Focal drug uncaging for the precise control of endogenous nicotinic receptors in behaving mice
- 1ESPCI Paris - PSL University
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.
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BibTeX
@misc{guyon2026focal,
title = {{Focal drug uncaging for the precise control of endogenous nicotinic receptors in behaving mice}},
author = {N. Guyon and M. Mohayyaei and A. Bergel and G. Grellier and J. Jehl and N. Pietrancosta and N. Rebola and A. Francois and P. Faure and G. C. R. Ellis-Davies and A. Mourot},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.02.755724},
url = {https://www.biorxiv.org/content/10.64898/2026.10.02.755724v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Focal drug uncaging for the precise control of endogenous nicotinic receptors in behaving mice
AU - N. Guyon
AU - M. Mohayyaei
AU - A. Bergel
AU - G. Grellier
AU - J. Jehl
AU - N. Pietrancosta
AU - N. Rebola
AU - A. Francois
AU - P. Faure
AU - G. C. R. Ellis-Davies
AU - A. Mourot
PY - 2026
DA - 2026/10/02
PB - bioRxiv
DO - 10.64898/2026.10.02.755724
UR - https://www.biorxiv.org/content/10.64898/2026.10.02.755724v1
AB - 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.
ER -