The glucagon-like peptide-1 (GLP-1) analogue semaglutide reduces alcohol drinking and modulates central GABA neurotransmission

Abstract

Growing evidence indicates that the glucagon-like peptide-1 (GLP-1) system is involved in the neurobiology of addictive behaviors, and GLP-1 analogues may be used for the treatment of alcohol use disorder (AUD). Here, we examined the effects of semaglutide, a long-acting GLP-1 analogue, on biobehavioral correlates of alcohol use in rodents. A drinking-in-the-dark procedure was used to test the effects of semaglutide on binge-like drinking in male and female mice. We also tested the effects of semaglutide on binge-like and dependence-induced alcohol drinking in male and female rats, as well as acute effects of semaglutide on spontaneous inhibitory postsynaptic currents (sIPSCs) from central amygdala (CeA) and infralimbic cortex (ILC) neurons. Semaglutide dose-dependently reduced binge-like alcohol drinking in mice; a similar effect was observed on the intake of other caloric/noncaloric solutions. Semaglutide also reduced binge-like and dependence-induced alcohol drinking in rats. Semaglutide increased sIPSC frequency in CeA and ILC neurons from alcohol-naive rats, suggesting enhanced GABA release, but had no overall effect on GABA transmission in alcohol-dependent rats. In conclusion, the GLP-1 analogue semaglutide decreased alcohol intake across different drinking models and species and modulated central GABA neurotransmission, providing support for clinical testing of semaglutide as a potentially novel pharmacotherapy for AUD.

Chronic ethanol exposure produces long-lasting, subregion-specific physiological adaptations in RMTg-projecting mPFC neurons

“…This is in contrast to Chuong et al (2023), which observed a significant increase in both the frequency and amplitude of sIPSCs after CIE exposure. Although seemingly in at least partial agreement with the current findings, Chuong et al (2023) performed recordings within an hour after the final ethanol vapor exposure session and allowed slices containing the IL mPFC to undergo acute withdrawal in vitro . In addition, neither study distinguished between distinct cortico-subcortical projections, making comparisons between the current findings and these studies difficult.…”

“…For example, heightened impulsivity (Irimia et al, 2014; Starski et al, 2020; Walker et al, 2011), deficits in behavioral flexibility (Badanich et al, 2011; Hu et al, 2015; Mejia-Toiber et al, 2014; Trantham-Davidson et al, 2014; Varodayan et al, 2018), impairments in fear extinction and retrieval (Holmes et al, 2012), and increased anxiety-like behavior (Hughes et al, 2021; Mejia-Toiber et al, 2014; Pleil et al, 2015; Starski et al, 2020; Varodayan et al, 2018) have been observed in rodents exposed to chronic ethanol. In some studies, these deficits are associated with physiological neuroadaptations in prelimbic (PL) (Holmes et al, 2012; Hughes et al, 2021; Kroener et al, 2012; Pleil et al, 2015) and infralimbic (IL) (Chuong et al, 2023; Flores-Ramirez et al, 2023; Pleil et al, 2015; Varodayan et al, 2018) subregions of the mPFC. Of note, while few studies report data from both mPFC subregions in the same experiment, those that do have found that PL and IL are differentially affected by chronic ethanol exposure (Pleil et al, 2015; Varodayan et al, 2018).…”

A Narrative Review of Current and Emerging Trends in the Treatment of Alcohol Use Disorder

“…Importantly, the effects were not specific to alcohol, as semaglutide also reduced the intake of various non-alcoholic solutions, suggesting a broader role in suppressing behaviors related to appetite, thirst, and palatability. The research suggested that semaglutide influenced GABAergic synaptic transmission in brain areas associated with alcohol-related behaviors [ 101 ].…”

Liraglutide-associated depression in a patient with type 2 diabetes: A case report and discussion

“…Its dysregulation may lead to anhedonia and other depressive symptoms. [ 17 ] In fact, studies have shown reduced cravings for addictive substances after using GLP-1RAs, [ 18 ] possibly related to their effect on the dopamine reward system. [ 19 ]…”