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Dopamine (DA) is an important and tightly regulated catecholaminergic neurotransmitter required for multiple modulatory functions throughout the central nervous system, including the retina. Dysregulation of DA homeostasis has been reported during neurodegeneration, but how it is regulated in RP remains poorly understood. Here, we demonstrate that early RP is associated with marked dysregulation of the dopaminergic system using two distinct disease models, P23H and rd10 mice. We found increased DA levels in RP retinas collected from pre\u2010weaned (P12), juvenile (P30), and adult (P60\u201390) mice by utilising ultra\u2010high\u2010performance liquid chromatography and matrix\u2010assisted laser desorption\/ionisation mass spectrometry. Consistently, DA levels were also elevated in the vitreous of P23H mice, where it likely diffuses from the retina. RP retinas additionally demonstrated higher levels of DA precursor l\u20103,4\u2010dihydroxyphenylalanine (L\u2010DOPA), as well as upregulated tyrosine hydroxylase gene expression, which suggests elevated DA synthesis. In parallel, we observed increased activity and expression of the catecholamine\u2010metabolising enzyme catechol\u2010O\u2010methyltransferase (COMT) during retinal degeneration. Comparative tissue analysis with cortex, striatum, retina, and eye cup samples further highlighted COMT as a major contributor to catecholamine inactivation in the mouse retina. Finally, RNA sequencing of P23H retinal extracts revealed widespread alterations related to the catecholaminergic system during disease progression, including upregulation of the solute carrier family 6 member 2 gene, encoding norepinephrine transporter, and the protein phosphatase 1 regulatory subunit 1B gene, which encodes DA\u2010 and cAMP\u2010regulated neuronal phosphoprotein. In conclusion, these data demonstrate elevated DA levels in P23H and rd10 mouse retinas, along with several other biochemical changes in the catecholamine system, suggesting a hyperexcited state in early RP progression.<\/jats:p>\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\/jnc70552-gra-0001-m.png\">\n                        <jats:alt-text>image<\/jats:alt-text>\n                      <\/jats:graphic>\n                    <\/jats:boxed-text>\n                  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