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The Endogenous Negative Allosteric Modulator, Lynx1, Inhibits Nicotinic Cholinergic Signaling in the Ventral Tegmental Area to Regulate Nicotine Reinforcement

Year: 2026

Type: article

Abstract: Neuronal nicotinic acetylcholine receptors (nAChRs) underlie many aspects of cholinergic signaling, including as essential contributors to learning and memory function. However, the functional impact of endogenous nAChR modulators remains largely unclear. Thus, the current investigations sought to define the function of lynx1 in reward-related reinforcement behaviors. First, male and female mice with constitutive lynx1 knock-out (lynx1 -/- ) or their wild-type littermates (lynx +/+ ) were examined with intravenous nicotine self-administration across a full doseresponse function. Knock-out of lynx1 induced an increase in nicotine intake at lower self-administered doses, with dose-specific effects in males and females. These actions appear to be selective for nicotine, as no phenotypic differences were found with operant food training. We next examined whether lynx1 in the ventral tegmental area (VTA) may underlie the increase in nicotine intake, and we found that administration of a low dose of nicotine increased cellular activation in the VTA of lynx1 -/- mice. To determine which nAChRs could be involved in lynx1's actions, coexpression of lynx1 with nAChR subunits in the VTA was assessed. Lynx1 was found to colocalize in VTA cells expressing a4, a6, a7, 2, and 3 nAChR subunits, with male lynx1 -/- mice exhibiting an increase in a4 expression compared with wild-type mice. Finally, site-specific lynx1 knockdown in the VTA recapitulated the behavioral phenotype found in the lynx1 global knock-out mice, in which an increase in nicotine reinforcement was evidenced. Taken together, these findings reveal that lynx1 acts on nAChRs in the VTA to dampen the reinforcing properties of nicotine.

Source: Journal of Neuroscience

DOI: 10.1523/jneurosci.0797-26.2026