Biology subjects

Gottlieb, S.

Publications and source records attributed to Gottlieb, S..

3 recordsLinked to original sources

bioRxiv2025

Tirzepatide attenuates dopamine reward signaling and suppresses alcohol drinking and relapse-like behaviors in rodents

Alcohol use disorder (AUD) remains a major public health problem, with few effective medications currently available. However, peptides of the gut-brain axis appear to offer promising therapeutic targets for AUD as they influence the mesolimbic reward circuitry. Here, we examined the effects of tirzepatide, a long-acting dual glucagon-like peptide-1 receptor (GLP-1R) and glucose-dependent insulinotropic polypeptide receptor (GIPR) agonist approved for diabetes and obesity, using behavioral assays, alcohol intake paradigms, and molecular analyses in rodents. First, tirzepatide effectively attenuated the rewarding properties of alcohol, measured through locomotor stimulation, conditioned place preference, and accumbal dopamine release. Subsequently, this GLP-1R/GIPR agonist dose-dependently reduced voluntary alcohol consumption, prevented binge and relapse-like drinking, and maintained efficacy during repeated administration. Finally, tirzepatide induced sustained synaptic depression in the lateral septum and further altered histone regulatory proteins in this region, suggesting a potential neural substrate for its effects. Moreover, the GLP-1R/GIPR agonist affected metabolic parameters including body weight, adipose tissue mass, hepatic triglycerides and circulating pro-inflammatory cytokines. Together, our findings suggest tirzepatide modulates alcohol-related behaviors through reward-related mechanisms while also affecting physiological consequences associated with long-term alcohol use. Given tirzepatides established clinical use and the consistency of effects observed here, these results support further investigation for treating AUD and associated complications. SIGNIFICANCE STATEMENTExisting treatments for alcohol use disorder show limited effectiveness, leaving patients without viable therapeutic options. We demonstrate that tirzepatide, a long-acting gut peptide-based drug already approved for diabetes and obesity, substantially reduces alcohol consumption and prevents relapse-like behavior across multiple preclinical models. Tirzepatide appears to work by influencing brain reward systems while simultaneously affecting metabolic complications common in alcohol disorders. Given tirzepatides clinical availability, these findings suggest repurposing a recently approved drug to tackle one of medicines more persistent treatment challenges.

neuroscience↗

bioRxiv2024

A selective GSK3β inhibitor, tideglusib, decreases intermittent access and binge ethanol self-administration in C57BL/6J mice

Over 10% of the US population over 12 years old meets criteria for Alcohol Use Disorder (AUD), yet few effective, long-term treatments are currently available. Glycogen synthase kinase 3 beta (GSK3{beta}) has been implicated in ethanol behaviors and poses as a potential therapeutic target in the treatment of AUD. Here we investigate the role of tideglusib, a selective GSK3{beta} inhibitor, in ethanol consumption and other behaviors. We have shown tideglusib decreases ethanol consumption in both a model of daily, progressive ethanol intake (two-bottle choice, intermittent ethanol access) and binge-like drinking behavior (drinking-in-the-dark) without effecting water intake. Further, we have shown tideglusib to have no effect on ethanol pharmacokinetics, taste preference, or anxiety-like behavior, though there was a transient increase in total locomotion following treatment. Additionally, we assessed liver health following treatment via serum levels of alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase and showed no effect on aminotransferase levels though there was a decrease in alkaline phosphatase. RNA sequencing studies revealed a role of GSK3{beta} inhibition via tideglusib on the canonical Wnt signaling pathway, suggesting tideglusib may carry out its effects on ethanol consumption through effects on {beta}-catenin binding to the transcription factors TCF3 and LEF1. The data presented here further implicate GSK3{beta} in alcohol consumption and support the use of tideglusib as a potential therapeutic in the treatment of AUD.

pharmacology and toxicology↗

bioRxiv2023

Dog Ecology and Rabies Knowledge, Attitude and Practice (KAP) in the Northern Communal Areas of Namibia

In 2021, a comprehensive dog demographic questionnaire combined with a KAP survey were conducted in the northern communal areas (NCAs) of Namibia with the aim of gaining a better understanding of dog populations, owner behaviour, and knowledge, attitudes and practices (KAP) relating to rabies. The survey of 3,726 households across the eight regions of the NCAs provided insights that will inform interventions on order to improve human rabies prevention and Namibias dog rabies control strategy. The results showed a relatively low average human/dog ratio (HDR) of 5.4:1 indicating a surprisingly high dog population of at least 272,000 dogs in the NCAs, 93% of which appear to be owned but are free-roaming. Data analysis revealed opportunities but also highlighted needs for improvements in rabies surveillance and mass dog vaccinations. Although knowledge, attitude, and practice scores towards epidemiologic and clinical aspects, human rabies prevention, and canine rabies vaccination were deemed to be acceptable, the survey nevertheless revealed deficiencies in some of the population. Interestingly, data seemed to indicate a certain number of unreported human rabies cases. Other findings included the very high number of dogs. However, only 50% of dog-owning households reported having vaccinated their dogs. In order to address these issues, the planning, announcement, and implementation of mass dog vaccination campaigns need to be adapted to achieve adequate vaccination coverage. Another focus needs to be on rabies awareness and education if Namibia is to be significantly contributing to the global goal of "Zero by 30". Author SummaryAs a neglected disease, rabies remains a major One Health problem in Africa and Asia. Here we report the results of an extensive community survey on dog ownership and knowledge, attitudes and practices (KAP) related to rabies control and prevention, covering the Northern Communal Areas of Namibia. Our results showed that the dog population is large with a human/dog ratio (HDR) of 5.4:1, of which the vast majority is free-roaming thus supporting disease transmission but complicating control efforts. The majority of people across this part of Namibia were aware of rabies and had acceptable levels of attitudes and practices. While dog bite incidences per 100,000 people were high, ranging between 262 and 1,369, more than 90% of bite victims reported having visited a hospital after a bite incident. Still, gaps in dog rabies surveillance exist and incomplete or missing post exposure prophylaxes caused human casualties and call for ongoing interventions aimed at increasing knowledge and awareness.

microbiology↗