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To find new anticonvulsive medications, we evaluated FDA\u2010approved drugs not known to be anticonvulsants. Using zebrafish larvae as an initial model system, we found that the opioid antagonist naltrexone exhibited an anticonvulsant effect. We validated this effect in three other epilepsy models and present naltrexone as a promising anticonvulsive candidate.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Candidate anticonvulsant drugs, determined by our prior transcriptomics analysis of hippocampal tissue, were evaluated in a larval zebrafish model of human Dravet syndrome (<jats:italic>scn1Lab<\/jats:italic> mutants), in wild\u2010type zebrafish larvae treated with the pro\u2010convulsant drug pentylenetetrazole (PTZ), in wild\u2010type C57bl\/6J acute brain slices exposed to PTZ, and in wild\u2010type mice treated with PTZ in vivo. Abnormal locomotion was determined behaviorally in zebrafish and mice and by field potential in neocortex layer IV\/V and CA1 stratum pyramidale in the hippocampus.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The opioid antagonist naltrexone decreased abnormal locomotion in the larval zebrafish model of human Dravet syndrome (<jats:italic>scn1Lab<\/jats:italic> mutants) and wild\u2010type larvae treated with the pro\u2010convulsant drug PTZ. Naltrexone also decreased seizure\u2010like events in acute brain slices of wild\u2010type mice, and the duration and number of seizures in adult mice injected with PTZ.<\/jats:p><\/jats:sec><jats:sec><jats:title>Significance<\/jats:title><jats:p>Our data reveal that naltrexone has anticonvulsive properties and is a candidate drug for seizure treatment.<\/jats:p><\/jats:sec>","DOI":"10.1002\/epi4.12512","type":"journal-article","created":{"date-parts":[[2021,5,24]],"date-time":"2021-05-24T11:32:51Z","timestamp":1621855971000},"page":"528-538","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["The opioid antagonist naltrexone decreases seizure\u2010like activity in genetic and chemically induced epilepsy models"],"prefix":"10.1002","volume":"6","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4814-1446","authenticated-orcid":false,"given":"Morgan 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