Lorcaserin Effects on Cocaine Craving and Drug-Reinforced Behavior

背景5-羟色胺（5-HT）是广泛分布于大脑中的三种单胺之一，在情感和目标导向行为中起重要作用。由可口的食物和滥用药物激发的行为背后的边缘结构接受脑干多巴胺能神经核的密集投射。在大鼠中，与可卡因相关的光和声音线索强烈刺激了药物寻求行为。2C型肾上腺素能受体（5-HT 2CR）的激动剂减弱这种反应。药物服用（可卡因自我给药）也在5-HT 2CR激动剂剂量下减弱，类似于降低食物强化反应并导致运动活性降低的剂量。氯卡色林是一种新型的5-HT 2CR选择性激动剂，最近被FDA批准用于减肥治疗。它选择性地作用于这种受体亚型，对5-HT 2AR或5-HT 2BR受体的活化最小。基于导致其批准的初步临床研究，氯卡色林耐受性良好，可能不会引起心脏瓣膜疾病或其他严重副作用。在临床前研究中，5-HT 2CR的激动剂有效地减弱可卡因寻求行为。氯卡色林是最近批准的选择性5-HT 2CR激动剂，在人体中具有可接受的安全性。没有研究报告其对可卡因引起的渴望或药物强化的反应的影响。具体目标：1。确定氯卡色林预处理是否减弱可卡因和药物强化行为的积极主观效应。2.评估积极治疗是否改变可卡因或脚本诱导的渴望。3.描述个体受试者中氯卡色林的生物利用度，并确定 是否会改变可卡因的血浆水平方法本研究采用随机、交叉、双盲、安慰剂对照、研究单元、单中心、多队列的方法， 口服氯卡色林以改变实验室环境中的渴望和可卡因自我给药。共有24名非寻求治疗的常规可卡因使用者将接受单次口服安慰剂、氯卡色林10 mg（队列1）或氯卡色林20 mg（队列2）的预治疗。自传体记忆的脚本引导图像将根据与可卡因使用，愤怒和中性事件相关的经验开发。氯卡色林治疗后，将测定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 mg/kg），参与者将选择自我给予额外的静脉注射剂量或接受货币替代品。还将对静脉输注的负面和正面主观影响进行详细测量。当给予可卡因非偶然输注时，将测定可卡因和氯卡色林的药代动力学。

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.