Glucagon-like peptide 1 receptor activation regulates cocaine actions and dopamine homeostasis in the lateral septum by decreasing arachidonic acid levels.
Glucagon-like peptide 1 receptor activation regulates cocaine actions and dopamine homeostasis in the lateral septum by decreasing arachidonic acid levels.
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DOI：
10.1038/tp.2016.86
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发表时间：
2016-05-17
影响因子：
6.8
通讯作者：
Galli A
中科院分区：
文献类型：
--
作者：
Reddy IA;Pino JA;Weikop P;Osses N;Sørensen G;Bering T;Valle C;Bluett RJ;Erreger K;Wortwein G;Reyes JG;Graham D;Stanwood GD;Hackett TA;Patel S;Fink-Jensen A;Torres GE;Galli A
胰高血糖素样肽1（GLP-1）受体（GLP-1 R）的激动作用可有效治疗包括可卡因在内的许多滥用物质的成瘾行为。然而，GLP-1 R信号传导对可卡因作用的治疗作用的分子机制和脑回路仍然难以捉摸。最近的证据表明，在前脑外侧隔（LS）内的GLP-1 R的内源性信号传导，以减少可卡因诱导的运动和可卡因条件性位置偏爱，都认为多巴胺（DA）相关的行为。DA终末从腹侧被盖区投射到LS，并表达DA转运体（DAT）。可卡因通过靶向DAT改变DA的生物利用度而起作用。因此，GLP-1 R信号可能对DAT产生影响，以解释其调节可卡因诱导的行为。我们发现GLP-1 R在LS中高度表达。在LS切片中，GLP-1显著增强DAT表面表达和DAT功能。艾塞那肽（Ex-4），GLP-1的一种长效合成类似物，可消除可卡因诱导的DA升高。有趣的是，Ex-4的急性给药降低了逆行信使2-花生四烯酸甘油（2-AG）以及其突触前降解产物花生四烯酸（AA）的隔表达。值得注意的是，AA减少隔DAT功能，这表明AA是中枢DA稳态的一种新型调节剂。我们进一步表明，AA氧化产物γ-酮醛（γ-KA）与DAT形成加合物，并降低DAT质膜表达和功能。这些结果支持突触后间隔GLP-1 R激活调节2-AG水平以通过AA改变突触前DA稳态和可卡因作用的机制。
Agonism of the glucagon-like peptide 1 (GLP-1) receptor (GLP-1R) has been effective at treating aspects of addictive behavior for a number of abused substances, including cocaine. However, the molecular mechanisms and brain circuits underlying the therapeutic effects of GLP-1R signaling on cocaine actions remain elusive. Recent evidence has revealed that endogenous signaling at the GLP-1R within the forebrain lateral septum (LS) acts to reduce cocaine-induced locomotion and cocaine conditioned place preference, both considered dopamine (DA)-associated behaviors. DA terminals project from the ventral tegmental area to the LS and express the DA transporter (DAT). Cocaine acts by altering DA bioavailability by targeting the DAT. Therefore, GLP-1R signaling might exert effects on DAT to account for its regulation of cocaine-induced behaviors. We show that the GLP-1R is highly expressed within the LS. GLP-1, in LS slices, significantly enhances DAT surface expression and DAT function. Exenatide (Ex-4), a long-lasting synthetic analog of GLP-1 abolished cocaine-induced elevation of DA. Interestingly, acute administration of Ex-4 reduces septal expression of the retrograde messenger 2-arachidonylglycerol (2-AG), as well as a product of its presynaptic degradation, arachidonic acid (AA). Notably, AA reduces septal DAT function pointing to AA as a novel regulator of central DA homeostasis. We further show that AA oxidation product γ-ketoaldehyde (γ-KA) forms adducts with the DAT and reduces DAT plasma membrane expression and function. These results support a mechanism in which postsynaptic septal GLP-1R activation regulates 2-AG levels to alter presynaptic DA homeostasis and cocaine actions through AA.
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影响因子：
25
作者：
Cremona, M. Laura;Matthies, Heinrich J. G.;Pau, Kelvin;Bowton, Erica;Speed, Nicole;Lute, Brandon J.;Anderson, Monique;Sen, Namita;Robertson, Sabrina D.;Vaughan, Roxanne A.;Rothman, James E.;Galli, Aurelio;Javitch, Jonathan A.;Yamamoto, Ai
通讯作者：
Yamamoto, Ai
影响因子：
14.8
作者：
Davies, Sean S.;Amarnath, Venkataraman;Roberts, L. Jackson, II
通讯作者：
Roberts, L. Jackson, II
影响因子：
4.8
作者：
Brame, CJ;Boutaud, O;Roberts, LJ
通讯作者：
Roberts, LJ
影响因子：
5.3
作者：
CILIAX, BJ;HEILMAN, C;LEVEY, AI
通讯作者：
LEVEY, AI
影响因子：
5.3
作者：
Egana, Loreto A.;Cuevas, Rolando A.;Torres, Gonzalo E.
通讯作者：
Torres, Gonzalo E.