BEHAVIORAL PHARMACOLOGY OF DOPAMINE SYSTEMS

多巴胺系统的行为药理学

• 批准号: 3838610
• 负责人: J L KATZ
• 金额: --
• 依托单位: NATIONAL INSTITUTE ON DRUG ABUSE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3838610
• 关键词: Primates; cocaine; dopamine; dopamine receptor; drug abuse; haloperidol; inhibitor /antagonist; laboratory rat; nucleus accumbens; psychopharmacology; stereochemistry; stimulant /agonist

Studies have been conducted to better document the behavioral pharmacology of drugs acting on dopaminergic systems. These studies have concentrated on the antagonism of dopamine-receptor subtype specific agonists with antagonists. These studies indicate that: (1) the D2 antagonist, sulpiride, is an effective antagonist of the behavioral effects of the D2 agonist, quinpirole in primates; (2) the D2 antagonist, haloperidol was no better antagonist of quinpirole than was a D1 antagonist. These results suggest important differences between antagonist effectiveness. (3) the Dl agonist, SKF 38393, is not well antagonized by Dl antagonists, whereas other Dl agonists are. These results indicate that much of the behavioral effects often attributed to Dl agonist activity of SKF 38393 are likely a result of activation of other mechanisms. (4) D2 agonists produce a unique scratching behavior in primates. This effect of these agonists is pharmacologically specific (drugs acting by other mechanisms do not produce this effect), there is stereospecificity (the active enantiomers of D2 agonists have the activity, whereas their racemates do not) it is antagonized by D2 antagonists but not Dl antagonists, and that antagonism shows stereospecificity. This behavior will be useful in documenting the D2 agonist activity of novel compounds. In addition, it may be used to characterize the D2 agonist sensitivity of primates with various exposures to cocaine, or those that may be acutely sensitive to the effects of drugs of abuse. The pharmacology of drugs binding irreversibly to the dopamine transporter has been pursued. One compound, para-isothiocyanato-benzyolecgonine methyl ester (para-isococaine), has been administered into the nucleus accumbens in rats and specifically antagonized the behavioral effects of cocaine 24 hours after this treatment. Several studies have indicated that this effect, at high doses, is due to non-specific neurotoxic actions. We are currently in the process of documenting the effects of lower non-toxic doses of para-isococaine.

进行了研究以更好地记录行为 作用于多巴胺能系统的药物。 这些研究有 集中于多巴胺受体亚型的拮抗作用 与对手的激动剂。 这些研究表明：（1）D2 拮抗剂，苏尔皮里德（Sulpiride）是行为的有效拮抗剂 D2激动剂，灵长类动物中的奎因螺菌素的影响； （2）D2拮抗剂， 氟哌啶醇与d1的拮抗剂没有比D1更好的拮抗剂 对手。 这些结果表明 对手的有效性。 （3）DL激动剂，SKF 38393，不好 由DL拮抗剂拮抗，而其他DL激动剂则是。 这些 结果表明，许多行为影响通常归因于 SKF 38393的DL激动剂活性可能是由于激活的结果 其他机制。 （4）D2激动剂在 灵长类动物。 这些激动剂的这种影响是药理学特定的 （通过其他机制作用的药物不会产生这种影响） 立体特定（D2激动剂的活跃对映异构体具有 活动，而他们的种族没有）被D2拮抗 拮抗剂，但没有DL拮抗剂，而拮抗作用显示 立体特定。 这种行为对于记录D2很有用 新颖化合物的激动剂活性。 另外，它可以用来 表征具有各种灵长类动物的D2激动剂灵敏度 暴露于可卡因，或可能对可卡因敏感的 滥用药物的影响。 药物的药理学与多巴胺不可逆地结合 运输者已被追捕。 一个化合物， para-isothiocyanato-benzyolecgonine甲基酯（para-异卡因），具有 被施用到大鼠中的伏隔核中 在此之后24小时拮抗可卡因的行为影响 治疗。 几项研究表明，这种影响在很高 剂量是由于非特异性神经毒性作用。 我们目前正在 记录较低无毒剂量的影响的过程 para-异卡因卡因。