Ultrastructural characterization of tryptophan hydroxylase 2-specific cortical serotonergic fibers and dorsal raphe neuronal cell bodies after MDMA treatment in rat.
BACKGROUND
3,4-Methylenedioxymethamphetamine (MDMA, "ecstasy") is a widely used recreational drug known to cause selective long-term serotonergic damage.


OBJECTIVE
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.
Department of Pharmacodynamics, Semmelweis University, Budapest, Hungary.
Csaba
C
Adori
Péter
P
Low
Rómeó D
RD
Andó
Lise
L
Gutknecht
Dorottya
D
Pap
Ferencné
F
Truszka
József
J
Takács
Gábor G
GG
Kovács
Klaus-Peter
KP
Lesch
György
G
Bagdy
D000818:Animals; D001369:Axons / Q000187:drug effects / Q000378:metabolism; D005625:Frontal Lobe / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D008297:Male; D008854:Microscopy, Electron; D016253:Microscopy, Immunoelectron; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000633:toxicity*; D016501:Neurites / Q000187:drug effects / Q000378:metabolism; D011903:Raphe Nuclei / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D051381:Rats; D012701:Serotonin / Q000378:metabolism*; D018490:Serotonin Agents / Q000633:toxicity*; D014365:Tryptophan Hydroxylase / Q000378:metabolism*
D018490:Serotonin Agents; D012701:Serotonin; D014365:Tryptophan Hydroxylase; C504569:tph2 protein, rat; D018817:N-Methyl-3,4-methylenedioxyamphetamine