Focal drug uncaging for the precise control of endogenous nicotinic receptors in behaving mice
Year: 2026
Type: preprint
Abstract: Nicotinic acetylcholine receptors shape diverse brain functions, including reward, aversion, and pain, but dissecting their roles in vivo requires drug delivery with spatiotemporal precision that conventional pharmacology cannot provide. Here we establish in vivo photopharmacology of endogenous nicotinic receptors: two complementary highly-potent agonists, administered systemically in an inactive caged form, are photoreleased locally in target brain circuits of behaving wild-type mice. Despite irreversible photochemistry, photoactivation can be repeated over many trials on a minute timescale, for hours following a single injection. Local uncaging evokes circuit-specific dopamine release, drives place preference from the ventral tegmental area and aversion from the interpeduncular nucleus, and, in pain circuits, reveals a pronociceptive effect masked when the same agonists are given systemically. By controlling where and when nicotinic signaling acts, this approach exposes circuit-specific drug effects invisible to conventional pharmacology, and outlines a general strategy for on-demand control of endogenous receptors in vivo .
Institutions: Centre National de la Recherche Scientifique, Université Paris Sciences et Lettres, Karolinska Institutet, Laboratoire Plasticité du Cerveau, ESPCI Paris, Inserm, Sorbonne Université, Institut du Cerveau, Université de Montpellier, Institut de Génomique Fonctionnelle, École Normale Supérieure - PSL, Institut de Biologie Paris-Seine, Laboratoire des Biomolécules, Neurosciences Paris-Seine, Icahn School of Medicine at Mount Sinai
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7220970637