COCAINE ANTAGONIST PROPERTIES OF D1 PARTIAL AGONIST SKF 83959: SQUIRREL MONKEYS

临床前研究表明，多巴胺部分激动剂 考虑作为可卡因滥用的候选药物。这个 苯扎西平衍生物SKF 83959是一种d1部分激动剂，具有 激动剂和拮抗剂性质的独特特征。这个 目前的研究评估了行为的潜在拮抗作用 可卡因对SKF 83959的影响。松鼠猴子也接受了训练 按固定时间间隔(FI)的刺激-电击时间表作出反应 使用两个杠杆终止或区分可卡因和生理盐水 毒品歧视程序。当与可卡因结合时(0.03- 10.0 mg/kg)，SKF 83959(0.10-1.0 mg/kg)可使小鼠 可卡因对固定间期反应和诱发电位的增频效应 可卡因的辨别刺激(DS)效应，导致 剂量效应函数随剂量的增加而右移。这些 其作用与先前报道的d1受体拮抗剂相似。 SCH 39166，但不是D1全激动剂SKF 82958。在没有的情况下 可卡因，SKF 83959既没有模仿可卡因的DS效应，也没有 提高了FI响应率。在观察性研究中，瑞典克朗83959(0.10 -1 mg/kg)和SCH 39166(0.01-0.3 mg/kg)产生剂量相关 运动能力、环境操控能力和自我导向能力下降 行为(梳理、抓挠)随着频率的增加而增加 物种--典型的睡眠姿势。尽管SCH 39166包括 在测试的最高剂量(0.30毫克/公斤)下出现过敏症和共济失调，这些 SKF 83959(1 mg/kg)对小鼠无明显影响。这些结果 提示SKF 83959具有功能性可卡因的特性 主要有镇静剂样副作用的拮抗剂。

Preclinical studies suggest that dopamine partial agonists warrant consideration as candidate medications for cocaine abuse. The benzazepine derivative SKF 83959 is a D1 partial agonist with a distinctive profile of agonist-like and antagonist properties. The present study assessed the potential antagonism of the behavioral effects of cocaine by SKF 83959. Squirrel monkeys were trained either to respond on a fixed-interval (FI) schedule of stimulus-shock termination or to discriminate cocaine from saline using a two-lever drug discrimination procedure. When combined with cocaine (0.03 - 10.0 mg/kg), SKF 83959 (0.10 - 1.0 mg/kg) attenuated both the rate-increasing effects of cocaine on fixed-interval responding and the discriminative stimulus (DS) effects of cocaine, resulting in dose-dependent rightward shifts in the dose-response functions. These effects are similar to those reported previously for the D1 antagonist SCH 39166, but not the D1 full agonist SKF 82958. In the absence of cocaine, SKF 83959 neither mimicked the DS effects of cocaine nor increased FI response rate. In observational studies, SKF 83959 (0.10 - 1.0 mg/kg) and SCH 39166 (0.01 - 0.30 mg/kg) produced dose-related decreases in locomotion, environmental manipulation, and self-directed behaviors (grooming, scratching) along with increases in the frequency of species-typical sleep postures. Although SCH 39166 included catalepsy and ataxia at the highest dose tested (0.30 mg/kg), these effects were not observed with SKF 83959 (1.0 mg/kg). These results suggest that SKF 83959 has properties of a functional cocaine antagonist with primarily sedative-like side effects.