Precise spatiotemporal photorelease of a systemically administered caged nicotine agonist in freely moving mice

Delivering drugs to specific brain nuclei in freely moving mice presents challenges such as anatomical selectivity, slow on/off rates, and the integration of pressure-infusion with electrophysiology. While caged drugs have been widely used in brain slices for optically releasing neurotransmitters, their in vivo application has been limited. In this study, we introduce NV-epibatidine and NV-ABT594, potent photoactivatable nicotinic agonists, inactive in the dark, enabling systemic administration for local photo-release in the brain. Local photoactivation of NV-epibatidine in the ventral tegmental area (VTA) induces a rapid increase in neuronal firing, translating into a potent release of dopamine in the nucleus accumbens (NAc), a major VTA output. This photoactivation can be repeated multiple times for at least 3 hours post a single intraperitoneal injection, providing a suitable time window for caged nicotinic agonists to facilitate drug delivery in reinforcement studies. Overall, these experiments demonstrate the feasibility of precisely photo-releasing caged nicotinic agonists locally in the brain for in vivo photopharmacological manipulations following a simple systemic injection. These photoactivatable nicotinic agonists hold promise for disentangling the distinct effects of nicotine and acetylcholine in the brain, while the developed technologies have broader applicability to caged drugs, potentially revolutionizing the way we investigate brain function.