{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T04:58:54Z","timestamp":1790398734780,"version":"4.1.0"},"reference-count":26,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T00:00:00Z","timestamp":1790208000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Octodrine (2-amino-6-methylheptane; DMHA) is a sympathomimetic stimulant detected in sports-performance and weight-loss supplements despite limited toxicological characterization and regulatory concerns. Here, we used 7-day-post-fertilization zebrafish larvae to characterize the acute cardiac, neurobehavioral, and transcriptional effects of octodrine after 2 h of exposure. Cardiac responses were biphasic: 5 \u00b5M octodrine significantly increased atrial and ventricular rates, whereas concentrations \u2265 150 \u00b5M produced progressive cardiac depression and higher concentrations disrupted atrioventricular conduction. At 450 \u00b5M, all larvae showed complete absence of detectable cardiac activity; mortality was not independently assessed. Modelling of the inhibitory phase yielded IC50 values of 195.6 \u00b5M for atrial rate and 188.8 \u00b5M for ventricular rate. At substantially lower concentrations, octodrine significantly reduced spontaneous locomotor activity. After Holm correction across all 24 planned time-by-treatment comparisons, a transient effect remained detectable at 50 nM, with more sustained hypoactivity at 0.5 and 5 \u00b5M across most of the 2 h exposure period. At the transcriptional level, 3.5 \u00b5M octodrine significantly reduced fosab and egr1 expression, whereas fkbp5 was induced at selected concentrations; npas4a showed a significant overall treatment effect but no dose-specific comparison remained significant after blocked analysis and multiplicity correction. nr4a1 was significantly downregulated at 350 \u00b5M, whereas th1 and kcnh2a expression was not significantly altered. Together, these findings show that neurobehavioral\/transcriptional responses and pronounced cardiac dysfunction occurred over different concentration ranges under the conditions tested. The results provide an initial in vivo hazard characterization of octodrine and support further investigation of its neuropharmacological mechanisms, internal exposure, and cardiovascular safety.<\/jats:p>","DOI":"10.3390\/ijms27198560","type":"journal-article","created":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T16:29:53Z","timestamp":1790267393000},"page":"8560","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Acute Octodrine (DMHA) Exposure Disrupts Cardiac Function, Locomotor Activity, and Neuronal Activity-Responsive Transcription in Zebrafish Larvae"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2916-0860","authenticated-orcid":false,"given":"Eduardo Kennedy","family":"Carr\u00e3o-Dantas","sequence":"first","affiliation":[{"name":"Laboratory of Environmental Mutagenesis, Department of Biophysics and Biometry, Rio de Janeiro State University (UERJ), Rio de Janeiro 20551-030, RJ, Brazil"},{"name":"Integrated Laboratory of Environmental Mutagenesis, Department of Genetics and Molecular Biology, Federal University of Rio de Janeiro State (UNIRIO), Rio de Janeiro 20211-010, RJ, Brazil"},{"name":"Institute for Environmental Assessment and Water Research (IDAEA-CSIC), Jordi Girona, 18, 08034 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-8226-276X","authenticated-orcid":false,"given":"Ouwais","family":"Aljabasini","sequence":"additional","affiliation":[{"name":"Institute for Environmental Assessment and Water Research (IDAEA-CSIC), Jordi Girona, 18, 08034 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7838-2027","authenticated-orcid":false,"given":"Eva","family":"Prats","sequence":"additional","affiliation":[{"name":"Research and Development Center (CID-CSIC), Jordi Girona, 18, 08034 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1677-197X","authenticated-orcid":false,"given":"Israel","family":"Felzenszwalb","sequence":"additional","affiliation":[{"name":"Laboratory of Environmental Mutagenesis, Department of Biophysics and Biometry, Rio de Janeiro State University (UERJ), Rio de Janeiro 20551-030, RJ, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9278-4441","authenticated-orcid":false,"given":"Carlos Fernando","family":"Araujo-Lima","sequence":"additional","affiliation":[{"name":"Laboratory of Environmental Mutagenesis, Department of Biophysics and Biometry, Rio de Janeiro State University (UERJ), Rio de Janeiro 20551-030, RJ, Brazil"},{"name":"Integrated Laboratory of Environmental Mutagenesis, Department of Genetics and Molecular Biology, Federal University of Rio de Janeiro State (UNIRIO), Rio de Janeiro 20211-010, RJ, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5256-1641","authenticated-orcid":false,"given":"Demetrio","family":"Rald\u00faa","sequence":"additional","affiliation":[{"name":"Institute for Environmental Assessment and Water Research (IDAEA-CSIC), Jordi Girona, 18, 08034 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1080\/15563650.2017.1398328","article-title":"Four experimental stimulants found in sports and weight loss supplements: 2-amino-6-methylheptane (octodrine), 1,4-dimethylamylamine (1,4-DMAA), 1,3-dimethylamylamine (1,3-DMAA) and 1,3-dimethylbutylamine (1,3-DMBA)","volume":"56","author":"Cohen","year":"2018","journal-title":"Clin. Toxicol."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Walpurgis, K., Thomas, A., Geyer, H., Mareck, U., and Thevis, M. (2020). Dietary supplement and food contaminations and their implications for doping controls. Foods, 9.","DOI":"10.3390\/foods9081012"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Catalani, V., Prilutskaya, M., Al-Imam, A., Marrinan, S., Elgharably, Y., Zloh, M., Martinotti, G., Chilcott, R., and Corazza, O. (2018). Octodrine: New questions and challenges in sport supplements. Brain Sci., 8.","DOI":"10.3390\/brainsci8020034"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1016\/j.jpba.2018.02.008","article-title":"1,5-Dimethylhexylamine (octodrine) in sports and weight loss supplements: Natural constituent or synthetic chemical?","volume":"152","author":"Wang","year":"2018","journal-title":"J. Pharm. Biomed. Anal."},{"key":"ref_5","unstructured":"FDA (2026, August 25). DMHA in Dietary Supplements, Available online: https:\/\/www.fda.gov\/food\/information-select-dietary-supplement-ingredients-and-other-substances\/dmha-dietary-supplements."},{"key":"ref_6","unstructured":"World Anti-Doping Agency (WADA) (2025). The 2026 Prohibited List: World Anti-Doping Code International Standard, WADA. Available online: https:\/\/www.wada-ama.org\/sites\/default\/files\/2025-09\/2026list_en_final_clean_september_2025.pdf."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1016\/S0022-3565(25)05793-3","article-title":"The pharmacology of 2-amino-6-methylheptane","volume":"90","author":"Fellows","year":"1947","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/j.vascn.2006.04.004","article-title":"Neurotoxicity assessment using zebrafish","volume":"55","author":"Parng","year":"2007","journal-title":"J. Pharmacol. Toxicol. Methods"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Teixid\u00f3, E., Riera-Colomer, C., Rald\u00faa, D., Pubill, D., Escubedo, E., Barenys, M., and L\u00f3pez-Arnau, R. (2023). First-generation synthetic cathinones produce arrhythmia in zebrafish eleutheroembryos: A new approach methodology for new psychoactive substances cardiotoxicity evaluation. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms241813869"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Aljabasini, O., Tagkalidou, N., Pazos, M.D., Garc\u00eda-D\u00edez, G., Prats, E., Seco, R., Berzosa, X., L\u00f3pez-Arnau, R., and Raldua, D. (2026). Integrated assessment of neurobehavioral and cardiotoxic effects of pyrrolidine-containing cathinones in zebrafish: Structural determinants of functional safety profiles. Int. J. Mol. Sci., 27.","DOI":"10.20944\/preprints202602.1702.v1"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1016\/j.pnpbp.2018.02.010","article-title":"Pharmacological analysis of zebrafish lphn3.1 morphant larvae suggests that saturated dopaminergic signaling could underlie the ADHD-like locomotor hyperactivity","volume":"84","author":"Lange","year":"2018","journal-title":"Prog. Neuro-Psychopharmacol. Biol. Psychiatry"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1016\/j.neuro.2008.09.011","article-title":"Locomotion in larval zebrafish: Influence of time of day, lighting and ethanol","volume":"30","author":"MacPhail","year":"2009","journal-title":"Neurotoxicology"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"eade9909","DOI":"10.1126\/sciadv.ade9909","article-title":"A single-cell resolution gene expression atlas of the larval zebrafish brain","volume":"9","author":"Shainer","year":"2023","journal-title":"Sci. Adv."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Boyer, B., Ernest, S., and Rosa, F. (2013). Egr-1 induction provides a genetic response to food aversion in zebrafish. Front. Behav. Neurosci., 7.","DOI":"10.3389\/fnbeh.2013.00051"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Klari\u0107, T., Lardelli, M., Key, B., Koblar, S., and Lewis, M. (2014). Activity-dependent expression of neuronal PAS domain-containing protein 4 (npas4a) in the developing zebrafish brain. Front. Neuroanat., 8.","DOI":"10.3389\/fnana.2014.00148"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"E654","DOI":"10.1073\/pnas.1514292113","article-title":"Assessment of fight outcome is needed to activate socially driven transcriptional changes in the zebrafish brain","volume":"113","author":"Oliveira","year":"2016","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Mech, A.M., Merteroglu, M., Sealy, I.M., Teh, M.-T., White, R.J., Havelange, W., Brennan, C.H., and Busch-Nentwich, E.M. (2022). Behavioral and gene regulatory responses to developmental drug exposures in zebrafish. Front. Psychiatry, 12.","DOI":"10.3389\/fpsyt.2021.795175"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Aljabasini, O., Tagkalidou, N., Bedrossiantz, J., Prats, E., Lopez-Arnau, R., and Raldua, D. (2026). Integrated assessment of the cardiotoxic and neurobehavioral effects of 3,4-methylenedioxypyrovalerone (MDPV) in zebrafish embryos. Int. J. Mol. Sci., 27.","DOI":"10.20944\/preprints202511.0075.v1"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Gans, I.M., Grendler, J., Babich, R., Jayasundara, N., and Coffman, J.A. (2021). Glucocorticoid-responsive transcription factor Kr\u00fcppel-like factor 9 regulates fkbp5 and metabolism. Front. Cell Dev. Biol., 9.","DOI":"10.3389\/fcell.2021.727037"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"dmm050141","DOI":"10.1242\/dmm.050141","article-title":"Glucocorticoid receptor regulates protein chaperone, circadian clock and affective disorder genes in the zebrafish brain","volume":"16","author":"Eachus","year":"2023","journal-title":"Dis. Model. Mech."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1355","DOI":"10.1161\/01.CIR.0000061912.88753.87","article-title":"Drugs that induce repolarization abnormalities cause bradycardia in zebrafish","volume":"107","author":"Milan","year":"2003","journal-title":"Circulation"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"e14075","DOI":"10.1111\/apha.14075","article-title":"ERG potassium channels and T-type calcium channels contribute to the pacemaker and atrioventricular conduction in zebrafish larvae","volume":"240","author":"Molina","year":"2024","journal-title":"Acta Physiol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1093\/toxsci\/kfac102","article-title":"Evaluation of the uptake, metabolism, and secretion of toxicants by zebrafish larvae","volume":"190","author":"Achenbach","year":"2022","journal-title":"Toxicol. Sci."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1089\/zeb.2023.0017","article-title":"Influence of methylene blue or dimethyl sulfoxide on larval zebrafish development and behavior","volume":"20","author":"Hedge","year":"2023","journal-title":"Zebrafish"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"682","DOI":"10.1002\/etc.3579","article-title":"Zebrafish embryo tolerance to environmental stress factors\u2014Concentration\u2013dose response analysis of oxygen limitation, pH, and UV-light irradiation","volume":"36","author":"Andrade","year":"2016","journal-title":"Environ. Toxicol. Chem."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Gauvrit, S., Bossaer, J., Lee, J., and Collins, M.M. (2022). Modeling human cardiac arrhythmias: Insights from zebrafish. J. Cardiovasc. Dev. Dis., 9.","DOI":"10.3390\/jcdd9010013"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/19\/8560\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T04:15:40Z","timestamp":1790396140000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/19\/8560"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,24]]},"references-count":26,"journal-issue":{"issue":"19","published-online":{"date-parts":[[2026,10]]}},"alternative-id":["ijms27198560"],"URL":"https:\/\/doi.org\/10.3390\/ijms27198560","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,24]]}}}