Reduced alcohol intake and reward associated with impaired endocannabinoid signaling in mice with a deletion of the glutamate transporter GLAST.
Reduced alcohol intake and reward associated with impaired endocannabinoid signaling in mice with a deletion of the glutamate transporter GLAST.
复制标题
DOI：
10.1016/j.neuropharm.2012.01.027
复制
发表时间：
2012-08
影响因子：
4.7
通讯作者：
Heilig M
中科院分区：
文献类型：
--
作者：
Karlsson RM;Adermark L;Molander A;Perreau-Lenz S;Singley E;Solomon M;Holmes A;Tanaka K;Lovinger DM;Spanagel R;Heilig M
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.
登录
查看更多内容
影响因子：
7.6
作者：
Hansson, Anita C.;Bermudez-Silvaz, Francisco J.;Heilig, Markus
通讯作者：
Heilig, Markus
DOI：
10.1073/pnas.0704848104
发表时间：
2007-09-11
影响因子：
11.1
作者：
Kargieman, Lucila;Santana, Noemi;Artigas, Francesc
通讯作者：
Artigas, Francesc
影响因子：
2.3
作者：
Dahchour, A;De Witte, P;Macher, JP
通讯作者：
Macher, JP
影响因子：
2.5
作者：
Flatscher-Bader, T;van der Brug, MP;Wilce, PA
通讯作者：
Wilce, PA
影响因子：
1.9
作者：
Boyce-Rustay, JM;Cunningham, CL
通讯作者：
Cunningham, CL