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

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

    36 Citationer (Scopus)

    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.

    OriginalsprogEngelsk
    TidsskriftNeuropharmacology
    Vol/bind63
    Udgave nummer2
    Sider (fra-til)181-9
    Antal sider9
    ISSN0028-3908
    DOI
    StatusUdgivet - aug. 2012

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