Reversible photocontrol of dopaminergic transmission in wild-type animals

17 May 2022, Version 1

Abstract

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 time scale 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 wildtype animals and opens the way to remotely controlling dopaminergic neurotransmission for fundamental and therapeutic purposes.

Keywords

photochromism
photoswitch
azobenzene
light
agonist
apomorphine
dopamine
G protein-coupled receptor
GPCR
behavior
biased signaling
neural oscillation
brainwave
in vivo electrophysiology
photopharmacology
optopharmacology
azologization
caged compound
optogenetics

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Reversible photocontrol of dopaminergic transmission in wild-type animals
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