Lack of self-administration of cocaine in dopamine D1 receptor knock-out mice
Lack of self-administration of cocaine in dopamine D1 receptor knock-out mice
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DOI：
10.1523/jneurosci.2284-07.2007
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发表时间：
2007-11-28
影响因子：
5.3
通讯作者：
Xu, Ming
中科院分区：
文献类型：
--
作者：
Caine, S. Barak;Thomsen, Morgane;Xu, Ming
有证据表明，多巴胺在可卡因对大鼠和灵长类动物的强化作用中起着关键作用。然而，在小鼠物种中很少研究自我给药，并且迄今为止，还没有报道小鼠中个体多巴胺相关基因的“敲除”会降低可卡因的强化作用。我们研究了多巴胺D-1受体和可卡因自我管理的小鼠使用基因靶向突变和药理学工具的组合。对具有不同育种和实验历史的两个组群进行了测试，在两个组群中，相对于野生型小鼠（32只中的27只），满足可卡因自我给药获得标准的D-1受体敲除小鼠（23只中的2只）的数量显著减少.在用盐水自我给药的反应消失后，剂量-反应研究表明，在所有野生型小鼠中可卡因可靠地和剂量依赖性地保持比盐水更大的反应，但在D-1受体敲除小鼠中没有一只. D-1-样激动剂SKF 82958（2，3，4，5，-tetrahydro-6-chloro-7，8-dihydroxy- 1-phenyl-1H-3-benzazepine hydrobromide）和D-2-样激动剂quinelorane在野生型小鼠中均起阳性抑制剂作用，但在D-1受体突变小鼠中不起作用，而食物和静脉注射阿片类激动剂remifentanil在两种基因型中均起阳性抑制剂作用。最后，用D-1样拮抗剂SCH 23390 [R-（+）-8-氯-2，3，4，5-四氢-3-甲基-5-苯基-1H-3-苯并氮杂卓-7 - 01]预处理，在常用菌株C57 BL/6 J中产生了对可卡因增强作用的可克服的拮抗作用。我们的结论是，D-1受体敲除小鼠不能可靠地自我施用可卡因，并且D-1受体对小鼠中可卡因和其他多巴胺激动剂的增强作用至关重要，但不是食物或阿片类药物。
Evidence suggests a critical role for dopamine in the reinforcing effects of cocaine in rats and primates. However, self- administration has been less often studied in the mouse species, and, to date, "knock-out" of individual dopamine- related genes in mice has not been reported to reduce the reinforcing effects of cocaine. We studied the dopamine D-1 receptor and cocaine self-administration in mice using a combination of gene- targeted mutation and pharmacological tools. Two cohorts with varied breeding and experimental histories were tested, and, in both cohorts, there was a significant decrease in the number of D-1 receptor knock- out mice that met criteria for acquisition of cocaine self- administration ( 2 of 23) relative to wild- type mice ( 27 of 32). After extinction of responding with saline self-administration, dose - response studies showed that cocaine reliably and dose dependently maintained responding greater than saline in all wild- type mice but in none of the D-1 receptor knock- out mice. The D-1-like agonist SKF 82958 (2,3,4,5,-tetrahydro-6-chloro-7,8-dihydroxy- 1-phenyl-1H-3-benzazepine hydrobromide) and the D-2-like agonist quinelorane both functioned as positive reinforcers in wild-type mice but not in D-1 receptor mutant mice, whereas food and intravenous injections of the opioid agonist remifentanil functioned as positive reinforcers in both genotypes. Finally, pretreatment with the D-1- like antagonist SCH 23390 [R-(+)-8-chloro-2,3,4,5-tetrahydro- 3-methyl-5-phenyl-1H-3-benzazepine-7- 01] produced surmountable antagonism of the reinforcing effects of cocaine in the commonly used strain C57BL/ 6J. We conclude that D-1 receptor knock- out mice do not reliably self- administer cocaine and that the D-1 receptor is critical for the reinforcing effects of cocaine and other dopamine agonists, but not food or opioids, in mice.