Lorcaserin Effects on Cocaine Craving and Drug-Reinforced Behavior

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。由美味食物和滥用药物引起的行为背后的边缘结构受到脑干血清素能核的密集投射。在老鼠身上，与获得可卡因有关的光和声音线索强烈地刺激了寻求毒品的行为。2C型血清素能受体（5-HT2CR）的激动剂减弱了这种反应。5-HT2CR激动剂的剂量与那些减少食物强化反应和导致运动活动减少的药物剂量相似，药物服用（可卡因自我给药）也会减弱。氯卡色林是一种新型的选择性5-HT2CR激动剂，最近被FDA批准用于减肥治疗。它选择性地作用于5-HT2AR或5-HT2BR受体亚型。根据初步临床研究，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的副作用。在临床前研究中，5-HT2CR激动剂能有效减弱可卡因寻求行为。氯卡色林是最近批准的选择性5-HT2CR激动剂，在人类中具有可接受的安全性。没有研究报告它对人类可卡因诱导的渴望或药物强化反应的影响。具体目标：1；确定氯卡色林预处理是否会减弱可卡因和药物强化行为的积极主观效应。2. 评估积极治疗是否能改变可卡因或剧本引起的渴望。3. 描述氯卡色林在个体参与者中的生物利用度并确定

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.