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Reduced alcohol intake and reward associated with impaired endocannabinoid signaling in mice with a deletion of the glutamate transporter GLAST.

Journal article
Authors Rose-Marie Karlsson
Louise Adermark
Anna Molander
Stephanie Perreau-Lenz
Erick Singley
Matthew Solomon
Andrew Holmes
Kohichi Tanaka
David M Lovinger
Rainer Spanagel
Markus Heilig
Published in Neuropharmacology
Volume 63
Issue 2
Pages 181-9
ISSN 1873-7064
Publication year 2012
Published at
Pages 181-9
Language en
Keywords Alcohol Drinking, genetics, metabolism, Animals, Association Learning, drug effects, physiology, Choice Behavior, drug effects, physiology, Conditioning, Classical, drug effects, physiology, Endocannabinoids, metabolism, Ethanol, pharmacology, Excitatory Amino Acid Transporter 1, genetics, physiology, Mice, Mice, Knockout, Neuronal Plasticity, drug effects, physiology, Reward, Signal Transduction, drug effects, physiology
Subject categories Biological research on drug dependence

Abstract

A hyperglutamatergic state has been hypothesized to drive escalation of alcohol intake. This hypothesis predicts that an impairment of glutamate clearance through inactivation of the astrocytic glutamate transporter, GLAST (EAAT1), will result in escalation of alcohol consumption. Here, we used mice with a deletion of GLAST to test this prediction. WT and GLAST KO mice were tested for alcohol consumption using two-bottle free-choice drinking. Alcohol reward was evaluated using conditioned place preference (CPP). Sensitivity to depressant alcohol effects was tested using the accelerating rotarod, alcohol-induced hypothermia, and loss of righting reflex. Extracellular glutamate was measured using microdialysis, and striatal slice electrophysiology was carried out to examine plasticity of the cortico-striatal pathway as a model system in which adaptations to the constitutive GLAST deletion can be studied. Contrary to our hypothesis, GLAST KO mice showed markedly decreased alcohol consumption, and lacked CPP for alcohol, despite a higher locomotor response to this drug. Alcohol-induced ataxia, hypothermia, and sedation were unaffected. In striatal slices from GLAST KO mice, long-term depression (LTD) induced by high frequency stimulation, or by post-synaptic depolarization combined with the l-type calcium channel activator FPL 64176 was absent. In contrast, normal synaptic depression was observed after application of the cannabinoid 1 (CB1) receptor agonist WIN55,212-2. Constitutive deletion of GLAST unexpectedly results in markedly reduced alcohol consumption and preference, associated with markedly reduced alcohol reward. Endocannabinoid signaling appears to be down-regulated upstream of the CB1 receptor as a result of the GLAST deletion, and is a candidate mechanism behind the reduction of alcohol reward observed.

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