Liraglutide attenuates nicotine reward in mice by downregulating hypothalamic prepro-orexin and NTS prepro-glucagon

Nicotine addiction is a major global health crisis, driving lung cancer and cardiovascular disorders. Nicotine's addictive properties stem from stimulating nicotinic acetylcholine receptors (nAChRs), leading to excessive dopamine release in the ventral tegmental area (VTA) and nucleus accumbens (NAc). This reward pathway is further reinforced by enhanced orexin activity in the hypothalamus and prepro-glucagon expression in the nucleus tractus solitarius (NTS). Current cessation strategies often have limited long-term success, highlighting the need for novel therapeutic targets that address these underlying neurobiological mechanisms. GLP-1 receptor agonists, known for metabolic benefits, are also implicated in modulating the mesolimbic reward system, making them a compelling area of study for addiction.

Researchers investigated liraglutide's impact on nicotine-induced reward in male ddy mice. Animals were divided into four groups: control, nicotine-only, nicotine + liraglutide (50 µg/kg), and nicotine + liraglutide (100 µg/kg). Nicotine was administered at 0.5 mg/kg. The primary behavioral endpoint was assessed using the conditioned place preference (CPP) test to quantify reward-related behaviors. Molecular changes were evaluated via RT-PCR to measure prepro-orexin mRNA expression in the hypothalamus and prepro-glucagon mRNA expression in the NTS. This design allowed for direct comparison of liraglutide's dose-dependent effects against nicotine-induced changes.

Nicotine administration at 0.5 mg/kg significantly increased CPP scores, confirming enhanced reward-related behaviors in the mice. This behavioral change was accompanied by elevated prepro-orexin mRNA expression in the hypothalamus and prepro-glucagon mRNA expression in the NTS. > Treatment with liraglutide (50 and 100 µg/kg) significantly reduced nicotine-induced CPP scores, indicating a clear attenuation of addictive behavior. Furthermore, liraglutide treatment downregulated the expression of both prepro-orexin and prepro-glucagon mRNA. The 100 µg/kg dose of liraglutide demonstrated greater efficacy in normalizing prepro-glucagon levels compared to the lower dose, suggesting a dose-dependent molecular effect. These findings collectively demonstrate that liraglutide mitigates nicotine reward by modulating these specific neuropeptide pathways.