The hallucinogen 2,5-dimethoxy-4-iodoamphetamine hydrochloride activates neurotrophin receptors in a neuronal cell line and promotes neurites extension.
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-HT2Areceptor, 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.
Department of Child and Adolescent Psychiatry and Psychotherapy, Psychiatric Hospital, University of Zürich, Wagistrasse 12, Schlieren, 8952, Zurich, Switzerland. Zoya.Marinova@barmelweid.ch.|Department of Psychosomatic Medicine, Clinic Barmelweid, 5017, Barmelweid, Switzerland. Zoya.Marinova@barmelweid.ch.
Zoya
Z
Marinova
Department of Child and Adolescent Psychiatry and Psychotherapy, Psychiatric Hospital, University of Zürich, Wagistrasse 12, Schlieren, 8952, Zurich, Switzerland.|Neuroscience Center Zürich, University of Zürich and ETH Zürich, Zurich, Switzerland.|Zürich Center for Integrative Human Physiology, University of Zürich, Zurich, Switzerland.
Susanne
S
Walitza
Department of Child and Adolescent Psychiatry and Psychotherapy, Psychiatric Hospital, University of Zürich, Wagistrasse 12, Schlieren, 8952, Zurich, Switzerland. edna.gruenblatt@kjpd.uzh.ch.|Neuroscience Center Zürich, University of Zürich and ETH Zürich, Zurich, Switzerland. edna.gruenblatt@kjpd.uzh.ch.|Zürich Center for Integrative Human Physiology, University of Zürich, Zurich, Switzerland. edna.gruenblatt@kjpd.uzh.ch.
Edna
E
Grünblatt
D000662:Amphetamines / Q000494:pharmacology*; D045744:Cell Line, Tumor; D006213:Hallucinogens / Q000494:pharmacology*; D006801:Humans; D008214:Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008297:Male; D020932:Nerve Growth Factor / Q000008:administration & dosage / Q000378:metabolism; D016501:Neurites / Q000187:drug effects* / Q000378:metabolism; D000071446:Neuronal Outgrowth / Q000187:drug effects* / Q000502:physiology; D010766:Phosphorylation / Q000187:drug effects; D044402:Receptor, Serotonin, 5-HT2A / Q000378:metabolism; D044403:Receptor, Serotonin, 5-HT2B / Q000378:metabolism; D020917:Receptor, trkA / Q000378:metabolism*; D020813:Receptor, trkB / Q000378:metabolism*; D058830:Serotonin 5-HT2 Receptor Antagonists / Q000494:pharmacology; D055815:Young Adult
D000662:Amphetamines; D006213:Hallucinogens; D044402:Receptor, Serotonin, 5-HT2A; D044403:Receptor, Serotonin, 5-HT2B; D058830:Serotonin 5-HT2 Receptor Antagonists; D020932:Nerve Growth Factor; D020917:Receptor, trkA; D020813:Receptor, trkB; C015952:4-iodo-2,5-dimethoxyphenylisopropylamine
Hallucinogen; Neurites; SK-N-SH neuroblastoma cells; Tropomyosin-related kinase receptors