Lorcaserin Effects on Cocaine Craving and Drug-Reinforced Behavior

背景5-羟色胺(5-HT)是大脑中广泛分布的三种单胺之一，在情感和目标导向行为中发挥重要作用。支持受美味食物和药物滥用的行为的边缘结构从脑干5-羟色胺能核接受密集的投射。在老鼠身上，与可卡因接触相关的光和声音线索强烈地刺激了寻找毒品的行为。2C型5-羟色胺能受体(5-HT2CR)激动剂可减弱这种反应。服药(可卡因自身给药)在5-HT2CR激动剂剂量下也会减弱，类似于那些降低食物强化反应和导致运动活动减少的药物。氯卡瑟林是FDA最近批准用于减肥治疗的5-HT2CR的一种新型选择性激动剂。它选择性地作用于这个受体亚型，最小限度地激活5-HT2AR或5-HT2BR受体。根据导致其获得批准的初步临床研究，氯卡色林耐受性良好，可能不会导致心脏瓣膜疾病或其他严重的副作用。在临床前研究中，5-HT2CR的激动剂有效地减弱了寻求可卡因的行为。氯卡瑟林是最近批准的一种选择性5-HT2CR激动剂，在人类中具有可接受的安全性。还没有研究报告它对可卡因诱导的欲望或人类的药物强化反应的影响。具体目的：1.确定氯酪蛋白预处理是否减弱可卡因的积极主观效应和药物强化行为。2.评估积极治疗是否能改变可卡因或剧本引发的渴望。3.确定氯酪蛋白在个体参与者体内的生物利用度，并确定 它是否会改变血浆中可卡因的水平。方法这是一项随机、交叉、双盲、安慰剂对照、研究单位、单中心、多小组的潜力评估。 用于在实验室环境下口服氯酪蛋白来改善饥饿感和可卡因自我给药。共有24名不寻求治疗的常规可卡因使用者将接受单剂量口服安慰剂、氯卡韦林10毫克(第一组)或氯卡斯林20毫克(第二组)的预治疗。自传体记忆的剧本引导图像将基于与可卡因使用、愤怒和中性事件相关的经验而开发。在使用氯卡瑟林治疗后，将分析脚本诱导的情绪状态。将给予抽样剂量的可卡因(0.0、0.23和0.46毫克/公斤)，参与者将在自我注射额外的静脉剂量或接受货币替代品之间进行选择。还将对静脉输液的消极和积极的主观影响进行详细的测量。随着非偶然输注可卡因的实施，可卡因和氯酪蛋白的药代动力学将被确定。

DESCRIPTION (provided by applicant): Background Serotonin (5-HT) is one of three monoamines that are widely distributed in the brain and play important roles in affect and goal-directed behaviors. Limbic structures that underlie behavior motivated by palatable food and drugs of abuse receive dense projections from brainstem serotonergic nuclei. In rats, light and sound cues associated with access to cocaine strongly stimulate drug-seeking behavior. Agonists for the type 2C serotonergic receptor (5-HT2CR) attenuate this responding. Drug taking (cocaine self-administration) is also attenuated at 5-HT2CR agonist doses similar to those that decrease food-reinforced responding and cause reductions in locomotor activity. Lorcaserin is a novel and selective agonist of the 5-HT2CR recently approved by the FDA for weight loss therapy. It acts selectively at this receptor subtype with minimal activation of 5-HT2AR or 5-HT2BR receptors. Based on initial clinical studies leading to its approval, lorcaserin is well tolerated and probably does not cause cardiac valve disease or other serious side effects. Rationale In preclinical studies, agonists for the 5-HT2CR potently attenuate cocaine-seeking behavior. Lorcaserin is a recently approved selective 5-HT2CR agonist with an acceptable safety profile in humans. No studies have reported its effects on cocaine-induced craving or drug-reinforced responding in humans. Specific Aims: 1. Determine whether lorcaserin pretreatment attenuates the positive subjective effects of cocaine and drug- reinforced behavior. 2. Evaluate whether active treatment modifies cocaine- or script- induced craving. 3. Characterize the bioavailability of lorcaserin in individual participants and determine whether it modifies plasma levels of cocaine. Methods This is a randomized, cross-over, double-blind, placebo-controlled, research-unit, single-center, multiple-panel evaluation of the potential for oral lorcaserin to modify craving and cocaine self-administration in a laboratory setting. A total of 24 non-treatment-seeking, regular cocaine users will receive pretreatment with single doses of oral placebo, lorcaserin 10 mg (panel 1), or lorcaserin 20 mg (panel 2). Script-guided imagery of autobiographical memories will be developed based on experiences related to cocaine use, anger, and a neutral event. Following treatment with lorcaserin, script-induced emotional states will be assayed. Sampling doses of cocaine (0.0, 0.23, and 0.46 mg/kg) will be administered, and participants will choose between self- administering additional intravenous doses or receiving monetary alternatives. Detailed measures of the negative and positive subjective effects of intravenous infusions will also be made. As noncontingent infusions of cocaine are administered, the pharmacokinetics of cocaine and lorcaserin will be determined.