a3b3f99f37abab44b116ce27bbe9727c pmc_9456102.pdf a70a078328f568c616f2631258ea995a1d8c1744 pmc_9456102.pdf 5aa0da0c8d9bc6c422ba88650e5160e0fb7eeb05b88892003a5c3bef31be655d pmc_9456102.pdf Title: Reversible Photocontrol of Dopaminergic Transmission in Wild-Type Animals Subject: Understanding the dopaminergic system is a priority in neurobiology and neuropharmacology. Dopamine receptors are involved in the modulation of fundamental physiological functions, and dysregulation of dopaminergic transmission is associated with major neurological disorders. However, the available tools to dissect the endogenous dopaminergic circuits have limited specificity, reversibility, resolution, or require genetic manipulation. Here, we introduce azodopa, a novel photoswitchable ligand that enables reversible spatiotemporal control of dopaminergic transmission. We demonstrate that azodopa activates D1-like receptors in vitro in a light-dependent manner. Moreover, it enables reversibly photocontrolling zebrafish motility on a timescale of seconds and allows separating the retinal component of dopaminergic neurotransmission. Azodopa increases the overall neural activity in the cortex of anesthetized mice and displays illumination-dependent activity in individual cells. Azodopa is the first photoswitchable dopamine agonist with demonstrated efficacy in wild-type animals and opens the way to remotely controlling dopaminergic neurotransmission for fundamental and therapeutic purposes. Keywords: azobenzene; behavior; brainwave; dopamine; GPCR; in vivo electrophysiology; optogenetics; optopharmacology; photochromism; photopharmacology; photoswitch; zebrafish Author: Carlo Matera, Pablo Calvé, Verònica Casadó-Anguera, Rosalba Sortino, Alexandre M. J. Gomila, Estefanía Moreno, Thomas Gener, Cristina Delgado-Sallent, Pau Nebot, Davide Costazza, Sara Conde-Berriozabal, Mercè Masana, Jordi Hernando, Vicent Casadó, M. Victoria Puig and Pau Gorostiza Creator: LaTeX with hyperref Producer: pdfTeX-1.40.21 CreationDate: Mon Sep 5 03:28:56 2022 CEST ModDate: Mon Sep 5 04:45:15 2022 CEST Custom Metadata: no Metadata Stream: no Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 18 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 2225748 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- NWAKBR+VnURWPalladioL-Bold Type 1 Custom yes yes no 10 0 LTMMUB+VnURWPalladioL Type 1 Custom yes yes no 15 0 ITRVIW+URWPalladioL-Bold Type 1 Custom yes yes no 19 0 PVAUCB+URWPalladioL-Roma Type 1 Custom yes yes no 24 0 ZISWCY+URWPalladioL-Ital Type 1 Custom yes yes no 28 0 IRWHZX+TimesNewRomanPSMT Type 1C WinAnsi yes yes no 46 0 CKUPDE+TimesNewRomanPS-BoldItalicMT Type 1C WinAnsi yes yes no 49 0 IHGURL+EURM7 Type 1 Builtin yes yes no 72 0 BCDEEE+PalatinoLinotype-Bold TrueType WinAnsi yes yes no 80 0 BCDFEE+PalatinoLinotype-Roman TrueType WinAnsi yes yes no 84 0 BCDGEE+PalatinoLinotype-Italic TrueType WinAnsi yes yes no 88 0 BCDIEE+PalatinoLinotype-Roman CID TrueType Identity-H yes yes yes 92 0 DOIMJC+EURM10 Type 1 Builtin yes yes no 103 0 VSEVPZ+CMSY10 Type 1 Builtin yes yes no 107 0 MPUDFL+PazoMath Type 1 Builtin yes yes no 111 0 BCDEEE+PalatinoLinotype-Bold TrueType WinAnsi yes yes no 129 0 BCDFEE+PalatinoLinotype-Roman TrueType WinAnsi yes yes no 133 0 BCDGEE+PalatinoLinotype-Italic TrueType WinAnsi yes yes no 137 0 BCDIEE+PalatinoLinotype-Roman CID TrueType Identity-H yes yes yes 141 0 BCDEEE+PalatinoLinotype-Bold TrueType WinAnsi yes yes no 163 0 BCDFEE+PalatinoLinotype-Roman TrueType WinAnsi yes yes no 167 0 BCDGEE+PalatinoLinotype-Italic TrueType WinAnsi yes yes no 171 0 BCDIEE+PalatinoLinotype-Roman CID TrueType Identity-H yes yes yes 175 0 OICFSO+URWPalladioL-BoldItal Type 1 Custom yes yes no 194 0 BCDEEE+PalatinoLinotype-Bold TrueType WinAnsi yes yes no 202 0 BCDFEE+PalatinoLinotype-Roman TrueType WinAnsi yes yes no 206 0 BCDGEE+PalatinoLinotype-Italic TrueType WinAnsi yes yes no 210 0 BCDIEE+PalatinoLinotype-Roman CID TrueType Identity-H yes yes yes 214 0 BCDJEE+PalatinoLinotype-BoldItalic TrueType WinAnsi yes yes no 221 0 Jhove (Rel. 1.28.0, 2023-05-18) Date: 2024-05-07 04:27:37 CEST RepresentationInformation: pmc_9456102.pdf ReportingModule: PDF-hul, Rel. 1.12.4 (2023-03-16) LastModified: 2022-09-23 02:14:53 CEST Size: 2225748 Format: PDF Version: 1.7 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 497 FreeObjects: 1 IncrementalUpdates: 0 DocumentCatalog: PageLayout: SinglePage PageMode: UseNone Outlines: Item: Title: Introduction Destination: section.1 Item: Title: Results Destination: section.2 Children: Item: Title: Design Strategy and Synthesis Destination: subsection.2.1 Item: Title: Photochemical Characterization Destination: subsection.2.2 Item: Title: In Vitro Pharmacology Destination: subsection.2.3 Item: Title: Behavioral Effects in Zebrafish Larvae Destination: subsection.2.4 Item: Title: Electrophysiological Recordings in Anesthetized Mice Destination: subsection.2.5 Item: Title: Discussion Destination: section.3 Item: Title: References Destination: section.3 Info: Title: Reversible Photocontrol of Dopaminergic Transmission in Wild-Type Animals Author: Carlo Matera, Pablo Calvé, Verònica Casadó-Anguera, Rosalba Sortino, Alexandre M. J. Gomila, Estefanía Moreno, Thomas Gener, Cristina Delgado-Sallent, Pau Nebot, Davide Costazza, Sara Conde-Berriozabal, Mercè Masana, Jordi Hernando, Vicent Casadó, M. Victoria Puig and Pau Gorostiza Subject: Understanding the dopaminergic system is a priority in neurobiology and neuropharmacology. Dopamine receptors are involved in the modulation of fundamental physiological functions, and dysregulation of dopaminergic transmission is associated with major neurological disorders. However, the available tools to dissect the endogenous dopaminergic circuits have limited specificity, reversibility, resolution, or require genetic manipulation. Here, we introduce azodopa, a novel photoswitchable ligand that enables reversible spatiotemporal control of dopaminergic transmission. We demonstrate that azodopa activates D1-like receptors in vitro in a light-dependent manner. Moreover, it enables reversibly photocontrolling zebrafish motility on a timescale of seconds and allows separating the retinal component of dopaminergic neurotransmission. Azodopa increases the overall neural activity in the cortex of anesthetized mice and displays illumination-dependent activity in individual cells. Azodopa is the first photoswitchable dopamine agonist with demonstrated efficacy in wild-type animals and opens the way to remotely controlling dopaminergic neurotransmission for fundamental and therapeutic purposes. 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