrastructural alteration. However, in the frontal cortex among intact fibers, numerous serotonergic axons with destructed microtubules were found. Most of their mitochondria were intact, albeit some injured axons also contained degenerating mitochondria; moreover, a few of them comprised confluent membrane whorls only.

Conclusions

Our treatment protocol does not lead to ultrastructural alteration in the serotonergic dorsal raphe cell bodies and in their proximal neurites but causes impairment in cortical serotonergic axons. In these, the main ultrastructural alteration is the destruction of microtubules although a smaller portion of these axons probably undergo an irreversible damage.

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Acknowledgement

We are grateful to Katalin Komjáti, Ágnes Druskóné, Ildikó Csontos, and Mariann Lenkey for their excellent technical assistance. We also thank Dr. Katalin Gallatz and Dr. Lajos László for the invaluable discussion.

This study was supported by the 6th Framework Program of the European Community, LSHM-CT-2004-503474, the Hungarian Research Fund Grant T020500, the Ministry of Welfare Research Grant 460/2006, the Deutsche Forschungsgemeinschaft (SFB 581/B9, and SFB TRR 58/A1, A5) and TAMOP-4.2.1.B-09/1/KMR-2010.

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Authors and Affiliations

  1. Department of Pharmacodynamics, Semmelweis University, Nagyvárad tér 4, 1089, Budapest, Hungary

    Csaba Ádori, Rómeó D. Andó & György Bagdy

  2. Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, 1089, Hungary

    Csaba Ádori, Dorottya Pap & György Bagdy

  3. Department of Anatomy, Cell and Developmental Biology, Eötvös Loránd University of Sciences, 1117, Budapest, Hungary

    Péter Lőw

  4. Institute of Exptl. Medicine, Hungarian Acad. of Sci, Budapest, 1089, Hungary

    Rómeó D. Andó

  5. ADHD Clinical Research Network, Unit of Molecular Psychiatry, Laboratory of Translational Neuroscience, Department of Psychiatry, Psychosomatics, and Psychotherapy, University of Wuerzburg, 97080, Wuerzburg, Germany

    Lise Gutknecht & Klaus-Peter Lesch

  6. 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, 1085, Budapest, Hungary

    Ferencné Truszka

  7. Infobionic and Neurobiological Plasticity Research Group, Hungarian Academy of Sciences—Peter Pazmany Catholic University—Semmelweis University, 1085, Budapest, Hungary

    József Takács

  8. Institute of Neurology, Medical University of Vienna, Vienna, 1097, Austria

    Gábor G. Kovács

  9. Group of Neurochemistry Hungarian Academy of Sciences and Semmelweis University Budapest, 1083, Budapest, Hungary

    György Bagdy

  10. Group of Neuropsychopharmacology, Hungarian Academy of Sciences and Semmelweis University Budapest, 1083, Budapest, Hungary

    György Bagdy

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  1. Csaba Ádori
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  7. József Takács
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  8. Gábor G. Kovács
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Correspondence to György Bagdy.

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Ádori, C., Lőw, P., Andó, R.D. et al. Ultrastructural characterization of tryptophan hydroxylase 2-specific cortical serotonergic fibers and dorsal raphe neuronal cell bodies after MDMA treatment in rat. Psychopharmacology 213, 377–391 (2011). https://doi.org/10.1007/s00213-010-2041-2

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