Nf1 Regulates Alcohol Dependence-associated Excessive Drinking and Gamma-aminobutyric Acid Release in the Central Amygdala in Mice and is Associated with Alcohol Dependence in Humans

Overview

Journal Biol Psychiatry

Publisher Elsevier

Specialty Psychiatry

Date 2014 Dec 9

PMID 25483400

Citations 11

Authors

Vez Repunte-Canonigo

Melissa Herman

Tomoya Kawamura

Henry R Kranzler

Richard Sherva

Joel Gelernter

Lindsay A Farrer

Marisa Roberto

Pietro Paolo Sanna

Affiliations

Soon will be listed here.

Abstract

Background: The neurofibromatosis type 1 (Nf1) gene encodes a GTPase activating protein that negatively regulates small GTPases of the Ras family.

Methods: We assessed alcohol-related behaviors including alcohol sensitivity, dependent and nondependent drinking, and basal and alcohol-induced gamma-aminobutyric acid (GABA) release in the central nucleus of the amygdala (CeA) in Nf1 heterozygous null mice (Nf1(+/-)). We also investigated the associations of NF1 polymorphisms with alcohol dependence risk and severity in humans.

Results: Nf1(+/-) mice do not differ from wild-type mice in nondependent drinking, such as 24-hour, 2-bottle choice drinking in the dark binge drinking or limited access 2-bottle choice. However, Nf1(+/-) mice failed to escalate alcohol drinking following chronic intermittent ethanol vapor exposure (CIE) to induce dependence. Alcohol acutely increases GABA release in the CeA and alcohol dependence is characterized by increased baseline GABA release in CeA. Interestingly, GABA release in Nf1(+/-) mice is greater at baseline than wild-type mice, is not elevated by induction of dependence by CIE, and failed to show alcohol-induced facilitation both before and after CIE. Additionally, we observed that multiple variants in the human NF1 gene are associated with a quantitative measure of alcohol dependence in both African Americans and European Americans.

Conclusions: In this translational investigation, we found that Nf1 activity regulates excessive drinking and basal and ethanol-stimulated GABA release in the mouse central amygdala. We also found that genetic variation in NF1 may confer an inherent susceptibility to the transition from nondependent to dependent drinking in humans.

Citing Articles

Serum metabolomics analysis in patients with alcohol dependence.

Zhang Y, Sun Y, Miao Q, Guo S, Wang Q, Shi T Front Psychiatry. 2023; 14:1151200.

PMID: 37139316 PMC: 10150058. DOI: 10.3389/fpsyt.2023.1151200.

Effects of central amygdala chemogenetic manipulation and prior chronic alcohol exposure on Pavlovian-to-instrumental transfer.

Shields C, Gremel C Alcohol Clin Exp Res. 2022; 46(11):1967-1979.

PMID: 36117381 PMC: 9722516. DOI: 10.1111/acer.14948.

Effect of chronic intermittent ethanol vapor exposure on RNA content of brain-derived extracellular vesicles.

Baratta A, Mangieri R, Aziz H, Lopez M, Farris S, Homanics G Alcohol. 2022; 105:9-24.

PMID: 36055466 PMC: 10173183. DOI: 10.1016/j.alcohol.2022.08.006.

Nociceptin attenuates the escalation of oxycodone self-administration by normalizing CeA-GABA transmission in highly addicted rats.

Kallupi M, Carrette L, Kononoff J, Solberg Woods L, Palmer A, Schweitzer P Proc Natl Acad Sci U S A. 2020; 117(4):2140-2148.

PMID: 31932450 PMC: 6994987. DOI: 10.1073/pnas.1915143117.

Optical dopamine monitoring with dLight1 reveals mesolimbic phenotypes in a mouse model of neurofibromatosis type 1.

Robinson J, Coughlin G, Hori A, Cho J, Mackey E, Turan Z Elife. 2019; 8.

PMID: 31545171 PMC: 6819083. DOI: 10.7554/eLife.48983.

References

Becker H, Lopez M . Increased ethanol drinking after repeated chronic ethanol exposure and withdrawal experience in C57BL/6 mice. Alcohol Clin Exp Res. 2004; 28(12):1829-38. DOI: 10.1097/01.alc.0000149977.95306.3a. View

Willer C, Li Y, Abecasis G . METAL: fast and efficient meta-analysis of genomewide association scans. Bioinformatics. 2010; 26(17):2190-1. PMC: 2922887. DOI: 10.1093/bioinformatics/btq340. View

Li J, Ji L . Adjusting multiple testing in multilocus analyses using the eigenvalues of a correlation matrix. Heredity (Edinb). 2005; 95(3):221-7. DOI: 10.1038/sj.hdy.6800717. View

Lopez M, Becker H . Effect of pattern and number of chronic ethanol exposures on subsequent voluntary ethanol intake in C57BL/6J mice. Psychopharmacology (Berl). 2005; 181(4):688-96. DOI: 10.1007/s00213-005-0026-3. View

Pierucci-Lagha A, Gelernter J, Feinn R, Cubells J, Pearson D, Pollastri A . Diagnostic reliability of the Semi-structured Assessment for Drug Dependence and Alcoholism (SSADDA). Drug Alcohol Depend. 2005; 80(3):303-12. DOI: 10.1016/j.drugalcdep.2005.04.005. View

Mulligan M, Ponomarev I, Hitzemann R, Belknap J, Tabakoff B, Harris R . Toward understanding the genetics of alcohol drinking through transcriptome meta-analysis. Proc Natl Acad Sci U S A. 2006; 103(16):6368-73. PMC: 1458884. DOI: 10.1073/pnas.0510188103. View

Goldowitz D, Matthews D, Hamre K, Mittleman G, Chesler E, Becker H . Progress in using mouse inbred strains, consomics, and mutants to identify genes related to stress, anxiety, and alcohol phenotypes. Alcohol Clin Exp Res. 2006; 30(6):1066-78. DOI: 10.1111/j.1530-0277.2006.00125.x. View

Price A, Patterson N, Plenge R, Weinblatt M, Shadick N, Reich D . Principal components analysis corrects for stratification in genome-wide association studies. Nat Genet. 2006; 38(8):904-9. DOI: 10.1038/ng1847. View

Crabbe J, Phillips T, Harris R, Arends M, Koob G . Alcohol-related genes: contributions from studies with genetically engineered mice. Addict Biol. 2006; 11(3-4):195-269. DOI: 10.1111/j.1369-1600.2006.00038.x. View

10.

Rhodes J, Ford M, Yu C, Brown L, Finn D, Garland Jr T . Mouse inbred strain differences in ethanol drinking to intoxication. Genes Brain Behav. 2007; 6(1):1-18. DOI: 10.1111/j.1601-183X.2006.00210.x. View

11.

Bajo M, Cruz M, Siggins G, Messing R, Roberto M . Protein kinase C epsilon mediation of CRF- and ethanol-induced GABA release in central amygdala. Proc Natl Acad Sci U S A. 2008; 105(24):8410-5. PMC: 2448850. DOI: 10.1073/pnas.0802302105. View

12.

Repunte-Canonigo V, Chen J, Lefebvre C, Kawamura T, Kreifeldt M, Basson O . MeCP2 regulates ethanol sensitivity and intake. Addict Biol. 2013; 19(5):791-9. PMC: 3692583. DOI: 10.1111/adb.12047. View

13.

Abecasis G, Altshuler D, Auton A, Brooks L, Durbin R, Gibbs R . A map of human genome variation from population-scale sequencing. Nature. 2010; 467(7319):1061-73. PMC: 3042601. DOI: 10.1038/nature09534. View

14.

Koob G . Theoretical frameworks and mechanistic aspects of alcohol addiction: alcohol addiction as a reward deficit disorder. Curr Top Behav Neurosci. 2011; 13:3-30. PMC: 3448980. DOI: 10.1007/7854_2011_129. View

15.

Ben Hamida S, Neasta J, Lasek A, Kharazia V, Zou M, Carnicella S . The small G protein H-Ras in the mesolimbic system is a molecular gateway to alcohol-seeking and excessive drinking behaviors. J Neurosci. 2012; 32(45):15849-58. PMC: 3514017. DOI: 10.1523/JNEUROSCI.2846-12.2012. View

16.

Stacey D, Bilbao A, Maroteaux M, Jia T, Easton A, Longueville S . RASGRF2 regulates alcohol-induced reinforcement by influencing mesolimbic dopamine neuron activity and dopamine release. Proc Natl Acad Sci U S A. 2012; 109(51):21128-33. PMC: 3529066. DOI: 10.1073/pnas.1211844110. View

17.

Herman M, Contet C, Justice N, Vale W, Roberto M . Novel subunit-specific tonic GABA currents and differential effects of ethanol in the central amygdala of CRF receptor-1 reporter mice. J Neurosci. 2013; 33(8):3284-98. PMC: 3711798. DOI: 10.1523/JNEUROSCI.2490-12.2013. View

18.

Gelernter J, Kranzler H, Sherva R, Almasy L, Koesterer R, Smith A . Genome-wide association study of alcohol dependence:significant findings in African- and European-Americans including novel risk loci. Mol Psychiatry. 2013; 19(1):41-9. PMC: 4165335. DOI: 10.1038/mp.2013.145. View

19.

Gelernter J, Sherva R, Koesterer R, Almasy L, Zhao H, Kranzler H . Genome-wide association study of cocaine dependence and related traits: FAM53B identified as a risk gene. Mol Psychiatry. 2013; 19(6):717-23. PMC: 3865158. DOI: 10.1038/mp.2013.99. View

20.

Roberts A, Heyser C, Cole M, Griffin P, Koob G . Excessive ethanol drinking following a history of dependence: animal model of allostasis. Neuropsychopharmacology. 2000; 22(6):581-94. DOI: 10.1016/S0893-133X(99)00167-0. View