[R01] Suppression of ethanol dependence-induced maladaptive appetitive and consummatory behavior by the GLP-1 system
Ente: National Institute on Alcohol Abuse and Alcoholism
Scadenza: 2031-01-31
Importo max: 564.306 EUR
Paese: US
Descrizione
PROJECT SUMMARY
People in recovery from alcohol use disorder (AUD) can experience a range of physiological and behavioral
effects during withdrawal. These effects include aberrant food consumption, and increased alcohol drinking and
seeking, which can increase stress and drive relapse. Ethanol dependence appears to dysregulate the glucagon-
like peptide-1 (GLP-1) system, and clinical drugs that target this system are now being investigated for their
ability to reduce food and alcohol intake. While GLP-1 is a gut peptide, it is also a neuropeptide, synthesized by
neurons of the nucleus tractus solitarius (NTS), and its receptor (GLP-1R) is expressed throughout the brain.
Several clinically approved GLP-1R agonist medications cross the blood brain-barrier, and work both peripherally
and centrally. While these medications hold promise, they also induce undesirable side-effects, largely due to
their effects in the hindbrain. Specific targeting of GLP-1Rs in regions of the forebrain could reduce the off-target
effects of GLP-1 medications, while still suppressing aberrant food and alcohol consumption during AUD
recovery. Thus, this proposal is designed to investigate the ability of GLP-1R in discrete CNS circuits to regulate
binge-like food and ethanol intake and relapse during withdrawal. We will model ethanol dependence using
chronic intermittent ethanol (CIE) exposure by vapor inhalation to test the overarching hypothesis that withdrawal
from ethanol in the CIE model leads to physiological dysregulation, including dysregulation of the central GLP-1
system and associated disruption in reward taking and seeking. Thus, by increasing GLP-1R activity in the
prefrontal cortex (PFC) and paraventricular nucleus of the thalamus (PVT), we can suppress CIE-induced
behavioral dysregulation, including escalated binge-like eating and ethanol drinking, and reinstatement of
seeking for palatable food and ethanol. Aim 1 is to examine the consequences of withdrawal from CIE on binge-
like intake, and associated stress and metabolic system dysregulation. Aim 2 is to characterize the contribution
of PFC and PVT circuit-specific GLP-1R signaling to dysregulated consumption of food and ethanol following
withdrawal. Aim 3 is to characterize the contribution of PFC and PVT circuit-specific GLP-1R signaling to relapse-
related appetitive behavior following withdrawal. To accomplish these aims, male and female mice will undergo
CIE or Air exposure and withdrawal and be tested for: CIE effects on binge-like eating and stress-induced
reinstatement of ethanol and palatable food seeking; effect of systemic GLP-1R and selective (PFC and PVT)
GLP-1R pharmacological manipulation on palatable food and ethanol intake and stress-induced reinstatement;
and the necessity of GLP-1R within discrete PFC and PVT circuits in regulating binge-like eating and ethanol
seeking through circuit-specific knockdown of GLP-1R. Understanding the role of the forebrain GLP-1 system
may aid with the imp
Istituzione: DREXEL UNIVERSITY
PI: JACQUELINE M BARKER, Jessica Rose Barson
Progetto: 1R01AA031732-01A1
Settori: National Institute on Alcohol Abuse and Alcoholism
Vai al bando originale
Registrati gratis su Bandolo per trovare bandi compatibili con la tua azienda.