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

Ádori, Csaba; Lőw, Péter; Andó, Rómeó D.; Gutknecht, Lise; Pap, Dorottya; Truszka, Ferencné; Takács, J.; Kovács, Gábor G.; Lesch, Klaus‐Peter; Bagdy, György

doi:10.1007/s00213-010-2041-2

Cited by 22 publications

(13 citation statements)

References 61 publications

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“…The changes in the DR region were mild in line with our previous results suggesting that MDMA-caused damage to these neurons are restricted to serotonergic axon terminals instead of neuronal cell bodies directly [71]. The caspase activation gene set significantly changed in the present study was not supported by individual genes, or other gene sets related to apoptotical processes.…”

Section: Discussionsupporting

confidence: 88%

RETRACTED ARTICLE: Gene expression analysis indicates CB1 receptor upregulation in the hippocampus and neurotoxic effects in the frontal cortex 3 weeks after single-dose MDMA administration in Dark Agouti rats

et al. 2013

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Background3,4-methylenedioxymethamphetamine (MDMA, "ecstasy") is a widely used recreational drug known to impair cognitive functions on the long-run. Both hippocampal and frontal cortical regions have well established roles in behavior, memory formation and other cognitive tasks and damage of these regions is associated with altered behavior and cognitive functions, impairments frequently described in heavy MDMA users. The aim of this study was to examine the hippocampus, frontal cortex and dorsal raphe of Dark Agouti rats with gene expression arrays (Illumina RatRef bead arrays) looking for possible mechanisms and new candidates contributing to the effects of a single dose of MDMA (15 mg/kg) 3 weeks earlier.ResultsThe number of differentially expressed genes in the hippocampus, frontal cortex and the dorsal raphe were 481, 155, and 15, respectively. Gene set enrichment analysis of the microarray data revealed reduced expression of 'memory’ and 'cognition’, 'dendrite development’ and 'regulation of synaptic plasticity’ gene sets in the hippocampus, parallel to the upregulation of the CB1 cannabinoid- and Epha4, Epha5, Epha6 ephrin receptors. Downregulated gene sets in the frontal cortex were related to protein synthesis, chromatin organization, transmembrane transport processes, while 'dendrite development’, 'regulation of synaptic plasticity’ and 'positive regulation of synapse assembly’ gene sets were upregulated. Changes in the dorsal raphe region were mild and in most cases not significant.ConclusionThe present data raise the possibility of new synapse formation/synaptic reorganization in the frontal cortex three weeks after a single neurotoxic dose of MDMA. In contrast, a prolonged depression of new neurite formation in the hippocampus is suggested by the data, which underlines the particular vulnerability of this brain region after the drug treatment. Finally, our results also suggest the substantial contribution of CB1 receptor and endocannabinoid mediated pathways in the hippocampal impairments. Taken together the present study provides evidence for the participation of new molecular candidates in the long-term effects of MDMA.

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Section: Discussionsupporting

confidence: 88%

RETRACTED ARTICLE: Gene expression analysis indicates CB1 receptor upregulation in the hippocampus and neurotoxic effects in the frontal cortex 3 weeks after single-dose MDMA administration in Dark Agouti rats

et al. 2013

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“…There were no swollen axons seen in the more proximal portions of the axonal trajectory including those that pass through the linear nucleus of the raphe, the posterior hypothalamus and the more caudal portions of the MFB (data not shown). This pattern is consistent with the early stages of retrograde axonal degeneration and is congruent with a well-established literature on amphetamine-induced degeneration of serotonin axons in rats, which has gone to great lengths to demonstrate the hallmarks of degeneration including swollen, irregular axons (Molliver et al, 1990) and has used immuno-electron microscopy to show amphetamine-evoked destruction of microtubules and degenerated mitochondria in such axons (Adori et al, 1980). Figure 2 shows representative images taken 1 week after PCA or saline treatment, starting with the serotonergic cell bodies of origin in the dorsal raphe nucleus and continuing with their long C-shaped projection through the MFB and ending in the occipital cortex.…”

Section: Resultssupporting

confidence: 87%

Regrowth of Serotonin Axons in the Adult Mouse Brain Following Injury

Jin

Dougherty

Wood

et al. 2016

Neuron

103

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Summary It is widely believed that damaged axons in the adult mammalian brain have little capacity to regrow, thereby impeding functional recovery after injury. Studies using fixed tissue have suggested that serotonin neurons might be a notable exception, but remain inconclusive. We have employed in vivo two-photon microscopy to produce time-lapse images of serotonin axons in the neocortex of the adult mouse. Serotonin axons undergo massive retrograde degeneration following amphetamine treatment and subsequent slow recovery of axonal density which is dominated by new growth with little contribution from local sprouting. A stab injury that transects serotonin axons running in the neocortex is followed by local regression of cut serotonin axons and followed by regrowth from cut ends into and across the stab rift zone. Regrowing serotonin axons do not follow the pathways left by degenerated axons. The regrown axons release serotonin and their regrowth is correlated with recovery in behavioral tests.

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“…In this regard, it has been shown that MDMA administration 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 undergoes an irreversible damage [196]. These data support the clinical findings reported by Kish et al .…”

Section: Neuroadaptation Vs Neurotoxicitysupporting

confidence: 81%

Methylenedioxymethamphetamine (MDMA, 'Ecstasy'): Neurodegeneration versus Neuromodulation

Puerta

Aguirre

2011

Pharmaceuticals

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The amphetamine analogue 3,4-methylenedioxymethamphetamine (MDMA, ‘ecstasy’) is widely abused as a recreational drug due to its unique psychological effects. Of interest, MDMA causes long-lasting deficits in neurochemical and histological markers of the serotonergic neurons in the brain of different animal species. Such deficits include the decline in the activity of tryptophan hydroxylase in parallel with the loss of 5-HT and its main metabolite 5-hydoxyindoleacetic acid (5-HIAA) along with a lower binding of specific ligands to the 5-HT transporters (SERT). Of concern, reduced 5-HIAA levels in the CSF and SERT density have also been reported in human ecstasy users, what has been interpreted to reflect the loss of serotonergic fibers and terminals. The neurotoxic potential of MDMA has been questioned in recent years based on studies that failed to show the loss of the SERT protein by western blot or the lack of reactive astrogliosis after MDMA exposure. In addition, MDMA produces a long-lasting down-regulation of SERT gene expression; which, on the whole, has been used to invoke neuromodulatory mechanisms as an explanation to MDMA-induced 5-HT deficits. While decreased protein levels do not necessarily reflect neurodegeneration, the opposite is also true, that is, neuroregulatory mechanisms do not preclude the existence of 5-HT terminal degeneration.

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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

Cited by 22 publications

References 61 publications

RETRACTED ARTICLE: Gene expression analysis indicates CB1 receptor upregulation in the hippocampus and neurotoxic effects in the frontal cortex 3 weeks after single-dose MDMA administration in Dark Agouti rats

RETRACTED ARTICLE: Gene expression analysis indicates CB1 receptor upregulation in the hippocampus and neurotoxic effects in the frontal cortex 3 weeks after single-dose MDMA administration in Dark Agouti rats

Regrowth of Serotonin Axons in the Adult Mouse Brain Following Injury

Methylenedioxymethamphetamine (MDMA, 'Ecstasy'): Neurodegeneration versus Neuromodulation

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