Selective Monoamine Release as a Treatment for Cocaine Use Disorders

描述（由申请人提供）：可卡因（COC）成瘾是一个无情的公共卫生问题。尽管近30年来国家药物滥用研究所一直高度重视COC依赖，科学和治疗界也做出了广泛的努力，但尚未确定有效的药物。临床前研究的结果表明，单胺释放剂减弱了COC的增强作用。人体实验室研究的结果还表明，单胺释放剂减弱了COC的强化作用，尽管这种作用的幅度很小，并且取决于用于评估药物强化的方法。测试COC滥用的单胺释放剂的临床试验结果好坏参半。单胺释放剂沿着从DA/NE选择性到5-HT选择性的连续体变化。理论家们推测，5-HT/DA释放比是单胺吸收剂减弱COC增强效应的有效性和特异性的关键决定因素。具有中间5-HT/DA释放比的化合物（即，30-40）在减少可卡因服用方面是最有效和最具体的。例如，甲基苯丙胺（5-HT/DA比值= 31）完全特异性消除了对COC的反应。与这些发现一致，甲基苯丙胺在临床试验中显著减少了COC的使用，尽管由于其高滥用和转移潜力，它不是管理COC滥用的可行选择。需要测试具有期望的5- HT/DA释放比率和最小滥用潜力的化合物的COC依赖性。苯甲曲嗪（PHEN）适用于治疗肥胖症。口服给药后，PHEN转化为苯甲曲嗪，这在很大程度上是其行为和神经药理学作用的原因。与具有中间5-HT/DA释放比率的化合物选择性地减弱COC的增强作用的概念一致，苯甲曲嗪（5-HT/DA比率= 37）也完全且特异性地消除COC维持的响应。此外，PHEN减少COC维持的反应，但不维持自我给药或产生高强度的积极主观效应，表明其滥用潜力低。尽管据我们所知，PHEN尚未在人体实验室实验或临床试验中被测试为COC依赖的潜在药物疗法，但现有临床前实验的结果表明它可能是一种可行的选择。我们将进行两个严格的受试者内实验来填补这一空白。这些研究将1）确定PHEN-COC组合的安全性和耐受性，和2）证明PHEN减少COC自我施用。该项目的结果将提供关于PHEN对COC依赖的初始疗效的关键信息，这将提高进入临床试验时成功的可能性。

DESCRIPTION (provided by applicant): Cocaine (COC) addiction is an unrelenting public health concern. An effective medication has not been identified for COC dependence despite being a high priority for the National Institute on Drug Abuse for nearly 30 years and extensive efforts by the scientific and treatment communities. The results of preclinical studies have shown that monoamine releasers attenuate the reinforcing effects of COC. The results of human laboratory studies also suggest that monoamine releasers attenuate the reinforcing effects of COC although the effects are small in magnitude and dependent on the methods used to assess drug reinforcement. The results of clinical trials that tested monoamine releasers for COC abuse are mixed. Monoamine releasers vary along a continuum from DA/NE selective to 5-HT selective. Theoreticians have postulated that the 5-HT/DA releasing ratio is a critical determinant of the efficacy and specificity of a monoamine releaser to attenuate the reinforcing effects of COC. Compounds with intermediate 5-HT/DA release ratios (i.e., 30-40) were the most effective and specific in terms of reducing cocaine taking. For example, methamphetamine (5-HT/DA ratio = 31) completely and specifically eliminated responding for COC. Consistent with these findings, methamphetamine dramatically reduced COC use in a clinical trial although it is NOT a viable option for managing COC abuse because of its high abuse and diversion potential. Compounds with a desirable 5- HT/DA releasing ratio and minimal abuse potential need to be tested for COC dependence. Phendimetrazine (PHEN) is indicated for treating obesity. After oral administration, PHEN is converted to phenmetrazine, which is largely responsible for its behavioral and neuropharmacological effects. Consistent with the notion that compounds with intermediate 5-HT/DA release ratios selectively attenuate the reinforcing effects of COC, phenmetrazine (5-HT/DA ratio = 37) also completely and specifically eliminated COC-maintained responding. Moreover, PHEN reduces COC-maintained responding, but does not maintain self-administration or produce high magnitude positive subjective effects suggesting that its abuse potential is low. Although PHEN has not yet been tested as a potential pharmacotherapy for COC dependence in human laboratory experiments or clinical trials to our knowledge, the results of extant preclinical experiments suggest it may be a viable option. We will conduct two rigorous within-subject experiments to fill this gap. These studies will 1) establish the safety and tolerability of PHEN-COC combinations and 2) demonstrate that PHEN reduces COC self- administration. The results of this project will provide critical information regarding the initial efficacy of PHEN for COC dependence, which will enhance the probability of success when advanced to a clinical trial.