Elsevier

Biological Psychiatry

Volume 77, Issue 10, 15 May 2015, Pages 870-879
Biological Psychiatry

Archival Report
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

https://doi.org/10.1016/j.biopsych.2014.07.031Get rights and content

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.

Section snippets

Mice

Nf1+/− mice established by Tyler Jacks, Ph.D. (Massachusetts Institute of Technology) were obtained from Alcino Silva, Ph.D. (University of California Los Angeles) and were backcrossed to C57BL/6J mice for more than eight generations.

Twenty-Four Hour, Two-Bottle Choice Paradigm

WT and Nf1+/− mice were single housed and presented with two 50 mL conical tubes filled with water and allowed to habituate for 1 week. After the habituation period, one of the two bottles was replaced with an ethanol solution in escalating concentrations (3, 6, 9,

Nf1 Regulates Dependence-Induced Increases in Drinking

Nf1+/− and WT mice were trained to consume ethanol in a 24-hour, 2BC paradigm at increasing concentrations of ethanol (Figure 1A). Ethanol intake of Nf1+/− and WT mice increased similarly with increasing ethanol concentrations and did not differ between the two genotypes (Figure 1A). Ethanol intake of Nf1+/− and WT mice also did not differ in the DID binge drinking paradigm (Figure 1B) or in the limited access 2BC baseline preceding CIE (Figure 2A–C), although a nonsignificant trend toward

Discussion

It has been hypothesized that alcohol ingestion is driven by multiple sources of reinforcement that change with the individual’s transition from social drinking to alcohol abuse and dependence on alcohol. Neuroadaptive changes within the brain reward and stress systems that include the CeA are key to this transition. In particular, electrophysiological studies have revealed that acute alcohol facilitates spontaneous and evoked GABAergic transmission in the CeA via presynaptic and postsynaptic

Acknowledgments and Disclosures

This work was supported by National Institutes of Health Grants F32 AA020430, AA015566, AA017371, AA020960, AA013191, AA013498, AA021491, AA021667, AA11330, AA17535, DA12690, DA12849, DA18432, and DA028909 and the Pearson Center for Alcoholism and Addiction Research. Genotyping services for a part of our genome-wide association study were provided by the Center for Inherited Disease Research and Yale University (Center for Genome Analysis). Center for Inherited Disease Research is fully funded

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