getting-to-compliance-forced-exercise-rodents-critical-standard-to

Getting to Compliance in Forced Exercise in Rodents: A Critical Standard to Evaluate Exercise Impact in Aging-related Disorders and Disease

There is a major increase in the awareness of the positive impact of exercise on improving several disease states with neurobiological basis; these ...

louisiana state university health sciences center

3-((2-Methyl-1,3-thiazol-4-yl)ethynyl)pyridine hydrochloride (MTEP) is a metabotropic glutamate receptor 5 (mGluR5) antagonist that may alter drug sensitivity in differentially reared rats due to its involvement in the psychostimulant reward pathway and plasticity.

Impact of mGluR5 during amphetamine-induced hyperactivity and conditioned hyperactivity in differentially reared rats.

&#x4E09;&#x4E2A;&#x8C37;&#x6C28;&#x9178;&#x8F6C;&#x8FD0;&#x4F53;&#x3001; GLT 1&#x3001; GLAST &#x548C; EAAC1&#xFF0C;&#x8868;&#x793A;&#x7EB9;&#x72B6;&#x4F53;&#x3002;GLT 1 &#x548C;&#x7A0B;&#x5EA6;&#x8F83;&#x8F7B; GLAST &#x601D;&#x60F3;&#x518D;&#x6444;&#x53D6;&#x8C37;&#x6C28;&#x9178;&#x4E2D;&#x53D1;&#x6325;&#x4E3B;&#x8981;&#x4F5C;&#x7528;&#xFF0C;&#x5E76;&#x51CF;&#x8F7B; excitoxicity&#x3002;&#x5E15;&#x91D1;&#x68EE;&#x75C5; (PD) &#x6240;&#x793A;&#x7684;&#x9010;&#x6B65;&#x916A;&#x6C28;&#x9178;&#x7F9F;&#x5316;&#x9176; (TH) &#x635F;&#x5931;&#x662F;&#x589E;&#x52A0;&#x80DE;&#x5916;&#x8C37;&#x6C28;&#x9178;&#x4E0E;&#x76F8;&#x5173;&#x8054;&#x3002;&#x8C37;&#x6C28;&#x9178;&#x53D7;&#x4F53;&#x62EE;&#x6297;&#x5242;&#x964D;&#x4F4E;&#x9ED1;&#x8D28;&#x7EB9;&#x72B6;&#x4F53;&#x5C40;&#x90E8;&#x653E;&#x7535;&#x6A21;&#x578B;&#x4E2D;&#x7684;&#x635F;&#x5931;&#x3002;&#x8FD9;&#x4E9B;&#x610F;&#x89C1;&#x8868;&#x660E;&#xFF0C;&#x8FC7;&#x91CF;&#x7684;&#x7A81;&#x89E6;&#x8C37;&#x6C28;&#x9178;&#x6709;&#x52A9;&#x4E8E;&#x9ED1;&#x8D28;&#x7EB9;&#x72B6;&#x4F53;&#x795E;&#x7ECF;&#x5143;&#x4E22;&#x5931;&#x7684;&#x770B;&#x5230;&#x5728; PD.&#x4E0B;&#x8DCC; GLT-1 &#x8868;&#x8FBE;&#x53D1;&#x751F;&#x5728;&#x795E;&#x7ECF;&#x9000;&#x884C;&#x6027;&#x75BE;&#x75C5;&#x548C; PD &#x6A21;&#x578B;&#xFF0C;&#x5EFA;&#x8BAE;&#x51CF;&#x5C11;&#x7684; GLT 1 &#x4ECB;&#x5BFC;&#x8C37;&#x6C28;&#x9178;&#x518D;&#x6444;&#x53D6;&#x6709;&#x52A9;&#x4E8E;&#x5174;&#x594B;&#x6BD2;&#x6027;&#x3002;&#x82E5;&#x8981;&#x786E;&#x5B9A;&#x5982;&#x4F55;&#x77AC;&#x6001; GLT 1 &#x5C01;&#x9501;&#x5F71;&#x54CD;&#x8C37;&#x6C28;&#x9178;&#x518D;&#x6444;&#x53D6;&#x52A8;&#x529B;&#x5B66;&#x548C;&#x9ED1;&#x8D28;&#x7EB9;&#x72B6;&#x4F53;&#x7EC8;&#x7AEF; Ca(2+) &#x4F9D;&#x8D56;&#x8FDB;&#x7A0B;&#xFF0C;ser(19) &#x78F7;&#x9178;&#x5316; TH&#xFF0C;GLT 1 &#x6291;&#x5236;&#x5242; dihydrokainic &#x9178; (DHK) &#x4EA4;&#x7ED9;&#x5355;&#x65B9;&#x9762;&#x4F53;&#x5185;&#x7684;&#x7EB9;&#x72B6;&#x4F53;&#x548C;&#x518D;&#x6444;&#x53D6;&#x8C37;&#x6C28;&#x9178;&#x91CF;&#x5316;&#x6269;&#x589E;&#x539F;&#x6CB9;&#x7A81;&#x89E6;&#x540E; 3 h&#x3002;Ca(2+) &#x6D8C;&#x5165;&#x662F;&#x4E0E;&#x5174;&#x594B;&#x6BD2;&#x6027;&#x6761;&#x4EF6;&#x76F8;&#x5173;&#x8054;&#x3002;&#x78F7;&#x9178;&#x5316;&#x7684; TH ser(19) &#x5728;&#x662F;&#x4E0E; Ca(2+) &#x76F8;&#x5173;&#x7684;&#x548C;&#x4ECE; GLT 1 &#x5C01;&#x9501;&#x6240;&#x9020;&#x6210;&#x7684;&#x53D8;&#x5316;&#x53EF;&#x80FD;&#x610F;&#x5473;&#x7740;&#x5BF9;&#x9ED1;&#x8D28;&#x7EB9;&#x72B6;&#x4F53;&#x795E;&#x7ECF;&#x5143;&#x5174;&#x594B;&#x6BD2;&#x6027;&#x7684;&#x53EF;&#x80FD;&#x6027;&#x3002;&#x4ECE; DHK &#x6CE8;&#x5165;&#x7EB9;&#x72B6;&#x4F53;&#x7A81;&#x89E6;&#x4F53;&#x8C37;&#x6C28;&#x9178;&#x518D;&#x6444;&#x53D6;&#x51CF;&#x5C11;&#x7684; ser(19) TH &#x78F7;&#x9178;&#x5316;&#x7ED3;&#x5408;&#x4E2D;&#x5DF2;&#x589E;&#x52A0;&#x4E86; 43%&#x3002;&#x4F7F;&#x7528;&#x65B0;&#x578B;&#x7684; GLAST &#x6291;&#x5236;&#x5242;&#x548C; DHK&#xFF0C;&#x6211;&#x4EEC;&#x51B3;&#x5B9A;&#x518D;&#x589E;&#x52A0;&#x7684;&#x8C37;&#x6C28;&#x9178;&#x6444;&#x53D6;&#x7684; GLAST &#x4ECB;&#x5BFC;&#x7EC4;&#x4EF6;&#x589E;&#x52A0; 3-fold GLAST &#x6216; GLT-1 &#x86CB;&#x767D;&#x8868;&#x8FBE;&#x4E0D;&#x53D8;&#x3002;&#x7136;&#x800C;&#xFF0C;GLT 1 &#x5C01;&#x9501;&#x589E;&#x52A0; EAAC1 &#x86CB;&#x767D;&#x8868;&#x8FBE; ~ 20%&#x3002;&#x603B;&#x4E4B;&#xFF0C;&#x8FD9;&#x4E9B;&#x7ED3;&#x679C;&#x8868;&#x660E; GLT 1 &#x5C01;&#x9501;&#x4EA7;&#x751F;&#x77AC;&#x6001; GLAST &#x4ECB;&#x5BFC;&#x518D;&#x6444;&#x53D6;&#x589E;&#x52A0;&#x548C; EAAC1 &#x8868;&#x8FBE;&#x5F0F;&#x52A0;&#x4E0A;&#x51CF;&#x5C11; ser(19) TH &#x78F7;&#x9178;&#x5316;&#x3002;&#x8FD9;&#x4E9B;&#x53CD;&#x5E94;&#x53EF;&#x80FD;&#x4EE3;&#x8868;&#x5174;&#x594B;&#x6BD2;&#x6027;&#x7684;&#x5185;&#x6E90;&#x6027;&#x9632;&#x5FA1;&#x5BF9;&#x9ED1;&#x8D28;&#x7EB9;&#x72B6;&#x4F53;&#x901A;&#x8DEF;&#x3002;

&#x77AC;&#x6001;&#x7EB9;&#x72B6;&#x4F53; GLT 1 &#x5C01;&#x9501;&#x589E;&#x52A0; EAAC1 &#x8868;&#x8FBE;&#x5F0F;&#xFF0C;&#x518D;&#x6444;&#x53D6;&#x8C37;&#x6C28;&#x9178;&#xFF0C;&#x5E76;&#x51CF;&#x5C11;&#x916A;&#x6C28;&#x9178;&#x7F9F;&#x5316;&#x9176;&#x5728; ser(19) &#x7684;&#x78F7;&#x9178;&#x5316;&#x3002;

Three glutamate transporters, GLT-1, GLAST, and EAAC1, are expressed in striatum. GLT-1 and, to a lesser extent, GLAST are thought to play a primary role in glutamate reuptake and mitigate excitoxicity. Progressive tyrosine hydroxylase (TH) loss seen in Parkinson's disease (PD) is associated with increased extracellular glutamate. Glutamate receptor antagonists reduce nigrostriatal loss in PD models. These observations suggest that excess synaptic glutamate contributes to nigrostriatal neuron loss seen in PD. Decreased GLT-1 expression occurs in neurodegenerative disease and PD models, suggesting decreased GLT-1-mediated glutamate reuptake contributes to excitotoxicity. To determine how transient GLT-1 blockade affects glutamate reuptake dynamics and a Ca(2+)-dependent process in nigrostriatal terminals, ser(19) phosphorylation of TH, the GLT-1 inhibitor dihydrokainic acid (DHK) was delivered unilaterally to striatum in vivo and glutamate reuptake was quantified ex vivo in crude synaptosomes 3h later. Ca(2+)-influx is associated with excitotoxic conditions. The phosphorylation of TH at ser(19) is Ca(2+)-dependent, and a change resulting from GLT-1 blockade may signify the potential for excitotoxicity to nigrostriatal neurons. Synaptosomes from DHK infused striatum had a 43% increase in glutamate reuptake in conjunction with decreased ser(19) TH phosphorylation. Using a novel GLAST inhibitor and DHK, we determined that the GLAST-mediated component of increased glutamate reuptake increased 3-fold with no change in GLAST or GLT-1 protein expression. However, GLT-1 blockade increased EAAC1 protein expression ~20%. Taken together, these results suggest that GLT-1 blockade produces a transient increase in GLAST-mediated reuptake and EAAC1 expression coupled with reduced ser(19) TH phosphorylation. These responses could represent an endogenous defense against excitotoxicity to the nigrostriatal pathway.

Transient striatal GLT-1 blockade increases EAAC1 expression, glutamate reuptake, and decreases tyrosine hydroxylase phosphorylation at ser(19).

Trois transporteurs de glutamate, GLT-1, GLAST et EAAC1, sont exprim&eacute;es dans le striatum. GLT-1 et, dans une moindre mesure, GLAST semblent jouer un r&ocirc;le primordial dans la recapture du glutamate et d&#39;att&eacute;nuer les excitoxicity. Perte de hydroxylase (TH) tyrosine progressive dans la maladie de Parkinson (MP) est associ&eacute;e &agrave; une augmentation glutamate extracellulaire. Antagonistes des r&eacute;cepteurs de glutamate r&eacute;duisent perte sont dans les mod&egrave;les de PD. Ces observations sugg&egrave;rent que cet exc&egrave;s de glutamate synaptique contribue &agrave; la perte de neurones sont vu dans PD. diminu&eacute; GLT-1 expression se produit dans les maladies neuro-d&eacute;g&eacute;n&eacute;ratives et mod&egrave;les PD, sugg&eacute;rant une diminution induite par la GLT-1 glutamate recaptage contribue &agrave; l&#39;excitotoxicit&eacute;. Pour d&eacute;terminer comment transitoire GLT-1 blocus affecte glutamate recaptage dynamique et un processus d&eacute;pendant du Ca(2+) dans les a&eacute;rogares sont, phosphorylation des ser(19) de TH, l&#39;acide de dihydrokainic GLT-1 inhibiteur (DHK) a &eacute;t&eacute; livr&eacute;e unilat&eacute;ralement au striatum in vivo et recaptage du glutamate a &eacute;t&eacute; quantifi&eacute; ex vivo synaptosomes brut 3 h plus tard. Ca(2+)-influx est associ&eacute; aux conditions excitotoxiques. La phosphorylation de TH &agrave; ser(19) d&eacute;pend de le Ca(2+), et un changement r&eacute;sultant du blocus de la GLT-1 peut signifier le potentiel d&#39;excitotoxicit&eacute; aux neurones sont. Synaptosomes de DHK infus&eacute; striatum ont eu une augmentation de 43 % recaptage du glutamate en conjonction avec une diminution ser(19) TH la phosphorylation. &Agrave; l&#39;aide d&#39;un nouvel inhibiteur de GLAST et DHK, nous avons d&eacute;termin&eacute; que la composante induite par GLAST du recaptage du glutamate accrue a augment&eacute; de 3 fois sans aucun changement dans l&#39;expression de la prot&eacute;ine GLAST ou GLT-1. Toutefois, les blocus GLT-1 a augment&eacute; de EAAC1 prot&eacute;ine, expression ~ 20 %. Pris ensemble, ces r&eacute;sultats sugg&egrave;rent que blocus GLT-1 produit une augmentation transitoire de la m&eacute;diation GLAST recaptage et EAAC1 expression coupl&eacute; avec ser(19) r&eacute;duit la phosphorylation TH. Ces r&eacute;ponses pourraient repr&eacute;senter une d&eacute;fense endog&egrave;ne contre l&#39;excitotoxicit&eacute; &agrave; la voie sont.

Transitoire striatale blocus GLT-1 augmente l&#39;expression de EAAC1, recaptage du glutamate et diminue la phosphorylation de la tyrosine hydroxylase &agrave; ser(19).

Drei Glutamat-Transporter, GLT-1, GLAST und EAAC1, werden im Striatum ausgedr&uuml;ckt. GLT-1 und, in geringerem Ma&szlig;e, GLAST werden gedacht, um eine prim&auml;re Rolle in Glutamat Reuptake und Excitoxicity zu mildern. Progressive Tyrosin-Hydroxylase (TH)-Verlust bei Parkinson-Krankheit (PD) gesehen ist erh&ouml;hte extrazellul&auml;re Glutamat zugeordnet. Glutamat-Rezeptor-Antagonisten verringern Nigrostriatal Verlust PD-Modelle. Diese Beobachtungen legen nahe, dass &uuml;bersch&uuml;ssige synaptische Glutamat tr&auml;gt zu Nigrostriatal Neuron Verlust gesehen in PD sank GLT-1 Ausdruck tritt in Neurodegenerative Krankheit und PD-Modelle, was darauf hindeutet, verminderte GLT-1-vermittelter Glutamat Reuptake zur Exzitotoxit&auml;t beitr&auml;gt. Um festzustellen, wie vor&uuml;bergehende GLT-1 Blockade wirkt Glutamat Reuptake Dynamik und ein Ca(2+)-abh&auml;ngigen Prozess Nigrostriatal Terminals, wurde ser(19) Phosphorylierung von TH, GLT-1-Inhibitor Dihydrokainic S&auml;ure (DHK) einseitig zum Striatum in-vivo geliefert und Glutamat Reuptake war ex Vivo in groben Synaptosomes 3 h sp&auml;ter quantifiziert. Ca(2+)-Zustrom ist mit excitotoxischem Auflagen verbunden. Die Phosphorylierung von TH am ser(19) h&auml;ngt vom Ca(2+) und ein &Auml;nderungen infolge GLT-1-Blockade, kann das Potenzial f&uuml;r Exzitotoxit&auml;t Nigrostriatal Neuronen bedeuten. Synaptosomes von DHK Striatum infundiert hatte eine Steigerung von 43 % Glutamat Reuptake in Verbindung mit verringerter ser(19) TH Phosphorylierung. Mit einem neuartigen GLAST-Inhibitor und DHK, wir entschlossen, dass die GLAST-vermittelte Komponente des erh&ouml;hten Glutamat Reuptake 3-fach erh&ouml;ht mit unver&auml;nderter GLAST oder GLT-1 Protein-Ausdruck. GLT-1-Blockade erh&ouml;ht EAAC1 Protein Expression ~ 20 %. Zusammengenommen deuten diese Ergebnisse GLT-1-Blockade produziert einen vor&uuml;bergehenden Anstieg der GLAST-vermittelte Reuptake und EAAC1 Ausdruck gepaart mit reduzierten ser(19) TH Phosphorylierung. Diese Antworten k&ouml;nnten eine endogene Verteidigung gegen Exzitotoxit&auml;t f&uuml;r die Nigrostriatal Pathway darstellen.

Transiente Striatale GLT-1-Blockade erh&ouml;ht Glutamat Reuptake, EAAC1 Ausdruck und verringert Tyrosin Hydroxylase Phosphorylierung an ser(19).

Tre trasportatori di glutammato GLT-1, GLAST ed EAAC1, sono espressi nello striato. GLT-1 e, in misura minore, GLAST si pensa per svolgere un ruolo primario nella ricaptazione del glutammato e ridurre excitoxicity. Progressiva tirosina idrossilasi (TH) perdita visto nella malattia di Parkinson (MdP) &egrave; associata con aumentato glutammato extracellulare. Antagonisti dei recettori del glutammato ridurre Sonografia perdita in modelli PD. Queste osservazioni suggeriscono che glutammato sinaptico in eccesso contribuisce alla perdita di neuroni Sonografia visto nel PD &egrave; diminuito GLT-1 espressione si verifica nelle malattie neurodegenerative e modelli PD, suggerendo di glutammato GLT-1-mediata diminuita ricaptazione contribuisce alla eccitotossicit&agrave;. Per determinare come transitoria GLT-1 blocco colpisce glutammato reuptake dinamica e un processo di Ca(2+)-dipendente nei terminali Sonografia, ser(19) fosforilazione di TH, acido dihydrokainic GLT-1 inibitore (DHK) fu consegnata unilateralmente a striato in vivo e ricaptazione del glutammato &egrave; stata quantificata ex vivo in grezzo ad 3 ore pi&ugrave; tardi. CA(2+)-afflusso &egrave; associato excitotoxic condizioni. La fosforilazione di TH a ser(19) &egrave; Ca(2+)-dipendente, e un cambiamento derivante dal blocco GLT-1 pu&ograve; significare il potenziale di eccitotossicit&agrave; a Sonografia neuroni. Ad da DHK infuso striato ha avuto un aumento del 43% nella ricaptazione del glutammato in concomitanza con la fosforilazione diminuito ser(19) TH. Utilizzando un romanzo GLAST inibitore e DHK, abbiamo determinato che il componente GLAST-mediata della ricaptazione di glutammato aumentata aumentata 3 volte con nessun cambiamento nell&#39;espressione della proteina GLAST o GLT-1. Tuttavia, GLT-1 blocco aumentata della proteina EAAC1 espressione ~ 20%. Presi insieme, questi risultati suggeriscono che GLT-1 blocco produce un aumento transitorio reuptake GLAST-mediata ed EAAC1 espressione accoppiato con ser(19) ridotta fosforilazione di TH. Queste risposte potrebbero rappresentare una difesa endogeno contro l&#39;eccitotossicit&agrave; del percorso Sonografia.

Transitoria striatal GLT-1 blocco aumenta EAAC1 espressione, della ricaptazione di glutammato e diminuisce la fosforilazione di tirosina idrossilasi presso ser(19).

&#x30B0;&#x30EB;&#x30BF;&#x30DF;&#x30F3;&#x9178;&#x30C8;&#x30E9;&#x30F3;&#x30B9;&#x30DD;&#x30FC;&#x30BF;&#x30FC;&#x3001;GLT 1&#x3001;GLAST, EAAC1, &#x306E; 3 &#x7DDA;&#x6761;&#x4F53;&#x3067;&#x8868;&#x73FE;&#x3055;&#x308C;&#x3066;&#x3044;&#x307E;&#x3059;&#x3002;GLT 1 &#x305D;&#x3057;&#x3066;&#x3088;&#x308A;&#x5C11;&#x306A;&#x3044;&#x7A0B;&#x5EA6;&#x306B;&#x3001;GLAST &#x30B0;&#x30EB;&#x30BF;&#x30DF;&#x30F3;&#x9178; reuptake &#x306E;&#x4E3B;&#x306A;&#x5F79;&#x5272;&#x3092;&#x518D;&#x751F;&#x3057;&#x3001;excitoxicity &#x3092;&#x8EFD;&#x6E1B;&#x3059;&#x308B;&#x8003;&#x3048;&#x3067;&#x3059;&#x3002;&#x30D1;&#x30FC;&#x30AD;&#x30F3;&#x30BD;&#x30F3;&#x75C5; (PD) &#x306B;&#x898B;&#x3089;&#x308C;&#x308B;&#x30D7;&#x30ED;&#x30B0;&#x30EC;&#x30C3;&#x30B7;&#x30D6; &#x30C1;&#x30ED;&#x30B7;&#x30F3;&#x6C34;&#x9178;&#x5316;&#x9175;&#x7D20; (TH) &#x640D;&#x5931;&#x5897;&#x52A0;&#x306E;&#x7D30;&#x80DE;&#x5916;&#x30B0;&#x30EB;&#x30BF;&#x30DF;&#x30F3;&#x9178;&#x3092;&#x95A2;&#x9023;&#x4ED8;&#x3051;&#x3089;&#x308C;&#x3066;&#x3044;&#x307E;&#x3059;&#x3002;&#x30B0;&#x30EB;&#x30BF;&#x30DF;&#x30F3;&#x9178;&#x53D7;&#x5BB9;&#x4F53;&#x62EE;&#x6297;&#x85AC;&#x306F; PD &#x30E2;&#x30C7;&#x30EB;&#x306B;&#x304A;&#x3051;&#x308B;&#x7DDA;&#x6761;&#x640D;&#x5931;&#x3092;&#x6E1B;&#x3089;&#x3057;&#x307E;&#x3059;&#x3002;&#x3053;&#x308C;&#x3089;&#x306E;&#x89B3;&#x5BDF;&#x306F;&#x3001;&#x305D;&#x306E;&#x4F59;&#x5206;&#x306A;&#x30B7;&#x30CA;&#x30D7;&#x30B9; &#x30B0;&#x30EB;&#x30BF;&#x30DF;&#x30F3;&#x9178;&#x3067;&#x8A0E;&#x6E1B;&#x5C11; GLT - &#x5F0F;&#x795E;&#x7D4C;&#x5909;&#x6027;&#x75BE;&#x60A3;&#x3068; PD &#x30E2;&#x30C7;&#x30EB;&#x3067;&#x767A;&#x751F;&#x3057;&#x305F;&#x6E1B;&#x5C11; GLT 1 &#x3092;&#x4ECB;&#x3059;&#x308B;&#x30B0;&#x30EB;&#x30BF;&#x30DF;&#x30F3;&#x9178; reuptake &#x5FDC;&#x9700;&#x578B;&#x306B;&#x5BC4;&#x4E0E;&#x3059;&#x308B;&#x3053;&#x3068;&#x3092;&#x793A;&#x5506; 1 &#x898B;&#x7DDA;&#x6761;&#x30CB;&#x30E5;&#x30FC;&#x30ED;&#x30F3;&#x306E;&#x640D;&#x5931;&#x306B;&#x8CA2;&#x732E;&#x3059;&#x308B;&#x3092;&#x304A;&#x52E7;&#x3081;&#x3057;&#x307E;&#x3059;&#x3002;&#x3069;&#x306E;&#x3088;&#x3046;&#x306B;&#x904E;&#x6E21; GLT 1 &#x5C01;&#x9396;&#x5F71;&#x97FF;&#x30B0;&#x30EB;&#x30BF;&#x30DF;&#x30F3;&#x9178; reuptake &#x30C0;&#x30A4;&#x30CA;&#x30DF;&#x30AF;&#x30B9;&#x3068;&#x7DDA;&#x6761;&#x7AEF;&#x672B;&#x3067;&#x306E; Ca(2+) &#x306B;&#x4F9D;&#x5B58;&#x3059;&#x308B;&#x30D7;&#x30ED;&#x30BB;&#x30B9;&#x3092;&#x6C7A;&#x5B9A;&#x3059;&#x308B;&#x306B;&#x306F;&#x3001;ser(19) &#x306E;&#x30EA;&#x30F3;&#x9178;&#x5316;&#x3001;GLT 1 &#x963B;&#x5BB3;&#x5264; NMDA &#x578B;&#x30B0;&#x30EB;&#x30BF;&#x30DF;&#x30F3;&#x9178;) &#x756A;&#x76EE;&#x306E;&#x4E00;&#x65B9;&#x7684;&#x7DDA;&#x6761;&#x4F53;&#x306B;&#x751F;&#x4F53;&#x5185;&#x3067;&#x914D;&#x4FE1;&#x3055;&#x308C;&#x305F;&#x3001;&#x30B0;&#x30EB;&#x30BF;&#x30DF;&#x30F3;&#x9178; reuptake ex vivo &#x539F;&#x6CB9;&#x30B7;&#x30CA;&#x30D7;&#x30C8;&#x30BD;&#x30FC;&#x30E0; 3 h &#x5F8C;&#x306B;&#x5B9A;&#x91CF;&#x5316;&#x3055;&#x308C;&#x307E;&#x3057;&#x305F;&#x3002;Ca(2+) &#x6D41;&#x5165; excitotoxic &#x6761;&#x4EF6;&#x306B;&#x95A2;&#x9023;&#x4ED8;&#x3051;&#x3089;&#x308C;&#x305F;&#x3067;&#x3059;&#x3002;&#x756A;&#x76EE;&#x306E;&#x30EA;&#x30F3;&#x9178;&#x5316; ser(19) &#x3067;&#x306F; Ca(2+) &#x306B;&#x4F9D;&#x5B58;&#x3057; GLT 1 &#x5C01;&#x9396;&#x304B;&#x3089;&#x751F;&#x3058;&#x308B;&#x5909;&#x66F4;&#x5FDC;&#x9700;&#x578B;&#x7DDA;&#x6761;&#x30CB;&#x30E5;&#x30FC;&#x30ED;&#x30F3;&#x3078;&#x306E;&#x53EF;&#x80FD;&#x6027;&#x3092;&#x793A;&#x3059;&#x53EF;&#x80FD;&#x6027;&#x304C;&#x3042;&#x308A;&#x307E;&#x3059;&#x3002;&#x7DDA;&#x6761;&#x4F53;&#x6CE8;&#x5165;&#x307F;&#x3089;&#x308C;&#x305F;&#x304B;&#x3089;&#x5F97;&#x305F;&#x30B7;&#x30CA;&#x30D7;&#x30C8;&#x30BD;&#x30FC;&#x30E0; &#x30B0;&#x30EB;&#x30BF;&#x30DF;&#x30F3;&#x9178; reuptake &#x6E1B;&#x5C11; ser(19) &#x756A;&#x76EE;&#x306E;&#x30EA;&#x30F3;&#x9178;&#x5316;&#x3068;&#x7D44;&#x307F;&#x5408;&#x308F;&#x305B;&#x3066;&#x306F; 43 &#xFF05; &#x5897;&#x52A0;&#x3057;&#x3066;&#x3044;&#x305F;&#x3002;&#x5C0F;&#x8AAC; GLAST &#x963B;&#x5BB3;&#x5264;&#x3068;&#x307F;&#x3089;&#x308C;&#x305F;&#x3092;&#x4F7F;&#x7528;&#x3057;&#x3066;&#x3001;&#x6211;&#x3005; GLAST &#x3092;&#x4ECB;&#x3057;&#x305F;&#x30B3;&#x30F3;&#x30DD;&#x30FC;&#x30CD;&#x30F3;&#x30C8;&#x518D;&#x5897;&#x52A0;&#x30B0;&#x30EB;&#x30BF;&#x30DF;&#x30F3;&#x9178;&#x53D6;&#x308A;&#x8FBC;&#x307F;&#x306E; 3 &#x500D;&#x306B;&#x5897;&#x52A0;&#x3059;&#x308B;&#x3053;&#x3068;&#x3092;&#x6C7A;&#x5B9A;&#x5909;&#x66F4; GLAST &#x307E;&#x305F;&#x306F; GLT 1 &#x86CB;&#x767D;&#x8CEA;&#x306E;&#x8868;&#x73FE;&#x306F;&#x3042;&#x308A;&#x307E;&#x305B;&#x3093;&#x3002;&#x305F;&#x3060;&#x3057;&#x3001;GLT 1 &#x5C01;&#x9396; EAAC1 &#x30BF;&#x30F3;&#x30D1;&#x30AF;&#x8CEA;&#x5F0F; ~ 20 &#xFF05; &#x5897;&#x52A0;&#x3057;&#x307E;&#x3057;&#x305F;&#x3002;&#x4E00;&#x7DD2;&#x306B;&#x53D6;&#x3089;&#x308C;&#x3066;&#x3001;&#x3053;&#x308C;&#x3089;&#x306E;&#x7D50;&#x679C;&#x306F;&#x3001;GLT 1 &#x5C01;&#x9396; GLAST &#x5A92;&#x4ECB;&#x518D;&#x53D6;&#x308A;&#x8FBC;&#x307F;&#x306E;&#x4E00;&#x904E;&#x6027;&#x306E;&#x4E0A;&#x6607;&#x3092;&#x751F;&#x6210;&#x304A;&#x3088;&#x3073; EAAC1 &#x5F0F;&#x524A;&#x6E1B; ser(19) &#x3068;&#x76F8;&#x307E;&#x3063;&#x3066;&#x756A;&#x76EE;&#x306E;&#x30EA;&#x30F3;&#x9178;&#x5316;&#x3092;&#x63D0;&#x6848;&#x3057;&#x307E;&#x3059;&#x3002;&#x3053;&#x308C;&#x3089;&#x306E;&#x5FDC;&#x7B54;&#x5FDC;&#x9700;&#x578B;&#x9632;&#x5FA1;&#x3001;&#x5185;&#x56E0;&#x6027;&#x7DDA;&#x6761;&#x7D4C;&#x8DEF;&#x3092;&#x8868;&#x3059;&#x3053;&#x3068;&#x304C;&#x3067;&#x304D;&#x307E;&#x3059;&#x3002;

&#x904E;&#x6E21;&#x7DDA;&#x6761;&#x4F53; GLT 1 &#x5C01;&#x9396; EAAC1 &#x5F0F;&#x3001;&#x30B0;&#x30EB;&#x30BF;&#x30DF;&#x30F3;&#x9178;&#x306E;&#x518D;&#x53D6;&#x308A;&#x8FBC;&#x307F;&#x3092;&#x5897;&#x52A0;&#x3057;&#x3001;ser(19) &#x3067;&#x30C1;&#x30ED;&#x30B7;&#x30F3;&#x6C34;&#x9178;&#x5316;&#x9175;&#x7D20;&#x306E;&#x30EA;&#x30F3;&#x9178;&#x5316;&#x304C;&#x6E1B;&#x5C11;&#x3057;&#x307E;&#x3059;&#x3002;

3 &#xC870;&#xBBF8;&#xB8CC; &#xC804;&#xC1A1;&#xAE30;, GLT 1, GLAST, &#xBC0F; EAAC1&#xAC00; &#xD45C;&#xC2DC; &#xB429;&#xB2C8;&#xB2E4;. GLT 1 &#xB0AE;&#xC740; &#xBC94;&#xC704; GLAST &#xC870;&#xBBF8;&#xB8CC; &#xC7AC;&#xD761;&#xC218;&#xC5D0; &#xC8FC;&#xC694; &#xC5ED;&#xD560;&#xC744; &#xD558; &#xACE0; excitoxicity&#xC744; &#xC644;&#xD654; &#xAC83;&#xC73C;&#xB85C; &#xC0DD;&#xAC01; &#xB418; &#xACE0;. &#xD30C; &#xD0A8; &#xC2A8; &#xBCD1; (PD)&#xC5D0; &#xC9C4;&#xBCF4;&#xC801;&#xC778; &#xD2F0;&#xB85C;&#xC2E0; hydroxylase (TH) &#xC190;&#xC2E4; &#xC99D;&#xAC00; &#xB41C; &#xC138;&#xD3EC; &#xC678; &#xC870;&#xBBF8;&#xB8CC;&#xC640; &#xC5F0;&#xACB0; &#xB429;&#xB2C8;&#xB2E4;. Glutamate &#xC218;&#xC6A9; &#xCCB4; &#xAE38; &#xD56D; &#xC81C; PD &#xBAA8;&#xB378;&#xC5D0;&#xC11C; nigrostriatal &#xC190;&#xC2E4;&#xC744; &#xC904;&#xC77C; &#xC218; &#xC788;&#xC2B5;&#xB2C8;&#xB2E4;. &#xC774;&#xB7EC;&#xD55C; &#xAD00;&#xCE21; nigrostriatal &#xC2E0;&#xACBD; &#xC190;&#xC2E4; &#xBCF8; PD. &#xAC10;&#xC18C; GLT 1 &#xC2DD; &#xC2E0;&#xACBD; &#xD1F4;&#xD589; &#xC131; &#xC9C8;&#xD658;&#xACFC; PD &#xBAA8;&#xB378;&#xC5D0;&#xC11C; &#xBC1C;&#xC0DD; &#xAC10;&#xC18C; GLT 1 &#xC911;&#xC7AC; &#xC870;&#xBBF8;&#xB8CC; &#xC7AC;&#xD761;&#xC218; excitotoxicity &#xAE30;&#xC5EC; &#xC81C;&#xC548;&#xC5D0; &#xAE30;&#xC5EC; &#xD558; &#xACE0; &#xCD08;&#xACFC; &#xC2DC; &#xB0C5; &#xC2A4; &#xC870;&#xBBF8;&#xB8CC;&#xB294; &#xAC83;&#xC774; &#xC88B;&#xC2B5;&#xB2C8;&#xB2E4;. &#xC5B4;&#xB5BB;&#xAC8C; &#xACFC;&#xB3C4; GLT 1 &#xBD09;&#xC1C4;&#xC5D0; &#xC601;&#xD5A5;&#xC744; &#xBBF8;&#xCE58;&#xB294; &#xC870;&#xBBF8;&#xB8CC; &#xC7AC;&#xD761;&#xC218; &#xC5ED;&#xD559; &#xBC0F; nigrostriatal &#xB2E8;&#xB9D0;&#xAE30;&#xC5D0; Ca(2+) &#xC885;&#xC18D; &#xD504;&#xB85C;&#xC138;&#xC2A4; &#xACB0;&#xC815;, TH, GLT 1 &#xC5B5;&#xC81C;&#xC81C; dihydrokainic &#xC0B0; (DHK)&#xC758; ser(19) &#xC778; &#xC0B0;&#xD654;&#xB294; &#xC77C;&#xBC29;&#xC801;&#xC73C;&#xB85C; &#xBC30;&#xB2EC;&#xAC00; vivo&#xC5D0;&#xC11C; &#xACE0; &#xC870;&#xBBF8;&#xB8CC; &#xC7AC;&#xD761;&#xC218; &#xC6D0;&#xC720; synaptosomes 3h &#xB098;&#xC911;&#xC5D0; &#xBE44;&#xBCF4; &#xC804; &#xACC4;&#xB7C9; &#xD588;&#xB2E4;. Ca(2+)-&#xC720;&#xC785; excitotoxic &#xC0C1;&#xD0DC;&#xC640; &#xC5F0;&#xACB0; &#xB429;&#xB2C8;&#xB2E4;. Ser(19)&#xC5D0;&#xC11C;&#xC758; &#xC778; &#xC0B0;&#xD654;&#xB294; ca(2+)&#xC5D0; &#xB530;&#xB77C; &#xB2E4;&#xB985;&#xB2C8;&#xB2E4; &#xBC0F; GLT 1 &#xBD09;&#xC1C4;&#xC5D0;&#xC11C; &#xBC1C;&#xC0DD; &#xD558;&#xB294; &#xBCC0;&#xD654;&#xB97C; &#xC54C;&#xB9AC;&#xB294; excitotoxicity nigrostriatal &#xC2E0;&#xACBD; &#xC138;&#xD3EC;&#xC5D0; &#xB300; &#xD55C; &#xAC00;&#xB2A5;&#xC131;. Synaptosomes&#xAC00; &#xC0DD;&#xAE34; DHK&#xC5D0;&#xC11C; glutamate &#xC7AC;&#xD761;&#xC218; &#xAC10;&#xC18C; ser(19) TH &#xC778; &#xC0B0;&#xD654;&#xC640; &#xD568;&#xAED8;&#xC5D0;&#xC11C; 43% &#xC99D;&#xAC00; &#xD588;&#xB2E4;. &#xC18C;&#xC124; GLAST &#xC5B5;&#xC81C;&#xC81C; &#xBC0F; DHK&#xB97C; &#xC0AC;&#xC6A9; &#xD558; &#xC5EC;, &#xC6B0;&#xB9AC;&#xB294; &#xACB0;&#xC815; GLAST &#xC911;&#xC7AC; &#xAD6C;&#xC131; &#xC694;&#xC18C; &#xC99D;&#xAC00; &#xC870;&#xBBF8;&#xB8CC; &#xC7AC;&#xD761;&#xC218;&#xC758; &#xC99D;&#xAC00; 3-fold GLAST &#xB610;&#xB294; GLT 1 &#xB2E8;&#xBC31;&#xC9C8; &#xD45C;&#xC815;&#xC5D0; &#xBCC0;&#xD654; &#xC5C6;&#xC774;. &#xADF8;&#xB7EC;&#xB098;, GLT 1 &#xBD09;&#xC1C4; EAAC1 &#xB2E8;&#xBC31;&#xC9C8; &#xC2DD; ~ 20%&#xC5D0; &#xC99D;&#xAC00; &#xD588;&#xB2E4;. &#xD568;&#xAED8; &#xCC0D;&#xC740;, &#xC774;&#xB7EC;&#xD55C; &#xACB0;&#xACFC; GLT 1 &#xBD09;&#xC1C4; &#xC0DD;&#xC0B0; GLAST &#xC911;&#xC7AC; &#xC7AC;&#xD761;&#xC218;&#xC758; &#xC77C;&#xC2DC;&#xC801;&#xC778; &#xC99D;&#xAC00; &#xD558; &#xACE0; &#xAC10;&#xC18C; &#xB41C; ser(19)&#xC640; EAAC1 &#xC2DD; &#xACB0;&#xD569; TH &#xC778; &#xC0B0;&#xD654; &#xC88B;&#xC2B5;&#xB2C8;&#xB2E4;. &#xC774;&#xB7EC;&#xD55C; &#xC751;&#xB2F5; nigrostriatal &#xD1B5;&#xB85C;&#xB97C; excitotoxicity &#xC0DD;&#xC73C;&#xB85C; &#xBC29;&#xC5B4;&#xB97C; &#xB098;&#xD0C0;&#xB0B4;&#xB294; &#xC218; &#xC788;&#xC2B5;&#xB2C8;&#xB2E4;.

&#xACFC;&#xB3C4; striatal GLT 1 &#xBD09;&#xC1C4; EAAC1 &#xC2DD; &#xC0B0; &#xC5FC; &#xC7AC;&#xD761;&#xC218;&#xB97C; &#xC99D;&#xAC00; &#xD558; &#xACE0; ser(19)&#xC5D0;&#xC11C; &#xD2F0;&#xB85C;&#xC2E0; hydroxylase &#xC778; &#xC0B0;&#xD654;&#xB97C; &#xAC10;&#xC18C;.

Tres transportadores de glutamato, GLT-1, GLAST y EAAC1, se expresan en el cuerpo estriado. GLT-1 y, en menor medida, GLAST se piensan para desempe&ntilde;ar un papel principal en la recaptaci&oacute;n de glutamato y mitigar excitoxicity. P&eacute;rdida de hidroxilasa (TH) tirosina progresiva en la enfermedad de Parkinson (EP) se asocia con aumento glutamato extracelular. Antagonistas de receptores de glutamato nigrostriatal perder en modelos PD. Estas observaciones sugieren que glutamato sin&aacute;ptico exceso contribuye a la p&eacute;rdida de la neurona de nigrostriatal vista en PD. disminuido GLT-1 expresi&oacute;n ocurre en enfermedades neurodegenerativas y modelos PD, sugiriendo la recaptaci&oacute;n disminuida GLT-1-mediada por glutamato contribuye a excitotoxicidad. Para determinar c&oacute;mo transitoria GLT-1 bloqueo afecta glutamato recaptaci&oacute;n din&aacute;mica y un proceso de Ca(2+)-dependiente en terminales nigrostriatal, fosforilaci&oacute;n de ser(19) de TH, el &aacute;cido de dihydrokainic GLT-1 inhibidor (DHK) entregaron unilateralmente a estriado en vivo y recaptaci&oacute;n de glutamato se cuantific&oacute; ex vivo en sinaptosomas crudos 3 h m&aacute;s tarde. CA(2+)-afluencia se asocia con condiciones excitatoria. La fosforilaci&oacute;n de TH en ser(19) depende de la Ca(2+), y un cambio resultantes GLT-1 bloqueo puede significar la posibilidad de excitotoxicidad nigrostriatal neuronas. Sinaptosomas de DHK infundido striatum tuvieron un incremento de 43% en la recaptaci&oacute;n de glutamato en conjunto con disminuci&oacute;n ser(19) TH fosforilaci&oacute;n. Utilizando un novedoso inhibidor de GLAST y DHK, determinamos que el componente de GLAST-mediada de recaptaci&oacute;n de glutamato aumento mayor 3-fold sin cambio en la expresi&oacute;n de la prote&iacute;na GLAST o GLT-1. Sin embargo, GLT-1 bloqueo aument&oacute; EAAC1 prote&iacute;na expresi&oacute;n ~ 20%. Tomados en conjunto, estos resultados sugieren que GLT-1 bloqueo produce un aumento transitorio en la recaptaci&oacute;n GLAST-mediada y EAAC1 expresi&oacute;n junto con el reducido ser(19) fosforilaci&oacute;n de TH. Estas respuestas podr&iacute;an representar una defensa end&oacute;gena contra excitotoxicidad al camino nigrostriatal.

Estriado transitoria GLT-1 bloqueo aumenta EAAC1 expresi&oacute;n, recaptaci&oacute;n de glutamato y disminuye la fosforilaci&oacute;n de tirosina hidroxilasa en ser(19).

Excess glutamatergic neurotransmission may contribute to excitotoxic loss of nigrostriatal neurons in Parkinson's disease (PD). Here, we determined if increasing glutamate uptake could reduce the extent of tyrosine hydroxylase (TH) loss in PD progression. The beta-lactam antibiotic, ceftriaxone, increases the expression of glutamate transporter 1 (GLT-1), a glutamate transporter that plays a major role in glutamate clearance in central nervous system and may attenuate adverse behavioral or neurobiological function in other neurodegenerative disease models. In association with >80% TH loss, we observed a significant decrease in glutamate uptake in the established 6-hydroxydopamine (6-OHDA) PD model. Ceftriaxone (200 mg/kg, i.p.) increased striatal glutamate uptake with >5 consecutive days of injection in nonlesioned rats and lasted out to 14 days postinjection, a time beyond that required for 6-OHDA to produce >70% TH loss (∼9 days). When ceftriaxone was given at the time of 6-OHDA, TH loss was ∼57% compared to ∼85% in temporally matched vehicle-injected controls and amphetamine-induced rotation was reduced about 2-fold. This attenuation of TH loss was associated with increased glutamate uptake, increased GLT-1 expression, and reduced Serine 19 TH phosphorylation, a calcium-dependent target specific for nigrostriatal neurons. These results reveal that glutamate uptake can be targeted in a PD model, decrease the rate of TH loss in a calcium-dependent manner, and attenuate locomotor behavior associated with 6-OHDA lesion. Given that detection of reliable PD markers will eventually be employed in susceptible populations, our results give credence to the possibility that increasing glutamate uptake may prolong the time period before locomotor impairment occurs.

Ceftriaxone increases glutamate uptake and reduces striatal tyrosine hydroxylase loss in 6-OHDA Parkinson's model.

Environmental stimuli play a key role in affecting the likelihood to abuse drugs. Environmental enrichment can reduce that likelihood. The neurotransmitter glutamate contributes to both drug reward and rearing-induced changes in the brain. The current study investigated the effects of the Group-2 metabotropic glutamate receptor (mGluR2/3) agonist, LY-379268 (0.5, 1.0 mg/kg), on acute and repeated amphetamine-induced locomotor activity in differentially reared male rats. Male Sprague-Dawley rats were randomly assigned to one of 3 environmental conditions postweaning: enriched (EC), isolated (IC), or standard (SC), where they reared for 30 days. The effect of LY-379268 on acute amphetamine-induced locomotor activity was assessed. Rats were injected with either LY-379268 (0.5, 1.0 mg/kg) or saline prior to an amphetamine (0.5 mg/kg) or saline challenge injection. Rats were also administered amphetamine (0.5 mg/kg) or saline injections prior to 5 locomotor sessions. Following a rest period of 14-15 days, the effects of repeated amphetamine exposure were evaluated using LY-379268 (0.5, 1.0 mg/kg) or saline injections 30 min prior to receiving amphetamine (0.5 mg/kg). Results showed that LY-379268 administration dose-dependently attenuated acute amphetamine-induced locomotor activity, with EC rats generally displaying less attenuation than IC or SC rats. After repeated amphetamine administrations, the ability of LY-379268 to attenuate the final expression of amphetamine-induced locomotor activity in differentially reared rats was dose-dependent. The differing effect of LY-379268 observed in EC rats suggests enrichment-induced glutamatergic alterations that may protect against sensitivity to psychostimulants.

Article	Year
Impact of mGluR5 during amphetamine-induced hyperactivity and conditioned hyperactivity in differentially reared rats. Psychopharmacology\| PubMed ID: 22139452	2012
Transient striatal GLT-1 blockade increases EAAC1 expression, glutamate reuptake, and decreases tyrosine hydroxylase phosphorylation at ser(19). Experimental neurology\| PubMed ID: 22285253	2012
Ceftriaxone increases glutamate uptake and reduces striatal tyrosine hydroxylase loss in 6-OHDA Parkinson's model. Molecular neurobiology\| PubMed ID: 24297323	2014
The effects of mGluR2/3 activation on acute and repeated amphetamine-induced locomotor activity in differentially reared male rats. Experimental and clinical psychopharmacology\| PubMed ID: 24467371	2014

Jennifer C. Arnold

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