REDUCTION OF COCAINE SELF ADMINISTRATION BY DOPAMINE D1 AGONISTS

多巴胺D1激动剂和部分激动剂具有药理学作用， 与可卡因的潜在治疗效用一致的性质 本研究评估了D1完全激动剂的作用， (SKF 82958，SKF 81297）和部分激动剂（SKF 83959，SKF 77434，SKF 38393）对静脉内可卡因自我给药的影响 接受了自我注射可卡因的训练， 最初，全范围剂量的药物注射的效果是显著的。 在每名受试者中测定自我施用的可卡因 随后，D1受体激动剂每日治疗的效果是 根据自我施用的可卡因剂量确定， 所有D1激动剂，无论疗效如何， 以剂量相关方式抑制可卡因自我给药， 导致应答率和注射量显著降低 频率每日治疗有效剂量的D1部分 激动剂SKF 83959和SKF 77434的含量 可卡因剂量-反应函数导致总体上的降低， 与此相反，每天用 D1完全激动剂SKF 82958和SKF 81297产生了 仅在观察性研究中，SKF 83959和SKF 77434 导致总体活性沿着剂量相关性降低， 增加物种典型的睡眠姿势，但没有诱导 剂量超过所需剂量的10-33倍时出现僵住或共济失调 抑制可卡因自我给药只有很小的活动变化 使用SKF 82958和SKF 81297观察到的水平结果显示 D1完全和部分激动剂在降低 可卡因的猴子自我管理，但可以区分 他们的能力的基础，以改变形状和位置的 可卡因剂量反应函数与镇静剂样副作用发生率 这些结果表明，D1激动剂是可行的候选药物， 作为可卡因成瘾的药物疗法进行进一步评价 出版物Platt DM，Rowlett JK and Spealman RD Suppression of D1部分激动剂可卡因自我给药 24：2135，1998

Dopamine D1 agonists and partial agonists have pharmacological properties consistent with potential therapeutic utility in cocaine addiction The present study assessed the effects of D1 full agonists (SKF 82958, SKF 81297) and partial agonists (SKF 83959, SKF 77434, SKF 38393) on intravenous cocaine self-administration Squirrel monkeys were trained to self-administer cocaine on a second-order schedule of i v drug injection Initially, the effects of a full range of doses of self-administered cocaine were determined in each subject Subsequently, the effects of daily treatment with D1 agonists were determined on self-administration of doses of cocaine that maintained maximum rates of responding All D1 agonists, regardless of efficacy, suppressed cocaine self-administration in a dose-related manner, resulting in marked reductions in both response rate and injection frequency Daily treatment with effective doses of the D1 partial agonists SKF 83959 and SKF 7 7434 durin g re-determinations of the cocaine dose-response functions resulted in overall rightward and downward shifts of the functions In contrast, daily treatment with the D1 full agonists SKF 82958 and SKF 81297 produced downward shifts of the functions only In observational studies, SKF 83959 and SKF 77434 produced dose-related decreases in overall activity along with increases in species-typical sleep postures, but did not induce catalepsy or ataxia at doses 10-33 times greater than those required to suppress cocaine self-administration Only small changes in activity levels were observed with SKF 82958 and SKF 81297 The results show that D1 full and partial agonists are similarly effective in reducing self-administration of cocaine in monkeys, but can be distinguished on the basis of their capacity to alter the shape and position of the cocaine dose-response function and the incidence of sedative-like side effects These results suggest that D1 agonists are viable candidates for fu rther evaluation as pharmacotherapies for cocaine addiction PUBLICATIONS Platt DM, Rowlett JK and Spealman RD Suppression of cocaine self-administration by D1 partial agonists Soc Neurosci Abstr 24:2135, 1998