Schindler C W, Gilman J P, Bergman J, Mello N K, Woosley R L, Goldberg S R
Preclinical Pharmacology Section, Behavioral Neuroscience Branch, National Institutes of Health/National Institute on Drug Abuse Intramural Research Program, Baltimore, Maryland 21224, USA.
J Pharmacol Exp Ther. 2002 Jan;300(1):180-7. doi: 10.1124/jpet.300.1.180.
Conscious squirrel monkeys were treated i.v. with cocaine and various dopamine agonist drugs. Cocaine produced a dose-dependent increase in blood pressure, heart rate, and the rate-pressure product (RPP). The dopamine D1 receptor agonist (+/-)-6-chloro-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide (SKF 82958) produced effects comparable to cocaine. The D1 agonist (+/-)-6-chloro-7, 8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide (SKF 81297) also produced increases in blood pressure and heart rate but was much less potent than either cocaine or SKF 82958. The partial D1 agonist (+/-)-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (SKF 77434) did not significantly affect any cardiovascular parameters. The D2 agonist quinpirole slightly decreased blood pressure and increased heart rate. As such, the RPP only slightly increased. The selective dopamine uptake inhibitor 1-[2-[bis-(4-fluorphenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine (GBR 12909) produced increases in blood pressure, heart rate, and RPP, but again these effects were smaller and only seen at doses higher than cocaine. Effects similar to those with GBR 12909 were seen with the dopamine autoreceptor antagonist cis-(+)-5-methoxy-1-methyl-2-(di-n-propylamino)tetralin (UH 232). The combination of GBR 12909, SKF 82958, or SKF 77434 with cocaine produced effects that were clearly subadditive. The effects of quinpirole in combination with cocaine were comparable to, or lower than, those of cocaine alone on blood pressure and RPP. The effects on heart rate were additive. Only UH 232 produced additive effects with cocaine for all three measures. As dopamine agonists have been proposed as potential treatments for cocaine abuse, these results suggest that dopamine D1 agonists and uptake inhibitors can be used safely in combination with cocaine. Caution may be warranted, however, with the use of dopamine autoreceptor antagonists in the treatment of cocaine abuse.
对清醒的松鼠猴进行静脉注射可卡因及多种多巴胺激动剂药物治疗。可卡因使血压、心率及速率 - 压力乘积（RPP）呈剂量依赖性增加。多巴胺D1受体激动剂（±）-6 - 氯 - 3 - 烯丙基 - 1 - 苯基 - 2,3,4,5 - 四氢 - 1H - 3 - 苯并氮杂卓氢溴酸盐（SKF 82958）产生的效果与可卡因相当。D1激动剂（±）-6 - 氯 - 7,8 - 二羟基 - 1 - 苯基 - 2,3,4,5 - 四氢 - 1H - 3 - 苯并氮杂卓氢溴酸盐（SKF 81297）也使血压和心率升高，但其效力远低于可卡因或SKF 82958。部分D1激动剂（±）-7,8 - 二羟基 - 3 - 烯丙基 - 1 - 苯基 - 2,3,4,5 - 四氢 - 1H - 3 - 苯并氮杂卓盐酸盐（SKF 77434）对任何心血管参数均无显著影响。D2激动剂喹吡罗使血压略有下降，心率升高。因此，RPP仅略有增加。选择性多巴胺摄取抑制剂1 - [2 - [双 - （4 - 氟苯基）甲氧基]乙基] - 4 - （3 - 苯基丙基）哌嗪（GBR 12909）使血压、心率及RPP升高，但同样这些作用较小，且仅在高于可卡因的剂量下才可见。多巴胺自身受体拮抗剂顺式 - （+）-5 - 甲氧基 - 1 - 甲基 - 2 - （二正丙基氨基）四氢萘（UH 232）产生了与GBR 12909类似的作用。GBR 12909、SKF 82958或SKF 77434与可卡因联合使用产生明显的亚相加效应。喹吡罗与可卡因联合使用对血压和RPP的作用与单独使用可卡因相当或更低。对心率的作用是相加的。只有UH 232在所有三项指标上与可卡因产生相加效应。由于多巴胺激动剂已被提议作为可卡因滥用的潜在治疗方法，这些结果表明多巴胺D1激动剂和摄取抑制剂可安全地与可卡因联合使用。然而，在可卡因滥用治疗中使用多巴胺自身受体拮抗剂时可能需要谨慎。
Zotero 插件