Zolpidem generalization and antagonism in male and female cynomolgus monkeys trained to discriminate 1.0 or 2.0 g/kg ethanol.
Zolpidem generalization and antagonism in male and female cynomolgus monkeys trained to discriminate 1.0 or 2.0 g/kg ethanol.
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DOI：
10.1111/j.1530-0277.2008.00674.x
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发表时间：
2008-07
期刊：
影响因子：
--
通讯作者：
Grant KA
中科院分区：
文献类型：
--
作者：
Helms CM;Rogers LS;Waters CA;Grant KA
γ-氨基丁酸A受体亚型在非人类灵长类动物中介导乙醇的区别性刺激作用的亚型尚未完全确定。GABAA受体阳性调节剂唑吡坦分别在含有α1、α2/3和α5亚基的受体上具有高、中和低活性，并在一些物种中部分地从乙醇中泛化出来。部分反向激动剂Ro15-4513对含α4/6受体的亲和力最强，对α5-的亲和力较高，对含有GABA受体的α1-和α2/3-的亲和力较低，但相当，可拮抗乙醇的区别性刺激效应。本研究评估了Ro15-4513在雄性(n=9)和雌性(n=8)食蟹猴(n=8)上对乙醇中唑吡坦泛化的拮抗作用。从30分钟的预处理间隔的水中提取。唑吡坦(0.017~5.6mgkg，肌肉注射)对于6/7只训练为辨别2.0g/kg乙醇的猴子和4/10训练为辨别1.0g/kg乙醇的猴子，完全从乙醇中泛化(≥80%的总会话反应在适当的乙醇水平上)。唑吡坦从1.0或2.0g/kg乙醇中部分推广到6/7剩余猴子。Ro15-4513(0.003~0.3 mg/kg，肌肉注射，预先给药5分钟)使所有猴子的唑吡坦剂量-反应曲线右移。拮抗试验对表观PKB的分析表明，乙醇与唑吡坦共同的区别性刺激效应是由低亲和力的Ro15-4513结合位点介导的。性别和训练剂量的主要效应表明，Ro15-4513在雄性和训练为辨别1.0g/kg乙醇的猴子中具有更高的效力。乙醇和唑吡坦具有相似的区别性刺激效应，很可能是通过含有α1亚单位的GABA受体实现的，然而，Ro15-4513拮抗训练剂量较低的乙醇(1.0g/kg)对唑吡坦的泛化可能涉及对唑吡坦敏感的GABA受体亚型(如α2/3和α5)。
The subtypes of γ-aminobutyric acid (GABA)A receptors mediating the discriminative stimulus effects of ethanol in nonhuman primates are not completely identified. The GABAA receptor positive modulator zolpidem has high, intermediate, and low activity at receptors containing α1, α2/3, and α5 subunits, respectively, and partially generalizes from ethanol in several species. The partial inverse agonist Ro15-4513 has the greatest affinity for α4/6-containing receptors, higher affinity for α5- and lower, but equal, affinity for α1- and α2/3-, containing GABAA receptors, and antagonizes the discriminative stimulus effects of ethanol. This study assessed Ro15-4513 antagonism of the generalization of zolpidem from ethanol in male (n = 9) and female (n = 8) cynomolgus monkeys (Macaca fascicularis) trained to discriminate 1.0 g/kg (n = 10) or 2.0 g/kg (n = 7) ethanol (i.g.) from water with a 30-minute pretreatment interval. Zolpidem (0.017 to 5.6 mg/kg, i.m.) completely generalized from ethanol (≥80% of total session responses on the ethanol-appropriate lever) for 6/7 monkeys trained to discriminate 2.0 g/kg and 4/10 monkeys trained to discriminate 1.0 g/kg ethanol. Zolpidem partially generalized from 1.0 or 2.0 g/kg ethanol in 6/7 remaining monkeys. Ro15-4513 (0.003 to 0.30 mg/kg, i.m., 5-minute pretreatment) shifted the zolpidem dose-response curve to the right in all monkeys showing generalization. Analysis of apparent pKB from antagonism tests suggested that the discriminative stimulus effects of ethanol common with zolpidem are mediated by low-affinity Ro15-4513 binding sites. Main effects of sex and training dose indicated greater potency of Ro15-4513 in males and in monkeys trained to discriminate 1.0 g/kg ethanol. Ethanol and zolpidem share similar discriminative stimulus effects most likely through GABAA receptors that contain α1 subunits, however, antagonism by Ro15-4513 of zolpidem generalization from the lower training dose of ethanol (1.0 g/kg) may involve additional zolpidem-sensitive GABAA receptor subtypes (e.g., α2/3 and α5).
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影响因子：
6.1
作者：
HOFFMAN, PL;TABAKOFF, B;PAUL, SM
通讯作者：
PAUL, SM
DOI：
10.1177/1534582303262095
发表时间：
2003-12-01
期刊：
Behavioral and cognitive neuroscience reviews
影响因子：
--
作者：
Kelly, Thomas H;Stoops, William W;Rush, Craig R
通讯作者：
Rush, Craig R
影响因子：
3.4
作者：
Grant, KA;Azarov, A;Purdy, RH
通讯作者：
Purdy, RH
影响因子：
3.6
作者：
Green, KL;Azarov, AV;Grant, KA
通讯作者：
Grant, KA
DOI：
10.1073/pnas.0509903103
发表时间：
2006-05-30
影响因子：
11.1
作者：
Hanchar, H. Jacob;Chutsrinopkun, Panida;Olsen, Richard W.
通讯作者：
Olsen, Richard W.