Journal of Neural Transmission

, Volume 124, Issue 6, pp 749–759 | Cite as

The hallucinogen 2,5-dimethoxy-4-iodoamphetamine hydrochloride activates neurotrophin receptors in a neuronal cell line and promotes neurites extension

Translational Neurosciences - Original Article

Abstract

Decreased neurotrophic factors expression and neurotrophin receptors signalling have repeatedly been reported in association with stress, depression, and neurodegenerative disorders. We have previously identified the hallucinogen 2,5-dimethoxy-4-iodoamphetamine hydrochloride (DOI) as protective against trophic deprivation-induced cytotoxicity in human neuroblastoma SK-N-SH cells and established the dependence of this effect on the 5-HT2A receptor, tyrosine kinases activity, and the extracellular signal-regulated kinase pathway. In the current study, we investigated the effect of DOI on tropomyosin-related kinase receptor A (TrkA) phosphorylation. Treatment with DOI increased TrkA tyrosine phosphorylation in SK-N-SH cells, determined by immunoprecipitation with TrkA antibody and immunoblotting with anti-phosphotyrosine- and TrkA-antibodies. Analysis of DOI’s effect on individual TrkA residues in SK-N-SH cells showed that it increases TrkA Tyr490 phosphorylation (177 ± 23% after 5 μM DOI for 30 min compared to vehicle). Furthermore, DOI treatment increased the percentage of SK-N-SH cells extending neurites in a TrkA-dependent manner (17.2 ± 2.2% after 5 μM DOI treatment for 6 days compared to 5.6 ± 1.7% after vehicle). In a different cell model—lymphoblastoid cell lines—DOI treatment increased tropomyosin-related kinase receptor B (TrkB) phosphorylation, determined by immunoprecipitation with TrkB antibody and immunoblotting with anti-phosphotyrosine antibody and total Trk antibody. Our results identify the Trk receptors as a downstream target of the hallucinogen DOI. In light of the known involvement of Trk receptors in mental diseases, their participation in DOI-mediated effects warrants further investigation.

Keywords

Hallucinogen Tropomyosin-related kinase receptors SK-N-SH neuroblastoma cells Neurites 

Abbreviations

5-HT2

Serotonin 2

TrkA

Tropomyosin-related kinase receptor A

TrkB

Tropomyosin-related kinase receptor B

DOI

2,5-Dimethoxy-4-iodoamphetamine hydrochloride

BDNF

Brain-derived neurotrophic factor

ERK

Extracellular signal-regulated kinase

NGF

Nerve growth factor

NT-4/5

Neurotrophin-4/5

NT-3

Neurotrophin-3

MAPK

Mitogen-activated protein kinase

PI3 K

Phosphatidylinositol 3-kinase

Akt

Protein kinase B

PLCγ

Phospholipase C-γ

PKC

Protein kinase C

FBS

Fetal bovine serum

PBS

Phosphate-buffered saline

EBV

Epstein-Barr virus

BS3

Bis(sulfosuccinimidyl)suberate

ANOVA

Analysis of variance

GPCR

G protein-coupled receptors

LSD

Least statistical difference

Notes

Acknowledgements

Financial support for the study was provided through the Marie Heim-Vögtlin program of the Swiss National Science Foundation.

Supplementary material

702_2017_1706_MOESM1_ESM.doc (1.4 mb)
Supplementary material 1 (DOC 1411 kb)

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Copyright information

© Springer-Verlag Wien 2017

Authors and Affiliations

  1. 1.Department of Child and Adolescent Psychiatry and Psychotherapy, Psychiatric HospitalUniversity of ZürichZurichSwitzerland
  2. 2.Neuroscience Center ZürichUniversity of Zürich and ETH ZürichZurichSwitzerland
  3. 3.Zürich Center for Integrative Human PhysiologyUniversity of ZürichZurichSwitzerland
  4. 4.Department of Psychosomatic MedicineClinic BarmelweidBarmelweidSwitzerland

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