DEVELOPMENT OF METHODS FOR OPTICAL INHIBITION OF NATIVE NICOTINIC ACETYLCHOLINE RECEPTORS IN BEHAVING MICE

Nicotinic acetylcholine receptors (nAChRs) are widely expressed throughout the central and peripheral nervous systems, where they support fast synaptic transmission and modulate attention, reward, and learning in the brain, while also regulating autonomic functions such as heart rate, respiration, and gastrointestinal activity. Despite this broad influence, the causal contribution of nAChR signaling within defined neural circuits to behavior remains poorly understood.
To address this gap, we previously developed a photopharmacological approach to activate native nAChRs in discrete brain regions of behaving mice using caged nicotinic agonists—molecules that are inert in the dark and released by near-UV light. These compounds can be administered systemically and uncaged with precise spatial and temporal control. Here, we extend this strategy to enable optical inhibition of nicotinic neurotransmission in freely moving animals.
We designed and synthesized NV-Mec, a caged derivative of mecamylamine, a non-competitive nAChR antagonist with known autonomic and dopaminergic effects. Systemic administration of mecamylamine reduced fecal output in the open-field task and decreased dopamine release in the nucleus accumbens, measured using fiber photometry and the GRAB-DA sensor. In contrast, NV-Mec produced no detectable autonomic or dopaminergic effects, indicating that it is inert in its caged form and suitable for systemic delivery.
Ongoing experiments test whether local uncaging of NV-Mec in the ventral tegmental area reproduces these dopaminergic effects and alters reward-seeking and aversion-related behaviors. This photochemical platform enables circuit-specific inhibition of nAChRs with unprecedented spatiotemporal precision, opening new avenues to dissect nicotinic contributions to reinforcement and aversion.