mGluR1 within the nucleus accumbens regulates alcohol intake in mice under limited-access conditions.
mGluR1 within the nucleus accumbens regulates alcohol intake in mice under limited-access conditions.
复制标题
DOI：
10.1016/j.neuropharm.2014.01.024
复制
发表时间：
2014-04
影响因子：
4.7
通讯作者：
Szumlinski KK
中科院分区：
文献类型：
--
作者：
Lum EN;Campbell RR;Rostock C;Szumlinski KK
特发性或酒精诱导的杏仁核延伸区域内第1组代谢型谷氨酸受体1亚型（mGluR1）表达和功能的增加，被认为会导致个体过度饮酒的倾向。过去，由于现有抑制剂溶解性差且有非特异性副作用，对动物模型中mGluR1与酗酒相关行为的功能相关性的详细研究受到阻碍；然而，高效且可溶的mGluR1负变构调节剂JNJ - 16259685[（3,4 - 二氢 - 2H - 吡喃[2,3 - b]喹啉 - 7 - 基） - （顺 - 4 - 甲氧基环己基） - 甲酮]的出现，促使人们重新审视这种mGluR亚型在介导酒精行为效应中的作用。在这方面，已证明用JNJ - 16259685进行全身性预处理可有效降低酒精强化作用和对酒精的渴望。mGluR1是一种Gαq/o偶联受体，其受刺激会激活磷脂酶C（PLC）。因此，本研究调查了与JNJ - 16259685降低酒精摄入能力相关的潜在神经解剖学底物和细胞内分子。将JNJ - 16259685（0 - 30皮克/侧）单独或与PLC抑制剂U - 73122（5.8飞克/侧）联合注入C57BL/6J和Homer2基因敲除（KO）小鼠的伏隔核壳区。然后在黑暗饮酒（DID）程序下评估酒精摄入量。伏隔核内注射JNJ - 16259685可剂量依赖性地减少C57BL/6J小鼠的酒精摄入量；这种效应与U - 73122产生的效应没有叠加性，在Homer2基因敲除动物中也不存在。这些数据提供了新的证据，支持在伏隔核壳区内由Homer2支撑的mGluR1 - PLC信号传导在有限获取程序下维持酒精摄入方面的关键作用。这些发现与危险饮酒和酗酒的药物治疗学及药物遗传学都相关。
Idiopathic or alcohol-induced increases in the expression and function of the Group1 metabotropic glutamate receptor subtype 1 (mGluR1) within the extended amygdala are theorized to contribute to an individual’s propensity to consume excessive amounts of alcohol. In the past, the detailed study of the functional relevance of mGluR1 for alcoholism-related behaviors in animal models was hampered by the poor solubility and non-specific side effects of available inhibitors; however, the advent of the highly potent and soluble mGluR1 negative allosteric modulator JNJ-16259685 [(3,4-Dihydro-2H-pyrano[2,3-b]quinolin-7-yl)-(cis-4-methoxycyclohexyl)-methanone] has instigated a re-examination of the role for this mGluR subtype in mediating the behavioral effects of alcohol. In this regard, systemic pretreatment with JNJ-16259685 was proven effective at reducing alcohol reinforcement and motivation for the drug. mGluR1 is a Gαq/o-coupled receptor, the stimulation of which activates phospholipase C (PLC). Thus, the present study investigated potential neuroanatomical substrates and intracellular molecules involved in the ability of JNJ-16259685 to reduce alcohol intake. JNJ-16259685 (0–30 pg/side) was infused into the shell subregion of the nucleus accumbens (NAC) of C57BL/6J and Homer2 knock-out (KO) mice, either alone or in combination with the PLC inhibitor U-73122 (5.8 fg/side). Alcohol intake was then assessed under Drinking-in-the-Dark (DID) procedures. Intra-NAC JNJ-16259685 infusion dose-dependently reduced alcohol consumption by C57BL/6J mice; this effect was not additive with that produced by U-73122, nor was it present in Homer2 KO animals. These data provide novel evidence in support of a critical role for mGluR1-PLC signaling, scaffolded by Homer2, within the NAC shell, in maintaining alcohol consumption under limited access procedures. Such findings have relevance for both the pharmacotherapeutics and pharmacogenetics of risky alcohol drinking and alcoholism.
登录
查看更多内容
DOI：
10.1111/j.1601-183x.2010.00647.x
发表时间：
2011-02
期刊：
Genes, brain, and behavior
影响因子：
--
作者：
Goulding SP;Obara I;Lominac KD;Gould AT;Miller BW;Klugmann M;Szumlinski KK
通讯作者：
Szumlinski KK
DOI：
10.1146/annurev.pharmtox.011008.145533
发表时间：
2010
影响因子：
12.5
作者：
Niswender CM;Conn PJ
通讯作者：
Conn PJ
影响因子：
3.4
作者：
Gass, Justin T.;Olive, M. Foster
通讯作者：
Olive, M. Foster
影响因子：
64.8
作者：
Ango, F;Prézeau, L;Fagni, L
通讯作者：
Fagni, L
对两项全基因组关联研究的荟萃分析，以鉴定最大含酒精饮料的新基因座。
影响因子：
5.3
作者：
Kapoor, Manav;Wang, Jen-Chyong;Wetherill, Leah;Le, Nhung;Bertelsen, Sarah;Hinrichs, Anthony L.;Budde, John;Agrawal, Arpana;Bucholz, Kathleen;Dick, Danielle;Harari, Oscar;Hesselbrock, Victor;Kramer, John;Nurnberger, John I., Jr.;Rice, John;Saccone, Nancy;Schuckit, Marc;Tischfield, Jay;Porjesz, Bernice;Edenberg, Howard J.;Bierut, Laura;Foroud, Tatiana;Goate, Alison
通讯作者：
Goate, Alison