Harvard Medical School, New England Primate Research Center, One Pine Hill Dr., Box 9102, Southborough, MA 01772-9102, USA.
J Pharmacol Exp Ther. 2010 Mar;332(3):985-95. doi: 10.1124/jpet.109.162941. Epub 2009 Dec 4.
Many polydrug abusers combine cocaine with heroin in the form of a "speedball." This study investigated the discriminative stimulus (DS) effects of speedballs in rhesus monkeys trained to discriminate either intravenous cocaine or intravenous heroin from vehicle. Initial substitution tests revealed an asymmetry in the generalization profile of dopamine and opioid agonists such that mu agonists partially substituted for cocaine, but direct and indirect dopamine agonists did not substitute for heroin. Subsequent speedball tests in which drug mixtures were administered by coinjecting the component drugs while keeping the dose-ratio constant revealed an additional asymmetry. In cocaine-trained monkeys, coadministration of cocaine and heroin produced leftward shifts in the cocaine dose-response function. Heroin's cocaine-enhancing effects were mimicked by the mu agonists fentanyl and methadone and less consistently by the delta agonist (+)-4-[(alphaR)-alpha-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide (SNC 80) and reversed by the mu antagonist naltrexone and the delta antagonist naltrindole. In heroin-trained monkeys, coadministration of cocaine and heroin attenuated the DS effects of heroin. Cocaine's heroin-attenuating effects were mimicked by the D1-like agonist 6-chloro-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine (SKF 81297) and the D2-like agonist R-(-)-propylnorapomorphine and reversed by the D1-like antagonist (6aS-trans)-11-chloro-6,6a,7,8,9,13b-hexahydro-7-methyl-5H- benzo[d] aphtha[2,1-b]azepin-12-ol hydrobromide (SCH 39166) and the D2-like antagonist raclopride. Attenuation of the effects of heroin was accompanied by decreases in response rate. These results suggest that heroin enhances the DS effects of cocaine via mu, and to a lesser extent delta, receptor mechanisms; whereas cocaine-induced inhibition of the DS effects of heroin probably was due at least in part to masking of the heroin DS presumably via stimulation of both D1- and D2-like receptors.
许多药物滥用者将可卡因与海洛因混合在一起形成“快球”。本研究调查了接受训练以辨别静脉内可卡因或静脉内海洛因与载体的恒河猴的辨别刺激（DS）效应。初步替代测试显示，多巴胺和阿片类激动剂的概括特征存在不对称，即μ激动剂部分替代可卡因，但直接和间接多巴胺激动剂不能替代海洛因。随后进行的快球测试中，通过同时注射组合药物而保持剂量比不变来给药药物混合物，结果显示出另一种不对称性。在接受可卡因训练的猴子中，可卡因和海洛因的共同给药导致可卡因剂量反应函数向左移位。μ激动剂芬太尼和美沙酮以及δ激动剂（+）-4-[(alphaR)-alpha-（（2S，5R）-4-丙烯基-2,5-二甲基-1-哌嗪基）-3-甲氧基苄基]-N，N-二乙基苯甲酰胺（SNC 80）模拟了海洛因的可卡因增强作用，而δ拮抗剂纳曲酮和纳曲吲哚则逆转了这种作用。在接受海洛因训练的猴子中，可卡因和海洛因的共同给药减弱了海洛因的 DS 效应。D1 样激动剂 6-氯-7,8-二羟基-1-苯基-2,3,4,5-四氢-（1H）-3-苯并氮杂卓（SKF 81297）和 D2 样激动剂 R-（-）-丙基诺拉吗啡模拟了可卡因的海洛因减弱作用，而 D1 样拮抗剂（6aS-trans）-11-氯-6,6a,7,8,9,13b-六氢-7-甲基-5H-苯并[d]aphtha[2,1-b]azepin-12-ol 氢溴化物（SCH 39166）和 D2 样拮抗剂雷氯必利则逆转了这种作用。海洛因作用的减弱伴随着反应率的降低。这些结果表明，海洛因通过μ受体机制，在较小程度上通过δ受体机制增强可卡因的 DS 效应；而可卡因引起的海洛因 DS 效应抑制可能至少部分归因于通过刺激 D1 和 D2 样受体对海洛因 DS 的掩蔽。
