Locomotor and discriminative-stimulus effects of cocaine in dopamine D5 receptor knockout mice
Locomotor and discriminative-stimulus effects of cocaine in dopamine D5 receptor knockout mice
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DOI：
10.1007/s00213-003-1494-y
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发表时间：
2003-09-01
影响因子：
3.4
通讯作者：
Katz, JL
中科院分区：
文献类型：
--
作者：
Elliot, EE;Sibley, DR;Katz, JL
理由。多巴胺D-1样拮抗剂阻断可卡因的几种作用，包括其运动刺激和辨别刺激作用。由于这些化合物通常缺乏多巴胺D-1和D-5受体之间的选择性，亚型的具体作用尚未确定。目标.多巴胺D-5受体敲除（DA D5 R KO）、杂合（HET）和野生型（WT）小鼠用于研究D-5多巴胺受体在可卡因作用中的作用。此外，还研究了D-1样拮抗剂SCH 39166的作用，以进一步阐明D-1和D-5多巴胺受体在可卡因的辨别刺激效应中的作用。方法.用可卡因（3-30 mg/kg）或媒介物处理DA D5 R KO、HET和WT小鼠，并评估它们的水平运动活性。还训练小鼠使用双杠杆食物强化（FR 10）程序区分盐水与可卡因（10 mg/kg）的IP注射。在15分钟测试前5分钟给予可卡因剂量（1.0-10 mg/kg）。结果在每种基因型中，辅酶A剂量依赖性地刺激活性，在DA D5 R WT小鼠中诱导的活性水平最高。与WT小鼠相比，DA D5 R KO和HET小鼠均显示水平活动水平降低。所有三种基因型获得10毫克/公斤可卡因的歧视;剂量为1.0-10.0毫克/公斤可卡因适当的反应的数量产生剂量相关的增加。SCH 39166在非活性至完全活性剂量（0.01-0.1 mg/kg）下主要产生生理盐水适当反应。在所有基因型中，SCH 39166均使可卡因剂量效应曲线产生剂量依赖性偏移，具有相似的表观亲和力。结论.目前的数据表明，DA D5 R参与可卡因的运动刺激作用。此外，数据表明，有很少参与的DA D5 R在可卡因的歧视性刺激作用。此外，拮抗数据表明D-1受体在可卡因的行为效应中的作用。
Rationale. Dopamine D-1-like antagonists block several effects of cocaine, including its locomotor-stimulant and discriminative-stimulus effects. Because these compounds generally lack selectivity among the dopamine D-1 and D-5 receptors, the specific roles of the subtypes have not been determined. Objectives. Dopamine D-5 receptor knockout (DA D5R KO), heterozygous (HET) and wild-type (WT) mice were used to study the role of D-5 dopamine receptors in the effects of cocaine. In addition, effects of the D-1-like antagonist, SCH 39166 were also studied to further clarify the roles of D-1 and D-5 dopamine receptors in the discriminative-stimulus effects of cocaine. Methods. DA D5R KO, HET and WT mice were treated with cocaine (3-30 mg/kg) or vehicle and their horizontal locomotor activity was assessed. The mice were also trained to discriminate IP injections of saline from cocaine (10 mg/kg) using a two-lever food-reinforcement (FR10) procedure. Doses of cocaine (1.0-10 mg/kg) were administered 5 min before 15-min test-sessions. Results. Cocaine dose-dependently stimulated activity in each genotype, with the highest level of activity induced in the DA D5R WT mice. Both DA D5R KO and HET mice showed reduced levels of horizontal activity compared to WT mice. All three genotypes acquired the discrimination of 10 mg/kg cocaine; doses of 1.0-10.0 mg/kg produced dose-related increases in the number of cocaine-appropriate responses. SCH 39166, at inactive to fully active doses (0.01-0.1 mg/kg) produced predominately saline-appropriate responding. SCH 39166 produced a dose-dependent rightward shift in the cocaine dose-effect curve in all genotypes, with similar apparent affinities. Conclusions. The present data suggest an involvement of DA D5R in the locomotor stimulant effects of cocaine. In addition, the data indicate that there is little involvement of the DA D5R in the discriminative-stimulus effects of cocaine. In addition, the antagonism data suggest a role of the D-1 receptor in the behavioral effects of cocaine.