An ACE Inhibitor as a Treatment for Methamphetamine Dependence

描述（由申请人提供）：血管紧张素II以其调节体液和电解质稳态的作用而闻名。此外，现在已知该系统在调节下丘脑-垂体-肾上腺轴和交感神经系统中起关键作用。由于这些系统在成瘾中起着关键作用，血管紧张素II也可能在成瘾中起着关键作用。事实上，血管紧张素II最近已被证明可以增强大鼠的乙醇自我给药。然而，到目前为止，还没有发表的研究评估影响血管紧张素II的药物对其他滥用药物（如甲基苯丙胺）相关行为的影响。在NIDA（R21 DA 17182）的资助下，我们进行了一项双盲、安慰剂对照研究，以评估培哚普利治疗对30名MA依赖性人类志愿者的MA主观和心血管效应的影响。培哚普利是一种血管紧张素转换酶抑制剂，可抑制血管紧张素II从其无活性前体合成。培哚普利治疗与MA给药后“任何药物效应”和“欲望"或渴望评分的统计学显著降低相关。药物引起的渴望是一个明显的治疗目标，因为在对MA和可卡因使用者的研究中，更高水平的渴望已被证明与药物使用概率的大幅增加有关。在本申请中，我们建议检查培哚普利治疗对非寻求治疗的志愿者中MA实验性给药产生的渴望的影响。然后，我们建议在为期6周的门诊临床试验中检查培哚普利治疗对这些相同参与者使用MA的影响。应急管理程序将用于加强门诊出勤率和减少MA使用，手动驱动的行为依从性增强和动机访谈技术将用于增加药物依从性和增强减少MA使用的内在动机。一项单独的人体实验室研究将检查培哚普利（8 mg和16 mg，与安慰剂相比）对MA诱导的渴望的剂量依赖性效应，尽管这些参与者不会参加临床试验。初步数据表明，培哚普利，血管紧张素转换酶抑制剂，与减少甲基苯丙胺诱导的渴望。因此，我们建议在一项大型人体实验室研究中检查培哚普利治疗（4 mg）对甲基苯丙胺诱导的渴求的影响，该研究仅招募在实验室中表现出甲基苯丙胺诱导渴求的受试者。然后，我们建议在为期6周的门诊临床试验中检查培哚普利治疗对这些相同参与者使用MA的影响。一项单独的人体实验室研究将检查培哚普利对MA诱导的渴望的剂量依赖性效应，尽管这些参与者将不参加临床试验。

DESCRIPTION (provided by applicant): Angiotensin II is best known for its role in regulating fluid and electrolyte homeostasis. In addition, this system is now known to play a key role in the regulation of the hypothalamic-pituitary-adrenal axis and of the sympathetic nervous system. Because these systems are known to play critical roles in addiction, angiotensin II is likely to play a key role in addiction as well. Indeed, angiotensin II has recently been shown to enhance ethanol self-administration in rats. As yet, however, no published studies have evaluated the effects of medications affecting angiotensin II on behaviors related to other drugs of abuse, such as methamphetamine (MA). Supported by a grant from NIDA (R21 DA17182), we conducted a double-blind, placebo-controlled study to evaluate the effects of treatment with perindopril on the subjective and cardiovascular effects of MA in 30 MA-dependent human volunteers. Perindopril is an angiotensin converting enzyme inhibitor that inhibits the synthesis of angiotensin II from its inactive precursor. Perindopril treatment was associated with statistically significant reductions in ratings of 'any drug effect' and 'desire,' or craving, following administration of MA. Drug-induced craving is an obvious target for treatment, as higher levels of craving has been shown to be associated with greatly increased probability of drug use in studies of both MA and cocaine users. In this application, we propose to examine effects of treatment with perindopril on craving produced by experimental administration of MA in non-treatment-seeking volunteers. We then propose to examine the effects of perindopril treatment on MA use in these same participants in a 6-week outpatient clinical trial. Contingency management procedures will be used to reinforce clinic attendance and reductions in MA use, and manual- driven behavioral compliance enhancement and motivational interviewing techniques will be used to increase medication adherence and to enhance intrinsic motivation to reduce MA use. A separate human laboratory study will examine the dose-dependent effects of perindopril (8mg and 16mg, compared to placebo), on MA- induced craving, though these participants will not take part in the clinical trial. Pilot data suggests that that perindopril, an angiotensin converting enzyme inhibitor, was associated with reductions in methamphetamine-induced craving. Therefore, we propose to examine effects of perindopril treatment (4mg) on methamphetamine-induced craving in a larger human laboratory study enrolling only participants who demonstrate methamphetamine-induced craving in the laboratory. We then propose to examine the effects of perindopril treatment on MA use in these same participants in a 6-week outpatient clinical trial. A separate human laboratory study will examine the dose-dependent effects of perindopril on MA- induced craving, though these participants will not take part in the clinical trial.