a-method-for-evaluating-reinforcing-properties-ethanol-rats-without

A Method for Evaluating the Reinforcing Properties of Ethanol in Rats without Water Deprivation, Saccharin Fading or Extended Access Training

Operant oral self-administration methods are commonly used to study the reinforcing properties of ethanol in animals. However, the standard methods ...

National Institutes of Health

There is an extensive literature showing that the CB(1) cannabinoid receptor antagonist rimonabant (SR141716) decreases alcohol consumption in animals, but little is known about its effects in human alcohol drinkers.

Rimonabant (SR141716) has no effect on alcohol self-administration or endocrine measures in nontreatment-seeking heavy alcohol drinkers.

Reinstatement of responding to a previously alcohol-associated lever following extinction is an established model of relapse-like behavior and can be triggered by stress exposure. Here, we examined whether neuropeptide Y (NPY), an endogenous anti-stress mediator, blocks reinstatement of alcohol-seeking induced by the pharmacological stressor yohimbine.

Neuropeptide Y (NPY) suppresses yohimbine-induced reinstatement of alcohol seeking.

Reduced voluntary alcohol consumption was recently found in neurokinin-1 receptor (NK1R)-deficient (KO) mice. It remains unknown whether this reflects developmental effects or direct regulation of alcohol consumption by NK1R:s, and whether the reduced consumption reflects motivational effects.

Neurokinin-1 receptors (NK1R:s), alcohol consumption, and alcohol reward in mice.

Glutamatergic neurotransmission has been implicated in mechanisms of alcohol-induced neurodegeneration and cognitive impairment, but the underlying mechanism remains unknown. Here, we examined whether the group II metabotropic glutamate receptor agonist LY379268 prevents neuronal death and learning deficits in a rat model of binge-like exposure to alcohol.

Alcohol-induced neurodegeneration, suppression of transforming growth factor-beta, and cognitive impairment in rats: prevention by group II metabotropic glutamate receptor activation.

Acamprosate is approved for the treatment of alcoholism, but its mechanism of action remains unclear. Results of animal studies suggest that a persistent hyperglutamatergic state contributes to the pathogenesis of alcoholism and that acamprosate may exert its actions by intervening in this process. Human translation of these findings is lacking.

Effect of acamprosate on magnetic resonance spectroscopy measures of central glutamate in detoxified alcohol-dependent individuals: a randomized controlled experimental medicine study.

Modulation of alcohol craving induced by challenge stimuli may predict the efficacy of new pharmacotherapies for alcoholism. We evaluated two pharmacological challenges, the α(2)-adrenergic antagonist yohimbine, which reinstates alcohol seeking in rats, and the serotonergic compound meta-chlorophenylpiperazine (mCPP), previously reported to increase alcohol craving in alcoholics. To assess the predictive validity of this approach, the approved alcoholism medication acamprosate was evaluated for its ability to modulate challenge-induced cravings. A total of 35 treatment seeking alcohol dependent inpatients in early abstinence were randomized to placebo or acamprosate (2997 mg daily). Following two weeks of medication, subjects underwent three challenge sessions with yohimbine, mCPP or saline infusion under double blind conditions, carried out in counterbalanced order, and separated by at least 5 days. Ratings of cravings and anxiety, as well as biochemical measures were obtained. In all, 25 subjects completed all three sessions and were included in the analysis. Cravings were modestly, but significantly higher following both yohimbine and mCPP challenge compared with saline infusion. The mCPP, but not yohimbine significantly increased anxiety ratings. Both challenges produced robust ACTH, cortisol and prolactin responses. There was a significant correlation between craving and the degree of alcoholism severity. Acamprosate administration did not influence craving. Both yohimbine and mCPP challenges lead to elevated alcohol craving in a clinical population of alcoholics, and these cravings correlate with alcoholism severity. Under the experimental conditions used, alcohol cravings induced by these two stimuli are not sensitive to acamprosate at clinically used doses.

Pharmacologically induced alcohol craving in treatment seeking alcoholics correlates with alcoholism severity, but is insensitive to acamprosate.

A dysregulation of the corticotropin-releasing hormone (CRH) system has been implicated in the development of excessive alcohol consumption and dependence. The aim of the present study was to evaluate whether the CRH system is also recruited when non-dependent Wistar rats escalate to high alcohol intake in the intermittent (alternate days) model of drinking.

Pharmacological blockade of corticotropin-releasing hormone receptor 1 (CRH1R) reduces voluntary consumption of high alcohol concentrations in non-dependent Wistar rats.

Hyperglutamatergic &#x72B6;&#x6001;&#x6709;&#x4E86;&#x9A71;&#x52A8;&#x5668;&#x5347;&#x7EA7;&#x9152;&#x7CBE;&#x6444;&#x5165;&#x91CF;&#x7684;&#x4E00;&#x79CD;&#x5047;&#x8BBE;&#x3002;&#x8FD9;&#x4E00;&#x5047;&#x8BBE;&#x9884;&#x6D4B;&#x635F;&#x5BB3;&#x7684;&#x8C37;&#x6C28;&#x9178;&#x95F4;&#x9699;&#x901A;&#x8FC7;&#x706D;&#x6D3B;&#x7684;&#x661F;&#x5F62;&#x80F6;&#x8D28;&#x7EC6;&#x80DE; glast&#xFF0C;&#xFF08;EAAT1&#xFF09;&#xFF0C;&#x5C06;&#x5BFC;&#x81F4;&#x9152;&#x7CBE;&#x6D88;&#x8D39;&#x5347;&#x7EA7;&#x3002;&#x5728;&#x8FD9;&#x91CC;&#xFF0C;&#x6211;&#x4EEC;&#x7528;&#x5C0F;&#x9F20;&#x4E0E;&#x5220;&#x9664;&#x64CD;&#x4F5C;&#x7684; GLAST &#x6765;&#x6D4B;&#x8BD5;&#x8FD9;&#x4E00;&#x9884;&#x6D4B;&#x3002;WT &#x548C; GLAST KO &#x5C0F;&#x9F20;&#x4E3A;&#x4F7F;&#x7528;&#x4E24;&#x74F6;&#x81EA;&#x7531;&#x9009;&#x62E9;&#x996E;&#x7528;&#x7684;&#x9152;&#x7CBE;&#x6D88;&#x8D39;&#x91CF;&#x8FDB;&#x884C;&#x4E86;&#x6D4B;&#x8BD5;&#x3002;&#x7528;&#x6761;&#x4EF6;&#x6027;&#x7684;&#x4F4D;&#x7F6E;&#x504F;&#x7231; (CPP) &#x8BC4;&#x4F30;&#x9152;&#x7CBE;&#x5956;&#x52B1;&#x3002;&#x4F7F;&#x7528;&#x52A0;&#x901F;&#x5B9E;&#x9A8C;&#x3001; &#x9152;&#x7CBE;&#x5F15;&#x8D77;&#x4F53;&#x6E29;&#x8FC7;&#x4F4E;&#x548C;&#x7EA0;&#x6B63;&#x53CD;&#x5C04;&#x635F;&#x5931;&#x6D4B;&#x8BD5;&#x5BF9;&#x6291;&#x5236;&#x9152;&#x7CBE;&#x5F71;&#x54CD;&#x7684;&#x654F;&#x611F;&#x6027;&#x3002;&#x80DE;&#x5916;&#x8C37;&#x6C28;&#x9178;&#x7684;&#x6D4B;&#x91CF;&#x503C;&#x662F;&#x4F7F;&#x7528;&#x5FAE;&#x900F;&#x6790;&#x6280;&#x672F;&#xFF0C;&#x5E76;&#x5F00;&#x5C55;&#x7EB9;&#x72B6;&#x4F53;&#x5207;&#x7247;&#x7535;&#x751F;&#x7406;&#x68C0;&#x67E5;&#x53EF;&#x4EE5;&#x5728;&#x54EA;&#x4E9B;&#x9002;&#x5E94;&#x672C;&#x6784;&#x7684; GLAST &#x7814;&#x7A76;&#x5220;&#x9664;&#x6A21;&#x578B;&#x7CFB;&#x7EDF;&#x4F5C;&#x4E3A;&#x79D1;&#x5C14;&#x8482;&#x7D22;-&#x7EB9;&#x72B6;&#x4F53;&#x901A;&#x8DEF;&#x7684;&#x53EF;&#x5851;&#x6027;&#x3002;&#x4E0E;&#x6211;&#x4EEC;&#x7684;&#x5047;&#x8BBE;&#xFF0C;GLAST KO &#x5C0F;&#x9F20;&#x660E;&#x663E;&#x8868;&#x660E;&#x51CF;&#x5C11;&#x9152;&#x7CBE;&#x6D88;&#x8D39;&#x548C;&#x7F3A;&#x4E4F; CPP &#x9152;&#x7CBE;&#xFF0C;&#x5C3D;&#x7BA1;&#x8FD9;&#x79CD;&#x836F;&#x7269;&#x7684;&#x9AD8;&#x81EA;&#x53D1;&#x54CD;&#x5E94;&#x3002;&#x9152;&#x7CBE;&#x6240;&#x81F4;&#x7684;&#x5171;&#x6D4E;&#x5931;&#x8C03;&#x3001; &#x4F53;&#x6E29;&#x8FC7;&#x4F4E;&#x548C;&#x9547;&#x9759;&#x672A;&#x53D7;&#x5F71;&#x54CD;&#x3002;&#x5728;&#x4ECE; GLAST KO &#x5C0F;&#x9F20;&#x7EB9;&#x72B6;&#x4F53;&#x5207;&#x7247;&#xFF0C;&#x957F;&#x671F;&#x8427;&#x6761; (&#x6709;&#x9650;&#x516C;&#x53F8;) &#x9AD8;&#x9891;&#x523A;&#x6FC0;&#x8BF1;&#x53D1;&#x6216;&#x7531;&#x7A81;&#x89E6;&#x7ED3;&#x5408; l-&#x578B;&#x9499;&#x901A;&#x9053;&#x6FC0;&#x52A8;&#x5242;&#x7B2C; 64176 &#x56DB;&#x65B9;&#x7684;&#x53BB;&#x6781;&#x5316;&#x662F;&#x7F3A;&#x5E2D;&#x3002;&#x76F8;&#x6BD4;&#x4E4B;&#x4E0B;&#xFF0C;&#x6B63;&#x5E38;&#x7684;&#x7A81;&#x89E6;&#x6291;&#x90C1;&#x75C7;&#x6307;&#x51FA;&#x540E;&#x7684;&#x5927;&#x9EBB;&#x5E94;&#x7528; 1 &#x7D20; &#xFF08;CB1&#xFF09; &#x53D7;&#x4F53;&#x6FC0;&#x52A8; WIN55&#xFF0C;212-2&#x3002;GLAST &#x6784;&#x5220;&#x9664;&#x610F;&#x5916;&#x7ED3;&#x679C;&#x663E;&#x8457;&#x51CF;&#x5C11;&#x7684;&#x9152;&#x7CBE;&#x6D88;&#x8D39;&#x548C;&#x559C;&#x597D;&#xFF0C;&#x663E;&#x8457;&#x51CF;&#x5C11;&#x7684;&#x9152;&#x7CBE;&#x5956;&#x52B1;&#x4E0E;&#x76F8;&#x5173;&#x8054;&#x3002;Endocannabinoid &#x4FE1;&#x53F7;&#x4F3C;&#x4E4E;&#x662F;&#x4E0B;&#x8C03;&#x4E0A;&#x6E38; CB1 &#x53D7;&#x4F53;&#x56E0; GLAST &#x5220;&#x9664;&#xFF0C;&#x800C;&#x662F;&#x80CC;&#x540E;&#x89C2;&#x5BDF;&#x9152;&#x7CBE;&#x5956;&#x52B1;&#x51CF;&#x5C11;&#x5019;&#x9009;&#x673A;&#x5236;&#x3002;

&#x51CF;&#x5C11;&#x9152;&#x7CBE;&#x6444;&#x5165;&#x91CF;&#x548C;&#x4E0E;&#x53D7;&#x635F; endocannabinoid &#x4FE1;&#x53F7;&#x8F6C;&#x5BFC;&#x5C0F;&#x9F20;&#x7684; glast &#x5220;&#x9664;&#x76F8;&#x5173;&#x8054;&#x7684;&#x5956;&#x52B1;&#x3002;

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.

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

Un &eacute;tat de hyperglutamatergic a &eacute;mis l&#39;hypoth&egrave;se d&#39;escalade de lecteur de la consommation d&#39;alcool. Cette hypoth&egrave;se suppose qu&#39;une alt&eacute;ration de la clearance du glutamate par inactivation du glutamate astrocytaires transporteur, GLAST (EAAT1), se traduira dans l&#39;escalade de la consommation d&#39;alcool. Ici, nous avons utilis&eacute; des souris avec une suppression de GLAST pour v&eacute;rifier cette pr&eacute;diction. Souris WT et GLAST KO ont &eacute;t&eacute; test&eacute;s pour la consommation d&#39;alcool &agrave; l&#39;aide de deux bouteilles &agrave; boire libre choix. R&eacute;compense de l&#39;alcool a &eacute;t&eacute; &eacute;valu&eacute;e &agrave; l&#39;aide de pr&eacute;f&eacute;rence de place conditionn&eacute;e (RPC). Sensibilit&eacute; aux effets d&eacute;presseurs de l&#39;alcool a &eacute;t&eacute; test&eacute;e &agrave; l&#39;aide de l&#39;acc&eacute;l&eacute;ration rotarod, hypothermie induite par l&#39;alcool et la perte du r&eacute;flexe de redressement. Glutamate extracellulaire a &eacute;t&eacute; mesur&eacute;e &agrave; l&#39;aide de la microdialyse, et &eacute;lectrophysiologie tranche striatales a &eacute;t&eacute; r&eacute;alis&eacute;e pour examiner la plasticit&eacute; de la voie cortico-striataux comme syst&egrave;me mod&egrave;le dans quelles adaptations pour le GLAST constitutive suppression peut &ecirc;tre &eacute;tudi&eacute;e. Contrairement &agrave; notre hypoth&egrave;se, GLAST KO souris a montr&eacute; nettement diminu&eacute; la consommation d&#39;alcool et manquaient de RPC pour l&#39;alcool, malgr&eacute; une r&eacute;ponse locomotrice plus &eacute;lev&eacute;e &agrave; ce m&eacute;dicament. S&eacute;dation, hypothermie et ataxie induite par l&#39;alcool ne sont pas affect&eacute;s. Dans des tranches striatales des souris KO GLAST, d&eacute;pression &agrave; long terme (DLT) induite par la stimulation &agrave; haute fr&eacute;quence, ou par une d&eacute;polarisation post-synaptique, combin&eacute;e avec l&#39;activateur de canaux calcium de type l FPL 64176 &eacute;tait absente. En revanche, la d&eacute;pression synaptique normale a &eacute;t&eacute; observ&eacute;e apr&egrave;s application le cannabino&iuml;de 1 (CB1) agoniste des r&eacute;cepteurs WIN55, 212-2. Suppression constitutive de GLAST inopin&eacute;ment entra&icirc;ne la consommation d&#39;alcool fortement r&eacute;duite et de pr&eacute;f&eacute;rence, associ&eacute; de r&eacute;compense de l&#39;alcool fortement r&eacute;duite. Signalisation des endocannabino&iuml;des semble &ecirc;tre diminu&eacute;es en amont du r&eacute;cepteur CB1 du fait de la suppression de GLAST, et est un m&eacute;canisme de candidat derri&egrave;re la r&eacute;duction de la r&eacute;compense d&#39;alcool observ&eacute;e.

R&eacute;duit la consommation d&#39;alcool et de la r&eacute;compense associ&eacute;e avec facult&eacute;s affaiblies endocannabino&iuml;de signalisation chez les souris pr&eacute;sentant une d&eacute;l&eacute;tion du glutamate transporteur GLAST.

Ein Hyperglutamatergic Staat hat zu Laufwerk Eskalation der Alkoholaufnahme vermutet wurde. Diese Hypothese sagt voraus, dass eine Wertminderung der Glutamat-Clearance durch Inaktivierung des astrozytische Glutamat-Transporters, GLAST (EAAT1), Eskalation der Alkoholkonsum f&uuml;hrt. Hier haben wir M&auml;use mit einer L&ouml;schung der GLAST um diese Vorhersage zu testen. WT und GLAST KO M&auml;usen wurden auf Alkoholkonsum mit zwei Flaschen trinken freien Wahl getestet. Alkohol Belohnung wurde mit klimatisierten Ort Pr&auml;ferenz (CPP) ausgewertet. Anf&auml;lligkeit f&uuml;r Beruhigungsmittel Alkohol Wirkungen wurde mithilfe der beschleunigenden Drehstabapparatur, Alkohol-induzierte Hypothermie und Verlust der aufrichtenden Reflex getestet. Extrazellul&auml;re Glutamat wurde gemessen mit Microdialysis und Striatale Segment Elektrophysiologie wurde durchgef&uuml;hrt, um die Plastizit&auml;t des Signalweges Kortikosteroide-Striatale als Modellsystem zu pr&uuml;fen, welche Anpassungen an die konstitutive GLAST L&ouml;schung untersucht werden kann. Entgegen unserer Hypothese GLAST KO M&auml;usen zeigten deutlich verringerte Alkoholkonsum und CPP f&uuml;r Alkohol, trotz h&ouml;herer lokomotorische Reaktion auf dieses Medikament fehlte. Alkoholinduzierte Ataxie, Unterk&uuml;hlung und Sedierung waren nicht betroffen. In Striatale Scheiben von GLAST KO-M&auml;usen langfristige Depression (LTD) induziert durch hochfrequente Stimulation oder durch post-synaptic Depolarisation kombiniert mit der l-Typ-Kalzium-Kanal-Aktivator FPL 64176 abwesend war. Im Gegensatz dazu wurde normal synaptische Depression nach Anwendung des Cannabinoids 1 (CB1)-Rezeptoragonist WIN55, 212-2 beobachtet. Konstitutive L&ouml;schung von GLAST f&uuml;hrt unerwartet deutlich reduzierten Alkoholkonsum und Pr&auml;ferenz, verbunden mit deutlich reduzierten Alkohol belohnen. Endocannabinoid Signalling scheint unten-geregelt oberhalb der den CB1-Rezeptor durch den L&ouml;schvorgang GLAST und ist ein Kandidat-Mechanismus hinter der Reduzierung der Alkohol Belohnung beobachtet.

Reduzierte Alkoholkonsum und Belohnung gest&ouml;rter Endocannabinoid signalisieren in M&auml;use mit einer L&ouml;schung der Glutamat-Transporters GLAST zugeordnet.

&Egrave; stato ipotizzato uno stato hyperglutamatergic a un&#39;escalation di azionamento dell&#39;assunzione di alcol. Questa ipotesi prevede che una compromissione della clearance glutammato attraverso l&#39;inattivazione del trasportatore del glutammato astrocitari, GLAST (EAAT1), si tradurr&agrave; in escalation di consumo di alcol. Qui, abbiamo utilizzato topi con una delezione di GLAST a testare questa previsione. Topi WT e GLAST KO sono stati testati per il consumo di alcol utilizzando due-bottiglia libera scelta potabile. Ricompensa di alcool &egrave; stata valutata utilizzando di preferenza di posto condizionata (CPP). Sensibilit&agrave; agli effetti alcool depressivo &egrave; stato testato utilizzando l&#39;accelerazione rotarod, ipotermia indotta da alcol e perdita del riflesso di raddrizzamento. Glutammato extracellulare &egrave; stata misurata mediante Microdialisi ed elettrofisiologia fetta striatali &egrave; stata effettuata per esaminare la plasticit&agrave; della via cortico-striatali come sistema di modello in cui adattamenti per la costitutiva GLAST delezione pu&ograve; essere studiato. Contrariamente alla nostra ipotesi, GLAST KO topi ha dimostrati nettamente diminuito il consumo di alcol e mancavano di CPP per l&#39;alcol, nonostante una maggiore risposta locomotore a questo farmaco. Sedazione, ipotermia e atassia indotta da alcol sono state influenzate. A fettine striatali da topi KO GLAST, depressione a lungo termine (LTD) indotta dalla stimolazione ad alta frequenza, o dalla depolarizzazione dei combinati con l&#39;attivatore di canale del calcio di tipo l FPL 64176 era assente. Al contrario, depressione sinaptica normale &egrave; stata osservata dopo l&#39;applicazione del cannabinoide 1 agonista del recettore (CB1) WIN55, 212-2. Eliminazione costitutiva di GLAST risultati inaspettatamente nel consumo di alcool nettamente ridotta e preferenza, associato a ricompensa di alcool nettamente ridotto. Endocannabinoide segnalazione sembra essere down-regolato a monte del recettore CB1 a seguito dell&#39;eliminazione di GLAST, ed &egrave; un meccanismo candidato dietro la riduzione di alcol ricompensa osservato.

Ridotta assunzione di alcol e ricompensa associato a compromissione endocannabinoide segnalazione nei topi con una delezione del trasportatore di glutammato GLAST.

&#x30A2;&#x30EB;&#x30B3;&#x30FC;&#x30EB;&#x6442;&#x53D6;&#x306E;&#x30C9;&#x30E9;&#x30A4;&#x30D6;&#x6607;&#x683C;&#x306B; hyperglutamatergic &#x72B6;&#x614B;&#x306E;&#x4EEE;&#x8AAC;&#x3092;&#x7ACB;&#x3066;&#x305F;&#x3002;&#x3053;&#x306E;&#x4EEE;&#x8AAC;&#x306F;&#x3001;&#x30B0;&#x30EB;&#x30BF;&#x30DF;&#x30F3;&#x9178;&#x30AF;&#x30EA;&#x30A2;&#x30E9;&#x30F3;&#x30B9; GLAST (EAAT1), &#x30A2;&#x30B9;&#x30C8;&#x30ED; &#x30B5;&#x30A4;&#x30C8;&#x306E;&#x30B0;&#x30EB;&#x30BF;&#x30DF;&#x30F3;&#x9178;&#x30C8;&#x30E9;&#x30F3;&#x30B9;&#x30DD;&#x30FC;&#x30BF;&#x30FC;&#x306E;&#x4E0D;&#x6D3B;&#x6027;&#x5316;&#x3092;&#x4ECB;&#x3057;&#x3066;&#x306E;&#x6E1B;&#x640D;&#x306E;&#x30A2;&#x30EB;&#x30B3;&#x30FC;&#x30EB;&#x6D88;&#x8CBB;&#x91CF;&#x306E;&#x30A8;&#x30B9;&#x30AB;&#x30EC;&#x30FC;&#x30B7;&#x30E7;&#x30F3;&#x306B;&#x306A;&#x308A;&#x307E;&#x3059;&#x4E88;&#x6E2C;&#x3057;&#x307E;&#x3059;&#x3002;&#x3053;&#x3053;&#x3067;&#x306F;&#x3001;&#x6211;&#x3005; &#x30DE;&#x30A6;&#x30B9; GLAST &#x306E;&#x524A;&#x9664;&#x3092;&#x3053;&#x306E;&#x4E88;&#x6E2C;&#x3092;&#x30C6;&#x30B9;&#x30C8;&#x3059;&#x308B;&#x306E;&#x306B;&#x4F7F;&#x7528;&#x3057;&#x307E;&#x3059;&#x3002;WT &#x304A;&#x3088;&#x3073; GLAST KO &#x30DE;&#x30A6;&#x30B9;&#x306F;&#x3001;&#x30A2;&#x30EB;&#x30B3;&#x30FC;&#x30EB;&#x6D88;&#x8CBB;&#x306E;&#x305F;&#x3081;&#x306E;&#x81EA;&#x7531;&#x9078;&#x629E; 2 &#x30DC;&#x30C8;&#x30EB;&#x3092;&#x98F2;&#x3080;&#x3092;&#x4F7F;&#x7528;&#x3057;&#x3066;&#x30C6;&#x30B9;&#x30C8;&#x3055;&#x308C;&#x307E;&#x3057;&#x305F;&#x3002;&#x30A2;&#x30EB;&#x30B3;&#x30FC;&#x30EB;&#x306E;&#x5831;&#x916C;&#x306F;&#x3001;&#x8ABF;&#x7BC0;&#x3055;&#x308C;&#x305F;&#x5834;&#x6240;&#x9078;&#x597D; (CPP) &#x3092;&#x4F7F;&#x7528;&#x3057;&#x3066;&#x8A55;&#x4FA1;&#x3057;&#x307E;&#x3057;&#x305F;&#x3002;&#x3046;&#x3064;&#x5264;&#x306E;&#x30A2;&#x30EB;&#x30B3;&#x30FC;&#x30EB;&#x306E;&#x52B9;&#x679C;&#x3078;&#x306E;&#x611F;&#x5EA6;&#x306F;&#x3001;&#x52A0;&#x901F; rotarod&#x3001;&#x30A2;&#x30EB;&#x30B3;&#x30FC;&#x30EB;&#x306B;&#x3088;&#x3063;&#x3066;&#x8A98;&#x767A;&#x3055;&#x308C;&#x305F;&#x4F4E;&#x4F53;&#x6E29;&#x75C7;&#x3068;&#x7ACB;&#x3061;&#x76F4;&#x308A;&#x53CD;&#x5C04;&#x306E;&#x640D;&#x5931;&#x3092;&#x4F7F;&#x7528;&#x3057;&#x3066;&#x30C6;&#x30B9;&#x30C8;&#x3055;&#x308C;&#x307E;&#x3057;&#x305F;&#x3002;&#x30DE;&#x30A4;&#x30AF;&#x30ED;&#x30C0;&#x30A4;&#x30A2;&#x30EA;&#x30B7;&#x30B9;&#x6CD5;&#x3001;&#x7D30;&#x80DE;&#x5916;&#x30B0;&#x30EB;&#x30BF;&#x30DF;&#x30F3;&#x9178;&#x304C;&#x6E2C;&#x5B9A;&#x3057;&#x305F;&#x3057;&#x3001;&#x7DDA;&#x6761;&#x4F53;&#x30B9;&#x30E9;&#x30A4;&#x30B9;&#x96FB;&#x6C17;&#x751F;&#x7406;&#x76AE;&#x8CEA;-&#x7DDA;&#x6761;&#x4F53;&#x7D4C;&#x8DEF;&#x306E;&#x5851;&#x6027;&#x69CB;&#x6210;&#x5F0F;&#x306E; GLAST &#x306F;&#x9069;&#x5FDC;&#x3067;&#x524A;&#x9664;&#x3092;&#x5B66;&#x3076;&#x3053;&#x3068;&#x304C;&#x3067;&#x304D;&#x307E;&#x3059;&#x30E2;&#x30C7;&#x30EB; &#x30B7;&#x30B9;&#x30C6;&#x30E0;&#x3068;&#x3057;&#x3066;&#x691C;&#x8A0E;&#x3092;&#x884C;&#x3063;&#x305F;&#x3002;&#x6211;&#x3005; &#x306E;&#x4EEE;&#x8AAC;&#x306B;&#x53CD;&#x3057;&#x3066; GLAST KO &#x30DE;&#x30A6;&#x30B9;&#x306E;&#x8457;&#x3057;&#x304F;&#x793A;&#x3057;&#x305F;&#x30A2;&#x30EB;&#x30B3;&#x30FC;&#x30EB;&#x6D88;&#x8CBB;&#x91CF;&#x306E;&#x6E1B;&#x5C11;&#x3057;&#x3001;CPP &#x3092;&#x6B20;&#x3044;&#x3066;&#x3044;&#x305F;&#x306B;&#x3082;&#x304B;&#x304B;&#x308F;&#x3089;&#x305A;&#x3053;&#x306E;&#x85AC;&#x5264;&#x306B;&#x9AD8;&#x3044;&#x904B;&#x52D5;&#x3059;&#x308B;&#x53CD;&#x5FDC;&#x306E;&#x30A2;&#x30EB;&#x30B3;&#x30FC;&#x30EB;&#x3002;&#x30A2;&#x30EB;&#x30B3;&#x30FC;&#x30EB;&#x8A98;&#x767A;&#x6027;&#x5931;&#x8ABF;&#x75C7;&#x3001;&#x4F4E;&#x4F53;&#x6E29;&#x75C7;&#x3001;&#x93AE;&#x9759;&#x306F;&#x5F71;&#x97FF;&#x3092;&#x53D7;&#x3051;&#x306A;&#x304B;&#x3063;&#x305F;&#x3002;&#x7DDA;&#x6761;&#x4F53;&#x30B9;&#x30E9;&#x30A4;&#x30B9; GLAST KO &#x30DE;&#x30A6;&#x30B9;&#x304B;&#x3089;&#x9577;&#x671F;&#x6291;&#x5727; (LTD) &#x9AD8;&#x983B;&#x5EA6;&#x523A;&#x6FC0;&#x306B;&#x3088;&#x308B;&#x307E;&#x305F;&#x306F; l &#x578B;&#x30AB;&#x30EB;&#x30B7;&#x30A6;&#x30E0; &#x30C1;&#x30E3;&#x30CD;&#x30EB; &#x30A2;&#x30AF;&#x30C6;&#x30A3;&#x30D9;&#x30FC;&#x30BF;&#x30FC; FPL 64176 &#x7D50;&#x5408;&#x30B7;&#x30CA;&#x30D7;&#x30B9;&#x306E;&#x8131;&#x5206;&#x6975;&#x3067;&#x6B20;&#x5E2D;&#x3057;&#x307E;&#x3057;&#x305F;&#x3002;&#x5BFE;&#x7167;&#x7684;&#x306B;&#x3001;&#x901A;&#x5E38;&#x306E;&#x30B7;&#x30CA;&#x30D7;&#x30B9;&#x3046;&#x3064;&#x75C5;&#x3001;&#x30AB;&#x30F3;&#x30CA;&#x30D3;&#x30CE;&#x30A4;&#x30C9;&#x306E;&#x9069;&#x7528;&#x5F8C; 1 &#xFF08;CB1&#xFF09; &#x53D7;&#x5BB9;&#x4F53;&#x30A2;&#x30B4;&#x30CB;&#x30B9;&#x30C8; WIN55, 212 2 &#x89B3;&#x5BDF;&#x3055;&#x308C;&#x307E;&#x3057;&#x305F;&#x3002;GLAST &#x306E;&#x69CB;&#x6210;&#x306E;&#x524A;&#x9664;&#x304C;&#x4E88;&#x671F;&#x305B;&#x305A;&#x8457;&#x3057;&#x304F;&#x6E1B;&#x5C11;&#x30A2;&#x30EB;&#x30B3;&#x30FC;&#x30EB;&#x6D88;&#x8CBB;&#x3068;&#x597D;&#x307F;&#x3001;&#x8457;&#x3057;&#x304F;&#x6E1B;&#x5C11;&#x30A2;&#x30EB;&#x30B3;&#x30FC;&#x30EB;&#x5831;&#x916C;&#x3068;&#x95A2;&#x9023;&#x4ED8;&#x3051;&#x3089;&#x308C;&#x3066;&#x3044;&#x308B;&#x7D50;&#x679C;&#x3057;&#x307E;&#x3059;&#x3002;&#x30AB;&#x30F3;&#x30CA;&#x30D3;&#x30CE;&#x30A4;&#x30C9;&#x3092;&#x30B7;&#x30B0;&#x30CA;&#x30EA;&#x30F3;&#x30B0; &#x30C0;&#x30A6;&#x30F3;&#x898F;&#x5236;&#x304C;&#x3042;&#x308B;&#x3088;&#x3046;&#x3001;CB1 &#x53D7;&#x5BB9;&#x4F53; GLAST &#x524A;&#x9664;&#x306E;&#x7D50;&#x679C;&#x3068;&#x3057;&#x3066;&#x306E;&#x4E0A;&#x6D41;&#x3068;&#x89B3;&#x6E2C;&#x3055;&#x308C;&#x305F;&#x30A2;&#x30EB;&#x30B3;&#x30FC;&#x30EB;&#x306E;&#x5831;&#x916C;&#x306E;&#x524A;&#x6E1B;&#x5F8C;&#x308D;&#x5019;&#x88DC;&#x306E;&#x30E1;&#x30AB;&#x30CB;&#x30BA;&#x30E0;&#x3067;&#x3059;&#x3002;

&#x30A2;&#x30EB;&#x30B3;&#x30FC;&#x30EB;&#x6442;&#x53D6;&#x3068;&#x30B0;&#x30EB;&#x30BF;&#x30DF;&#x30F3;&#x9178;&#x30C8;&#x30E9;&#x30F3;&#x30B9;&#x30DD;&#x30FC;&#x30BF;&#x30FC; GLAST &#x306E;&#x524A;&#x9664;&#x30DE;&#x30A6;&#x30B9;&#x306B;&#x304A;&#x3051;&#x308B;&#x30B7;&#x30B0;&#x30CA;&#x30EB;&#x4F1D;&#x9054;&#x969C;&#x5BB3;&#x30AB;&#x30F3;&#x30CA;&#x30D3;&#x30CE;&#x30A4;&#x30C9;&#x95A2;&#x9023;&#x4ED8;&#x3051;&#x3089;&#x308C;&#x305F;&#x5831;&#x916C;&#x3092;&#x524A;&#x6E1B;&#x3057;&#x307E;&#x3057;&#x305F;&#x3002;

Hyperglutamatergic &#xC0C1;&#xD0DC; &#xC54C;&#xCF54;&#xC62C; &#xC12D;&#xCDE8;&#xC758; &#xB4DC;&#xB77C;&#xC774;&#xBE0C; &#xC5D0;&#xC2A4;&#xCEEC;&#xB808;&#xC774;&#xC158;&#xC5D0; &#xAC00;&#xC124; &#xB418;&#xC5B4; &#xC788;&#xB2E4;. &#xC774; &#xAC00;&#xC124; astrocytic &#xC870;&#xBBF8;&#xB8CC; &#xC6B4;&#xC1A1;&#xC5C5; &#xC790;, GLAST (EAAT1)&#xC758; &#xBE44;&#xD65C;&#xC131;&#xD654;&#xB97C; &#xD1B5;&#xD574; &#xC870;&#xBBF8;&#xB8CC; &#xD074;&#xB9AC;&#xC5B4;&#xB7F0;&#xC2A4;&#xC758; &#xC7A5;&#xC560; &#xC54C;&#xCF54;&#xC62C; &#xC18C;&#xBE44;&#xC758; &#xD655;&#xB300; &#xB420; &#xC804;&#xB9DD; &#xD588;&#xB2E4;. &#xC5EC;&#xAE30;,&#xC774; &#xC608;&#xCE21;&#xC744; &#xD14C;&#xC2A4;&#xD2B8;&#xD560; GLAST&#xC758; &#xC0AD;&#xC81C;&#xC640; &#xB9C8;&#xC6B0;&#xC2A4; &#xC0AC;&#xC6A9;. WT &#xBC0F; GLAST &#xCF54; &#xC950; &#xC54C;&#xCF54;&#xC62C; &#xC18C;&#xBE44; 2 &#xBCD1; &#xBB34;&#xB8CC; &#xC120;&#xD0DD; &#xC74C;&#xC8FC;&#xB97C; &#xC0AC;&#xC6A9; &#xD558; &#xC5EC; &#xD14C;&#xC2A4;&#xD2B8; &#xD588;&#xB2E4;. &#xC54C;&#xCF54;&#xC62C; &#xBCF4;&#xC0C1; &#xC870;&#xAC74;&#xB41C; &#xC7A5;&#xC18C; &#xC124;&#xC815; (CPP)&#xB97C; &#xC0AC;&#xC6A9; &#xD558; &#xC5EC; &#xD3C9;&#xAC00; &#xB418;&#xC5C8;&#xC2B5;&#xB2C8;&#xB2E4;. &#xAC10;&#xB3C4; depressant &#xC54C;&#xCF54;&#xC62C; &#xD6A8;&#xACFC;&#xB97C; &#xAC00;&#xC18D; rotarod, &#xC54C;&#xCF54;&#xC62C; &#xC720;&#xB3C4; &#xC800;&#xCCB4;&#xC628;&#xC99D; righting &#xBC18;&#xC0AC;&#xC758; &#xC0C1;&#xC2E4;&#xC744; &#xC0AC;&#xC6A9; &#xD558; &#xC5EC; &#xD14C;&#xC2A4;&#xD2B8;&#xB97C; &#xD588;&#xB2E4;. &#xC138;&#xD3EC; &#xC678; &#xC0B0; &#xC5FC; microdialysis&#xB97C; &#xC0AC;&#xC6A9; &#xD558; &#xC5EC; &#xCE21;&#xC815; &#xBC0F; striatal &#xC2AC;&#xB77C;&#xC774;&#xC2A4; &#xC804;&#xAE30; &#xC0DD;&#xB9AC;&#xD559; &#xC81C;&#xC815; GLAST &#xAC01; &#xC0C9; &#xD55C;&#xC740; &#xC0AD;&#xC81C; &#xACF5;&#xBD80; &#xBAA8;&#xB378; &#xC2DC;&#xC2A4;&#xD15C;&#xC73C;&#xB85C; cortico striatal &#xD1B5;&#xB85C;&#xC758; &#xC18C;&#xC131;&#xC744; &#xAC80;&#xC0AC;&#xB97C; &#xC2E4;&#xC2DC; &#xD588;&#xB2E4;. &#xC6B0;&#xB9AC;&#xC758; &#xAC00;&#xC124;&#xC5D0; &#xBC18;&#xD558;&#xB294; GLAST &#xCF54; &#xC950; &#xB208;&#xC5D0; &#xB744;&#xAC8C; &#xBCF4;&#xC600;&#xB2E4; &#xC54C;&#xCF54;&#xC62C; &#xC18C;&#xBE44;&#xB97C; &#xAC10;&#xC18C; &#xD558; &#xACE0; &#xB192;&#xC740; &#xC6B4;&#xC804; &#xC751;&#xB2F5;&#xC774;&#xC774; &#xC57D;&#xC5D0;&#xB3C4; &#xBD88;&#xAD6C; &#xD558; &#xACE0; &#xC54C;&#xCF54;&#xC62C;&#xC5D0; &#xB300; &#xD55C; &#xD1B5;&#xD654; &#xB2F9; &#xC5C6;&#xC5C8;&#xC2B5;&#xB2C8;&#xB2E4;. &#xC54C;&#xCF54;&#xC62C; &#xC720;&#xBC1C; &#xC6B4;&#xB3D9; &#xC2E4; &#xC870; &#xC99D;, &#xC800;&#xCCB4;&#xC628;&#xC99D;, &#xADF8;&#xB9AC;&#xACE0; &#xC9C4;&#xC815; &#xC601;&#xD5A5;&#xC744; &#xD588;&#xB2E4;. GLAST &#xCF54; &#xC950;&#xC5D0;&#xC11C; striatal &#xC2AC;&#xB77C;&#xC774;&#xC2A4;, &#xC7A5;&#xAE30; &#xBD88;&#xD669; (&#xC8FC;) &#xACE0;&#xC8FC;&#xD30C; &#xC790;&#xADF9;&#xC5D0; &#xC758;&#xD574; &#xC720;&#xBC1C; &#xB610;&#xB294; post-synaptic depolarization l &#xD0C0;&#xC785; &#xCE7C;&#xC298; &#xCC44;&#xB110; &#xD65C;&#xC131; &#xC81C; FPL 64176&#xC640; &#xACB0;&#xD569; &#xD558; &#xC5EC; &#xACB0; &#xC11D; &#xD588;&#xB2E4;. &#xB300;&#xC870;&#xC801;&#xC73C;&#xB85C;, &#xAE38; &#xD56D; 1 (CB1) &#xC218;&#xC6A9; &#xCCB4; &#xC81C; WIN55, 212-2 &#xC815;&#xC0C1;&#xC801;&#xC778; &#xC2DC; &#xB0C5; &#xC2DC;&#xC2A4; &#xBD88;&#xACBD;&#xAE30;&#xB294; cannabinoid &#xC801;&#xC6A9; &#xD6C4; &#xAD00;&#xCC30; &#xB418;&#xC5C8;&#xB2E4;. GLAST &#xC81C;&#xC815; &#xC0AD;&#xC81C; &#xD604;&#xC800; &#xD558; &#xAC8C; &#xAC10;&#xC18C; &#xB41C; &#xC54C;&#xCF54;&#xC62C; &#xC18C;&#xBE44;&#xC640; &#xD658;&#xACBD; &#xC124;&#xC815;, &#xD604;&#xC800; &#xD558; &#xAC8C; &#xAC10;&#xC18C; &#xB41C; &#xC54C;&#xCF54;&#xC62C; &#xBCF4;&#xC0C1; &#xC5F0;&#xAD00; &#xC608;&#xAE30;&#xCE58; &#xC54A;&#xAC8C; &#xBC1C;&#xC0DD; &#xD569;&#xB2C8;&#xB2E4;. &#xC544;&#xB798;&#xB85C; &#xB098;&#xD0C0;&#xB0A9;&#xB2C8;&#xB2E4; Endocannabinoid &#xC2E0;&#xD638; GLAST &#xC0AD;&#xC81C; &#xACB0;&#xACFC;&#xB85C; CB1 &#xC218;&#xC6A9; &#xCCB4;&#xC758; &#xC5C5;&#xC2A4;&#xD2B8;&#xB9BC; &#xAD00;&#xCC30; &#xC54C;&#xCF54;&#xC62C; &#xBCF4;&#xC0C1; &#xAC10;&#xC18C; &#xB4A4;&#xC5D0; &#xD6C4;&#xBCF4; &#xBA54;&#xCEE4;&#xB2C8;&#xC998;&#xC785;&#xB2C8;&#xB2E4;.

&#xC54C;&#xCF54;&#xC62C; &#xC12D;&#xCDE8;&#xC640; &#xC870;&#xBBF8;&#xB8CC; &#xC804;&#xC1A1; GLAST&#xC758; &#xC0AD;&#xC81C;&#xC640; &#xC0DD;&#xC950;&#xC5D0;&#xC11C; &#xC2E0;&#xD638; &#xC7A5;&#xC560; endocannabinoid&#xC640; &#xAD00;&#xB828; &#xB41C; &#xBCF4;&#xC0C1; &#xAC10;&#xC18C;.

Un estado de hyperglutamatergic ha planteado la hip&oacute;tesis a la escalada de la unidad de consumo de alcohol. Esta hip&oacute;tesis predice que una debilitaci&oacute;n de la separaci&oacute;n de glutamato a trav&eacute;s de la inactivaci&oacute;n del transportador astroc&iacute;ticos glutamato, GLAST (EAAT1), resultar&aacute; en la escalada del consumo de alcohol. Aqu&iacute;, utilizamos ratones con una canceladura de GLAST para probar esta predicci&oacute;n. Ratones WT y GLAST KO fueron probados para el consumo de alcohol con dos botellas bebiendo de libre elecci&oacute;n. Recompensa del alcohol se evalu&oacute; con preferencia condicionada lugar (CPP). Sensibilidad a los efectos depresores del alcohol se evalu&oacute; mediante la aceleraci&oacute;n rotarod, hipotermia inducida por alcohol y p&eacute;rdida del reflejo de enderezamiento. Glutamato extracelular se midi&oacute; usando microdialysis y electrofisiolog&iacute;a de rebanada estriado se llev&oacute; a cabo para examinar la plasticidad de la v&iacute;a cortico-estriatal como modelo en que las adaptaciones a la constitutiva GLAST eliminaci&oacute;n puede estudiarse. Contrario a nuestra hip&oacute;tesis, ratones KO GLAST mostr&oacute; marcadamente disminuci&oacute;n el consumo de alcohol y carec&iacute;an de CPP para el alcohol, a pesar de una mayor respuesta locomotor a esta droga. Sedaci&oacute;n, hipotermia y ataxia inducida por el alcohol eran inafectadas. En rebanadas de estriado de ratones KO GLAST, depresi&oacute;n a largo plazo (LTD) inducida por la estimulaci&oacute;n de alta frecuencia o por despolarizaci&oacute;n postsin&aacute;pticos combinado con el activador de canales de calcio tipo l FPL 64176 estuvo ausente. Por el contrario, depresi&oacute;n sin&aacute;ptica normal fue observada despu&eacute;s de la aplicaci&oacute;n de los cannabinoides 1 (CB1) receptor agonist WIN55, 212-2. Deleci&oacute;n constitutiva de GLAST inesperadamente produce alcohol marcadamente reducido consumo y preferencia, asociados con la recompensa del alcohol marcadamente reducido. Se&ntilde;alizaci&oacute;n endocannabinoide parece ser regula aguas arriba del receptor CB1 como consecuencia de la supresi&oacute;n de GLAST, y es un mecanismo de candidato tras la reducci&oacute;n de la recompensa del alcohol observado.

Reduce el consumo de alcohol y recompensa asociada deteriorada endocannabinoide se&ntilde;alizaci&oacute;n en ratones con una canceladura del transportador glutamato GLAST.

Article	Year
Rimonabant (SR141716) has no effect on alcohol self-administration or endocrine measures in nontreatment-seeking heavy alcohol drinkers. Psychopharmacology\| PubMed ID: 19902183	2010
Neuropeptide Y (NPY) suppresses yohimbine-induced reinstatement of alcohol seeking. Psychopharmacology\| PubMed ID: 20012021	2010
Neurokinin-1 receptors (NK1R:s), alcohol consumption, and alcohol reward in mice. Psychopharmacology\| PubMed ID: 20112009	2010
Alcohol-induced neurodegeneration, suppression of transforming growth factor-beta, and cognitive impairment in rats: prevention by group II metabotropic glutamate receptor activation. Biological psychiatry\| PubMed ID: 20132926	2010
Effect of acamprosate on magnetic resonance spectroscopy measures of central glutamate in detoxified alcohol-dependent individuals: a randomized controlled experimental medicine study. Archives of general psychiatry\| PubMed ID: 20921123	2010
Pharmacologically induced alcohol craving in treatment seeking alcoholics correlates with alcoholism severity, but is insensitive to acamprosate. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology\| PubMed ID: 21289601	2011
Pharmacological blockade of corticotropin-releasing hormone receptor 1 (CRH1R) reduces voluntary consumption of high alcohol concentrations in non-dependent Wistar rats. Pharmacology, biochemistry, and behavior\| PubMed ID: 22036774	2012
Reduced alcohol intake and reward associated with impaired endocannabinoid signaling in mice with a deletion of the glutamate transporter GLAST. Neuropharmacology\| PubMed ID: 22342743	2012

Erick Singley

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