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Tyrosine hydroxylase (TH) is the rate\u2010limiting enzyme in dopamine biosynthesis. TH increases in vitro formation of reactive oxygen species, and previous animal studies have reported links between cytosolic dopamine build\u2010up and oxidative stress. To examine effects of increased TH activity in catecholaminergic neurons in vivo, we generated TH\u2010over\u2010expressing mice (TH\u2010HI) using a BAC\u2010transgenic approach that results in over\u2010expression of TH with endogenous patterns of expression. The transgenic mice were characterized by western blot, qPCR, and immunohistochemistry. Tissue contents of dopamine, its metabolites, and markers of oxidative stress were evaluated. TH\u2010HI mice had a 3\u2010fold increase in total and phosphorylated TH levels and an increased rate of dopamine synthesis. Coincident with elevated dopamine turnover, TH\u2010HI mice showed increased striatal production of H\n                      <jats:sub>2<\/jats:sub>\n                      O\n                      <jats:sub>2<\/jats:sub>\n                      and reduced glutathione levels. In addition, TH\u2010HI mice had elevated striatal levels of the neurotoxic dopamine metabolites 3,4\u2010dihydroxyphenylacetaldehyde and 5\u2010S\u2010cysteinyl\u2010dopamine and were more susceptible than wild\u2010type mice to the effects of amphetamine and methamphetamine. These results demonstrate that increased TH alone is sufficient to produce oxidative stress in vivo, build up autotoxic dopamine metabolites, and augment toxicity.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:label\/>\n                    <jats:p>\n                      <jats:boxed-text content-type=\"graphic\" position=\"anchor\">\n                        <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc15432-fig-0007-m.png\">\n                          <jats:alt-text>image<\/jats:alt-text>\n                        <\/jats:graphic>\n                      <\/jats:boxed-text>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/jnc.15432","type":"journal-article","created":{"date-parts":[[2021,5,15]],"date-time":"2021-05-15T05:10:46Z","timestamp":1621055446000},"page":"960-979","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":55,"title":["Enhanced tyrosine hydroxylase activity induces oxidative stress, causes accumulation of autotoxic catecholamine metabolites, and augments amphetamine effects in vivo"],"prefix":"10.1111","volume":"158","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1520-9336","authenticated-orcid":false,"given":"Laura M.","family":"Vecchio","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Toxicology Faculty of Medicine University of Toronto Toronto ON Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patricia","family":"Sullivan","sequence":"additional","affiliation":[{"name":"Autonomic Medicine Section Clinical Neurosciences Program Division of Intramural Research National Institute of Neurological Disorders and Stroke National Institutes of Health Bethesda MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6437-6099","authenticated-orcid":false,"given":"Amy R.","family":"Dunn","sequence":"additional","affiliation":[{"name":"The Jackson Laboratory. 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