Brain region specific glucagon-like peptide-1 receptors regulate alcohol-induced behaviors in rodents

Vallöf, Daniel; Kalafateli, Aimilia Lydia; Jerlhag, Elisabet

doi:10.1016/j.psyneuen.2019.02.006

Cited by 41 publications

(56 citation statements)

References 79 publications

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“…In contrast to liraglutide, semaglutide significantly decreased EtOH preference and did not affect water intake, suggesting that its effects are more selective for EtOH. Consistent with our findings, previous studies suggest that the effects of GLP-1 analogs in reducing EtOH intake are due to reduced EtOH rewarding properties rather than nausea, which is a common side effect of GLP-1 analogs (Buse et al, 2009;Egecioglu et al, 2013b;Shirazi et al, 2013;Sirohi et al, 2016;Vallöf et al, 2016Vallöf et al, , 2019aVallöf et al, , 2020Hall et al, 2018). Altogether, our results suggest that semaglutide is more specific for alcohol than liraglutide, and given its more favorable prescription dosing (i.e., once a week), may be better suited for use in patients with AUD.…”

Section: Discussionsupporting

confidence: 91%

“…Previous findings that the inhibitory effect of exendin-4 on EtOH intake was blunted in mice lacking GLP-1Rs in the CNS suggest that central GLP-1Rs play a key role in mediating the effects of GLP-1 analogs on EtOH intake (Sirohi et al, 2016). A recent study demonstrated that microinjection of Ex9-39 into the NTS was able to prevent the suppressing effect of exendin-4 on EtOH-induced increase in locomotor activity (Vallöf et al, 2019a). Here, we showed that co-administration of Ex9-39 with liraglutide or semaglutide did not prevent the reduction in EtOH intake and weight.…”

Section: Discussionmentioning

confidence: 99%

“…Ex9-39 has been shown to antagonize the effects of GLP-1R activation in rodents and humans (Thorens et al, 1993;Wang et al, 1995;Edwards et al, 1999;Vallöf et al, 2019a). Blockade of GLP-1R by co-administration of Ex9-39 did not prevent the decrease in EtOH intake induced by liraglutide (treatment × time-point interaction: F(2,22) = 49.22, p < 0.001; post hoc test, baseline vs. liraglutide + Ex9-39 injection day, p < 0.001; liraglutide + Ex9-39 injection day vs. + 2d, p < 0.001) ( Figure 4A).…”

Section: Glp-1 Receptor Antagonism Does Not Prevent the Suppressing Ementioning

confidence: 99%

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Long-Acting Glucagon-Like Peptide-1 Receptor Agonists Suppress Voluntary Alcohol Intake in Male Wistar Rats

et al. 2020

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Alcohol use disorder (AUD) is a chronic relapsing condition characterized by compulsive alcohol-seeking behaviors, with serious detrimental health consequences. Despite high prevalence and societal burden, available approved medications to treat AUD are limited in number and efficacy, highlighting a critical need for more and novel pharmacotherapies. Glucagon-like peptide-1 (GLP-1) is a gut hormone and neuropeptide involved in the regulation of food intake and glucose metabolism via GLP-1 receptors (GLP-1Rs). GLP-1 analogs are approved for clinical use for diabetes and obesity. Recently, the GLP-1 system has been shown to play a role in the neurobiology of addictive behaviors, including alcohol seeking and consumption. Here we investigated the effects of different pharmacological manipulations of the GLP-1 system on escalated alcohol intake and preference in male Wistar rats exposed to intermittent access 2-bottle choice of 10% ethanol or water. Administration of AR231453 and APD668, two different agonists of G-protein receptor 119, whose activation increases GLP-1 release from intestinal L-cells, did not affect voluntary ethanol intake. By contrast, injections of either liraglutide or semaglutide, two long-acting GLP-1 analogs, potently decreased ethanol intake. These effects, however, were transient, lasting no longer than 48 h. Semaglutide, but not liraglutide, also reduced ethanol preference on the day of injection. As expected, both analogs induced a reduction in body weight. Co-administration of exendin 9-39, a GLP-1R antagonist, did not prevent liraglutide- or semaglutide-induced effects in this study. Injection of exendin 9-39 alone, or blockade of dipeptidyl peptidase-4, an enzyme responsible for GLP-1 degradation, via injection of sitagliptin, did not affect ethanol intake or preference. Our findings suggest that among medications targeting the GLP-1 system, GLP-1 analogs may represent novel and promising pharmacological tools for AUD treatment.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Section: Glp-1 Receptor Antagonism Does Not Prevent the Suppressing Ementioning

confidence: 99%

See 1 more Smart Citation

Long-Acting Glucagon-Like Peptide-1 Receptor Agonists Suppress Voluntary Alcohol Intake in Male Wistar Rats

et al. 2020

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“…While the effects of GLP-1 are thought to be centrally mediated (Sirohi et al, 2016), the specific sites of action were unclear. Several studies implicate the VTA as a nuclear substrate responsible for the effects of GLP-1 on home cage alcohol intake (Shirazi et al, 2013) and alcohol-induced locomotor activity (Vallof et al, 2019a). However, whether GLP-1R signaling in the VTA also reduces other aspects of alcohol intake behaviors was unknown.…”

Section: Discussionmentioning

confidence: 99%

“…1). Previous studies show that the effects of Ex4 on alcohol intake can be dependent upon VTA region such that Ex4 delivered to posterior VTA reduces home cage alcohol intake but not when delivered to anterior VTA (Vallof et al, 2019a). Thus, we performed additional analysis to determine whether there are regional differences for Ex4-induced suppression of alcohol intake.…”

Section: Vta Regional Differences Do Not Contribute To the Effects Ofmentioning

confidence: 99%

Glucagon‐Like Peptide‐1 Receptor Signaling in the Ventral Tegmental Area Reduces Alcohol Self‐Administration in Male Rats

Dixon

McNally

Ong

2020

Alcoholism Clin & Exp Res

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Background: The misuse and abuse of alcohol is a major public health issue. However, available treatments are limited with variable efficacy. Recently, preclinical studies show that glucagon-like-peptide-1 (GLP-1) and its analogue Exendin-4 (Ex4) potently reduce a range of alcohol intake behaviors, thus highlighting its potential as a treatment for alcohol use disorders. However, the neural mechanisms and sites of action mediating the effects of Ex4 on alcohol intake behaviors remain to be characterized. This study examined the ventral tegmental area (VTA) as a site of action for the effects of GLP-1 on alcohol intake. Methods: Male Long-Evans rats were given intermittent access to 20% alcohol and trained to nose poke for 20% alcohol. Rats received intra-VTA injections of Ex4 (vehicle, 0.01, 0.05 lg), and the effects of VTA Ex4 on alcohol self-administration, motivation, and relapse were assessed. Results: When compared to vehicle treatment, intra-VTA Ex4 (0.01, 0.05 lg) delivery significantly reduced alcohol self-administration, an effect that was particularly prominent in high alcohol drinkers. However, VTA Ex4 did not reduce reacquisition of alcohol self-administration after extinction nor the motivation to obtain alcohol. Importantly, the lower dose of Ex4 (0.01 lg) used had no effect on food intake or locomotor activity, suggesting that the reduction in alcohol self-administration observed was not secondary to caloric intake or motor deficits. Conclusions: Together, these findings provide support for the VTA as a key site of action for GLP-1 on alcohol self-administration but not the reacquisition of alcohol self-administration or motivation to work for alcohol.

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Endocrine Manifestations of Alcohol and Other Drug Use Disorders

Quirk

Twigg

2020

Textbook of Addiction Treatment

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Brain region specific glucagon-like peptide-1 receptors regulate alcohol-induced behaviors in rodents

Cited by 41 publications

References 79 publications

Long-Acting Glucagon-Like Peptide-1 Receptor Agonists Suppress Voluntary Alcohol Intake in Male Wistar Rats

Long-Acting Glucagon-Like Peptide-1 Receptor Agonists Suppress Voluntary Alcohol Intake in Male Wistar Rats

Glucagon‐Like Peptide‐1 Receptor Signaling in the Ventral Tegmental Area Reduces Alcohol Self‐Administration in Male Rats

Endocrine Manifestations of Alcohol and Other Drug Use Disorders

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