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The glucagon-like peptide-1 receptor as a potential treatment target in alcohol use disorder: evidence from human genetic association studies and a mouse model of alcohol dependence.

Suchankova P, Yan J, Schwandt ML, Stangl BL, Caparelli EC, Momenan R, Jerlhag E, Engel JA, Hodgkinson CA, Egli M, Lopez MF, Becker HC, Goldman D, Heilig M, Ramchandani VA, Leggio L - Transl Psychiatry (2015)

Bottom Line: The previously reported functional allele 168Ser (rs6923761) was nominally associated with AUD (P = 0.004) in the NIAAA sample, which was partially replicated in males of the SAGE sample (P = 0.033).The 168 Ser/Ser genotype was further associated with increased alcohol administration and breath alcohol measures in the IV-ASA experiment and with higher BOLD response in the right globus pallidus when receiving notification of outcome for high monetary reward.These convergent findings suggest that the GLP-1R may be an attractive target for personalized pharmacotherapy treatment of AUD.

View Article: PubMed Central - PubMed

Affiliation: 1] Section on Clinical Psychoneuroendocrinology and Neuropsychopharmacology, Laboratory of Clinical and Translational Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA [2] Department of Pharmacology, The Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.

ABSTRACT
The hormone glucagon-like peptide-1 (GLP-1) regulates appetite and food intake. GLP-1 receptor (GLP-1R) activation also attenuates the reinforcing properties of alcohol in rodents. The present translational study is based on four human genetic association studies and one preclinical study providing data that support the hypothesis that GLP-1R may have a role in the pathophysiology of alcohol use disorder (AUD). Case-control analysis (N = 908) was performed on a sample of individuals enrolled in the National Institute on Alcohol Abuse and Alcoholism (NIAAA) intramural research program. The Study of Addiction: Genetics and Environment (SAGE) sample (N = 3803) was used for confirmation purposes. Post hoc analyses were carried out on data from a human laboratory study of intravenous alcohol self-administration (IV-ASA; N = 81) in social drinkers and from a functional magnetic resonance imaging study in alcohol-dependent individuals (N = 22) subjected to a Monetary Incentive Delay task. In the preclinical study, a GLP-1R agonist was evaluated in a mouse model of alcohol dependence to demonstrate the role of GLP-1R for alcohol consumption. The previously reported functional allele 168Ser (rs6923761) was nominally associated with AUD (P = 0.004) in the NIAAA sample, which was partially replicated in males of the SAGE sample (P = 0.033). The 168 Ser/Ser genotype was further associated with increased alcohol administration and breath alcohol measures in the IV-ASA experiment and with higher BOLD response in the right globus pallidus when receiving notification of outcome for high monetary reward. Finally, GLP-1R agonism significantly reduced alcohol consumption in a mouse model of alcohol dependence. These convergent findings suggest that the GLP-1R may be an attractive target for personalized pharmacotherapy treatment of AUD.

No MeSH data available.


Related in: MedlinePlus

Statistical maps for fMRI analysis contrasting the genotype groups 168Gly/Gly × 168Ser/Gly+168Ser/Ser in the rs6923761 SNP. Statistical maps (top) and ROI results (bottom) for notification of high reward (left) and its net difference with low reward (right) contrasting (168Gly/Gly)−(168Ser/Gly+168Ser/Ser) are shown; ROI localization is displayed in yellow at the axial view in the bottom. fMRI, functional magnetic resonance imaging; SNP, single-nucleotide polymorphism.
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fig2: Statistical maps for fMRI analysis contrasting the genotype groups 168Gly/Gly × 168Ser/Gly+168Ser/Ser in the rs6923761 SNP. Statistical maps (top) and ROI results (bottom) for notification of high reward (left) and its net difference with low reward (right) contrasting (168Gly/Gly)−(168Ser/Gly+168Ser/Ser) are shown; ROI localization is displayed in yellow at the axial view in the bottom. fMRI, functional magnetic resonance imaging; SNP, single-nucleotide polymorphism.

Mentions: There was a significant difference (Pcorr<0.05) in brain activation within the right globus pallidus when contrasting the genotypes (168Gly/Gly) vs (168Ser/Gly+168Ser/Ser) for the rs6923761 SNP. Those carrying the non-risk allele (that is, 168Gly/Gly group) had lower BOLD response than those carrying the risk allele (168Ser/Gly+168Ser/Ser group) when receiving notification of outcome (feedback) for high reward (peak T=−4.8). A similar group difference was observed for the contrasted task condition: notification of outcome of high reward vs low reward (peak T=−3.4). We then computed the mean percent signal change of ROIs as described above to further verify these findings. The only significant difference was found from the ROI located on right globus pallidus for high reward between group contrast (Figure 2). No significant group difference was observed for other task conditions (contrasts) or other brain areas under the same contrast.


The glucagon-like peptide-1 receptor as a potential treatment target in alcohol use disorder: evidence from human genetic association studies and a mouse model of alcohol dependence.

Suchankova P, Yan J, Schwandt ML, Stangl BL, Caparelli EC, Momenan R, Jerlhag E, Engel JA, Hodgkinson CA, Egli M, Lopez MF, Becker HC, Goldman D, Heilig M, Ramchandani VA, Leggio L - Transl Psychiatry (2015)

Statistical maps for fMRI analysis contrasting the genotype groups 168Gly/Gly × 168Ser/Gly+168Ser/Ser in the rs6923761 SNP. Statistical maps (top) and ROI results (bottom) for notification of high reward (left) and its net difference with low reward (right) contrasting (168Gly/Gly)−(168Ser/Gly+168Ser/Ser) are shown; ROI localization is displayed in yellow at the axial view in the bottom. fMRI, functional magnetic resonance imaging; SNP, single-nucleotide polymorphism.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4490279&req=5

fig2: Statistical maps for fMRI analysis contrasting the genotype groups 168Gly/Gly × 168Ser/Gly+168Ser/Ser in the rs6923761 SNP. Statistical maps (top) and ROI results (bottom) for notification of high reward (left) and its net difference with low reward (right) contrasting (168Gly/Gly)−(168Ser/Gly+168Ser/Ser) are shown; ROI localization is displayed in yellow at the axial view in the bottom. fMRI, functional magnetic resonance imaging; SNP, single-nucleotide polymorphism.
Mentions: There was a significant difference (Pcorr<0.05) in brain activation within the right globus pallidus when contrasting the genotypes (168Gly/Gly) vs (168Ser/Gly+168Ser/Ser) for the rs6923761 SNP. Those carrying the non-risk allele (that is, 168Gly/Gly group) had lower BOLD response than those carrying the risk allele (168Ser/Gly+168Ser/Ser group) when receiving notification of outcome (feedback) for high reward (peak T=−4.8). A similar group difference was observed for the contrasted task condition: notification of outcome of high reward vs low reward (peak T=−3.4). We then computed the mean percent signal change of ROIs as described above to further verify these findings. The only significant difference was found from the ROI located on right globus pallidus for high reward between group contrast (Figure 2). No significant group difference was observed for other task conditions (contrasts) or other brain areas under the same contrast.

Bottom Line: The previously reported functional allele 168Ser (rs6923761) was nominally associated with AUD (P = 0.004) in the NIAAA sample, which was partially replicated in males of the SAGE sample (P = 0.033).The 168 Ser/Ser genotype was further associated with increased alcohol administration and breath alcohol measures in the IV-ASA experiment and with higher BOLD response in the right globus pallidus when receiving notification of outcome for high monetary reward.These convergent findings suggest that the GLP-1R may be an attractive target for personalized pharmacotherapy treatment of AUD.

View Article: PubMed Central - PubMed

Affiliation: 1] Section on Clinical Psychoneuroendocrinology and Neuropsychopharmacology, Laboratory of Clinical and Translational Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA [2] Department of Pharmacology, The Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.

ABSTRACT
The hormone glucagon-like peptide-1 (GLP-1) regulates appetite and food intake. GLP-1 receptor (GLP-1R) activation also attenuates the reinforcing properties of alcohol in rodents. The present translational study is based on four human genetic association studies and one preclinical study providing data that support the hypothesis that GLP-1R may have a role in the pathophysiology of alcohol use disorder (AUD). Case-control analysis (N = 908) was performed on a sample of individuals enrolled in the National Institute on Alcohol Abuse and Alcoholism (NIAAA) intramural research program. The Study of Addiction: Genetics and Environment (SAGE) sample (N = 3803) was used for confirmation purposes. Post hoc analyses were carried out on data from a human laboratory study of intravenous alcohol self-administration (IV-ASA; N = 81) in social drinkers and from a functional magnetic resonance imaging study in alcohol-dependent individuals (N = 22) subjected to a Monetary Incentive Delay task. In the preclinical study, a GLP-1R agonist was evaluated in a mouse model of alcohol dependence to demonstrate the role of GLP-1R for alcohol consumption. The previously reported functional allele 168Ser (rs6923761) was nominally associated with AUD (P = 0.004) in the NIAAA sample, which was partially replicated in males of the SAGE sample (P = 0.033). The 168 Ser/Ser genotype was further associated with increased alcohol administration and breath alcohol measures in the IV-ASA experiment and with higher BOLD response in the right globus pallidus when receiving notification of outcome for high monetary reward. Finally, GLP-1R agonism significantly reduced alcohol consumption in a mouse model of alcohol dependence. These convergent findings suggest that the GLP-1R may be an attractive target for personalized pharmacotherapy treatment of AUD.

No MeSH data available.


Related in: MedlinePlus