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 knockout (lynx1
-/-
) or their wildtype littermates (lynx
+/+
) were examined with intravenous nicotine self-administration across a full dose response function. Knockout 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, co-expression of lynx1 with nAChR subunits in the VTA was assessed. Lynx1 was found to co-localize in VTA cells expressing α4, α6, α7, and β2 and β3 nAChR subunits, with male lynx1
-/-
mice exhibiting an increase in α4 expression compared to wildtype mice. Finally, site-specific lynx1 knockdown in the VTA recapitulated the behavioral phenotype found in the lynx1 global knockout 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.
Significance Statement
Lynx1 plays a critical regulatory role in cholinergic signaling by modulating the function of neuronal nicotinic acetylcholine receptors. Our data show that loss of lynx1 enhances nicotine self-administration, particularly at lower doses, through actions in the ventral tegmental area. Together, these findings position lynx1 as a key gatekeeper of nicotine reward, thereby providing critical insight into the neural mechanisms that drive nicotine intake and identifying a potential target for therapeutic intervention.