GLP-1 Agonist Attenuates Nicotine Reward-Related Behavior by Regulating the Prepro-Orexin in the Hypothalamus and Prepro-Glucagon in the Nucleus Tractus Solitarius.

Tobacco consumption has significantly increased globally, contributing to various degenerative diseases such as lung cancer and cardiovascular disorders. Nicotine, the primary addictive component in tobacco, exerts its effects by stimulating nicotinic acetylcholine receptors (nAChRs), leading to excessive dopamine release in the ventral tegmental area (VTA) and nucleus accumbens (NAc), which underlies its rewarding and addictive properties. Additionally, nicotine enhances orexin activity in the hypothalamus and prepro-glucagon expression in the nucleus tractus solitarius (NTS), further reinforcing addictive behaviors. This study is aimed at investigating the effects of liraglutide, a GLP-1 receptor agonist, on nicotine-induced reward. Male mice strain ddy were divided into four groups: control, nicotine, nicotine + liraglutide (50 μg/kg), and nicotine + liraglutide (100 μg/kg). The conditioned place preference (CPP) test was used to evaluate nicotine's rewarding effects, whereas RT-PCR assessed the expression of prepro-orexin and prepro-glucagon mRNA in the hypothalamus and NTS, respectively. The results confirmed that nicotine administration (0.5 mg/kg) significantly increased CPP scores, indicating enhanced reward-related behaviors. Correspondingly, nicotine elevated prepro-orexin and prepro-glucagon mRNA expression levels. Treatment with liraglutide (50 and 100 μg/kg) significantly reduced nicotine-induced CPP scores, suggesting an attenuation of addictive behavior. Liraglutide downregulated the expression of prepro-orexin and prepro-glucagon, with the 100 μg/kg dose demonstrating greater efficacy in normalizing prepro-glucagon levels. These findings indicate that liraglutide mitigates nicotine reward by modulating neuropeptide pathways, including orexin and glucagon signaling. The dual impact of liraglutide on behavioral and molecular markers highlights its potential as a therapeutic agent for treating nicotine induce reward-related behavior. Further research is warranted to explore its long-term efficacy and underlying mechanisms in addiction modulation.