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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

Comparison of risk allele frequencies between non-smoking controls, non-smoking subjects with alcohol use disorder (AUD) and smoking subjects with AUD in the LCTS study using Pearson χ2 test. Total n for the three groups were 125–130, 121–128, 202–215 for the Caucasian sample and 26–29, 47–50, 137–147 for the African American sample, respectively. *P<0.05, **P<0.01, ***P<0.005. LCTS, Laboratory of Clinical and Translational Studies.
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fig1: Comparison of risk allele frequencies between non-smoking controls, non-smoking subjects with alcohol use disorder (AUD) and smoking subjects with AUD in the LCTS study using Pearson χ2 test. Total n for the three groups were 125–130, 121–128, 202–215 for the Caucasian sample and 26–29, 47–50, 137–147 for the African American sample, respectively. *P<0.05, **P<0.01, ***P<0.005. LCTS, Laboratory of Clinical and Translational Studies.

Mentions: We conducted post hoc analyses with the four associated SNPs and the two functional SNPs included in the haplotype block (see Supplementary Information). Comparing allele frequencies among non-smoking controls, non-smoking AUD and smoking AUD subjects using a χ2 test revealed that the non-smoking AUD group formed an intermediate group with the highest risk allele frequencies in the smoking AUD group (Figure 1). This was replicated across the two ancestral groups and seen for three of the six SNPs (Caucasians: rs2235868 P=0.030, rs7769547 P=0.026, rs10305512 P<0.001; African-Americans: rs2235868 P=0.0043, rs7769547 P<0.001, rs10305512 P=0.012). In addition, the results of the χ2 analyses suggested linear trends in allele frequencies across the three groups. Consequently, we applied the Cochran–Armitage test and found that the results remained significant for all SNPs, with P-values even smaller than those reported for the χ2 analyses. To investigate whether non-smoking AUD and smoking AUD subjects differed in AUD severity, we performed a linear regression using group as the independent factor, and, as the dependent factor, we used number of heavy drinking days (defined as ⩾4/5 drinks per day for women/men) during a 90-day-period as reported in the timeline follow-back self-report questionnaire,28 controlling for age and gender. We found significantly more heavy drinking days in the smoking AUD subjects (F(3,568)=13.5, B=11.6, P<0.001).


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)

Comparison of risk allele frequencies between non-smoking controls, non-smoking subjects with alcohol use disorder (AUD) and smoking subjects with AUD in the LCTS study using Pearson χ2 test. Total n for the three groups were 125–130, 121–128, 202–215 for the Caucasian sample and 26–29, 47–50, 137–147 for the African American sample, respectively. *P<0.05, **P<0.01, ***P<0.005. LCTS, Laboratory of Clinical and Translational Studies.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig1: Comparison of risk allele frequencies between non-smoking controls, non-smoking subjects with alcohol use disorder (AUD) and smoking subjects with AUD in the LCTS study using Pearson χ2 test. Total n for the three groups were 125–130, 121–128, 202–215 for the Caucasian sample and 26–29, 47–50, 137–147 for the African American sample, respectively. *P<0.05, **P<0.01, ***P<0.005. LCTS, Laboratory of Clinical and Translational Studies.
Mentions: We conducted post hoc analyses with the four associated SNPs and the two functional SNPs included in the haplotype block (see Supplementary Information). Comparing allele frequencies among non-smoking controls, non-smoking AUD and smoking AUD subjects using a χ2 test revealed that the non-smoking AUD group formed an intermediate group with the highest risk allele frequencies in the smoking AUD group (Figure 1). This was replicated across the two ancestral groups and seen for three of the six SNPs (Caucasians: rs2235868 P=0.030, rs7769547 P=0.026, rs10305512 P<0.001; African-Americans: rs2235868 P=0.0043, rs7769547 P<0.001, rs10305512 P=0.012). In addition, the results of the χ2 analyses suggested linear trends in allele frequencies across the three groups. Consequently, we applied the Cochran–Armitage test and found that the results remained significant for all SNPs, with P-values even smaller than those reported for the χ2 analyses. To investigate whether non-smoking AUD and smoking AUD subjects differed in AUD severity, we performed a linear regression using group as the independent factor, and, as the dependent factor, we used number of heavy drinking days (defined as ⩾4/5 drinks per day for women/men) during a 90-day-period as reported in the timeline follow-back self-report questionnaire,28 controlling for age and gender. We found significantly more heavy drinking days in the smoking AUD subjects (F(3,568)=13.5, B=11.6, P<0.001).

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