Pharmacokinetic correlates of the effects of a heroin vaccine on heroin self-administration in rats.
Pharmacokinetic correlates of the effects of a heroin vaccine on heroin self-administration in rats.
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DOI：
10.1371/journal.pone.0115696
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
LeSage MG
中科院分区：
文献类型：
--
作者：
Raleigh MD;Pentel PR;LeSage MG
本研究的目的是评价吗啡结合疫苗（M-KLH）对大鼠海洛因自我给药（HSA）的获得、维持和恢复的影响，以及对海洛因给药期间海洛因和代谢物分布的影响，其近似于自我给药的剂量率。M-KLH疫苗接种阻断了海洛因引发的海洛因反应的恢复。接种疫苗也降低了低剂量海洛因的HSA，但产生了补偿性增加海洛因自我管理在高单位剂量。疫苗接种使海洛因剂量-反应曲线右移，表明海洛因效力降低，行为经济需求曲线分析进一步证实了这一效应。在一个单独的实验中，以模拟HSA期间海洛因暴露的速率给予海洛因。海洛因及其活性代谢物，6-乙酰吗啡（6-AM）和吗啡，保留在血浆中，代谢物浓度降低，在接种疫苗的大鼠与对照组相比，在大脑中。疫苗接种后大脑中6-AM浓度的降低与疫苗接种后HSA率的变化一致。这些数据提供的证据表明，在这个模型中，6-AM是海洛因强化的主要介质，也是M-KLH疫苗的主要靶点。虽然海洛因疫苗可能具有治疗海洛因成瘾的潜力，但高抗体与药物的比例似乎对获得最大疗效很重要。
The purpose of this study was to evaluate the effects of a morphine-conjugate vaccine (M-KLH) on the acquisition, maintenance, and reinstatement of heroin self-administration (HSA) in rats, and on heroin and metabolite distribution during heroin administration that approximated the self-administered dosing rate. Vaccination with M-KLH blocked heroin-primed reinstatement of heroin responding. Vaccination also decreased HSA at low heroin unit doses but produced a compensatory increase in heroin self-administration at high unit doses. Vaccination shifted the heroin dose-response curve to the right, indicating reduced heroin potency, and behavioral economic demand curve analysis further confirmed this effect. In a separate experiment heroin was administered at rates simulating heroin exposure during HSA. Heroin and its active metabolites, 6-acetylmorphine (6-AM) and morphine, were retained in plasma and metabolite concentrations were reduced in brain in vaccinated rats compared to controls. Reductions in 6-AM concentrations in brain after vaccination were consistent with the changes in HSA rates accompanying vaccination. These data provide evidence that 6-AM is the principal mediator of heroin reinforcement, and the principal target of the M-KLH vaccine, in this model. While heroin vaccines may have potential as therapies for heroin addiction, high antibody to drug ratios appear to be important for obtaining maximal efficacy.
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影响因子：
3.6
作者：
Grebenstein, Patricia;Burroughs, Danielle;Zhang, Yan;LeSage, Mark G.
通讯作者：
LeSage, Mark G.
影响因子：
2.7
作者：
Hursh, Steven R.;Roma, Peter G.
通讯作者：
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DOI：
10.1016/j.jpba.2012.10.033
发表时间：
2013-02-23
影响因子：
3.4
作者：
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通讯作者：
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影响因子：
6.7
作者：
Girardin, F;Rentsch, KM;Fattinger, K
通讯作者：
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影响因子：
64.8
作者：
BONESE, KF;WAINER, BH;SCHUSTER, CR
通讯作者：
SCHUSTER, CR