Neu1 deficiency is associated with reduced nicotine responsiveness and dopamine D3 receptor downregulation in zebrafish.

Nicotine induces pronounced neural and behavioral activation through dopaminergic signaling. However, the underlying molecular mechanisms that regulate nicotine sensitivity remain poorly understood. Here, we investigated the roles of lysosomal sialidase Neu1 and neural glycan polysialic acid (PSA) in nicotine-induced responses in zebrafish, a vertebrate model. Western blot analyses revealed reduced PSA levels and significantly upregulated neu1 expression in the zebrafish brain following acute nicotine exposure. Behavioral assays revealed increased tolerance to nicotine-induced lethality and attenuated nicotine-evoked swimming excitation in neu1-knockout (neu1-KO) zebrafish compared with those in wild-type fish. Nicotine-induced neuronal activation, assessed based on c-Fos expression, was markedly reduced in neu1-KO zebrafish. Gene expression analyses revealed altered dopaminergic signaling, including reduced drd3 expression, in neu1-KO zebrafish. Pharmacological experiments demonstrated that blocking dopamine D2/D3 receptors suppressed nicotine-induced swimming excitation in wild-type zebrafish, whereas treatment with a selective dopamine D3 receptor agonist partially rescued the attenuated nicotine responsiveness observed in neu1-KO zebrafish. Nicotine-induced c-Fos activation occurred predominantly in PSA-positive neurons within the hypothalamus, a brain region implicated in dopaminergic signaling. These findings suggest that Neu1-mediated PSA degradation may modulate dopamine D3 receptor-dependent nicotine sensitivity. We propose a conceptual model wherein nicotine-induced Neu1 activation may contribute to reduced PSA levels and altered dopamine D3 receptor-related signaling, thereby influencing the threshold for nicotine-induced neural and behavioral activation.