Lorcaserin Effects on Cocaine Craving and Drug-Reinforced Behavior

氯卡色林对可卡因渴望和药物强化行为的影响

基本信息

批准号：
8918564
负责人：
KENNETH W. GRASING
金额：
$ 15.63万
依托单位：
MIDWEST VETERANS' BIOMEDICAL RESEARCH FOUNDATION
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-01 至 2019-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8918564
关键词：
Adverse effects Affect Agonist Amphetamines Anger Animals Attenuated Basal Ganglia Behavior Behavioral Biological Assay Biological Availability Body Weight decreased Brain Brain Stem CYP2D6 gene Cell Nucleus Cell Respiration Clinical Research Cocaine Cocaine Abuse Cocaine Users Complex Cues Cytochrome P450 Disease Dopamine Dose Double-Blind Method Drug Kinetics Drug usage Economics Emotional Enzymes Evaluation Event Exhibits Exposure to FDA approved Fluoxetine Food G-Protein-Coupled Receptors Goals Guided imagery Health Heart Valve Diseases Hepatic Human Hypothalamic structure Individual Infusion procedures Injectable Injection of therapeutic agent Intravenous Intravenous infusion procedures Laboratories Laboratory Animals Light Measures Medical Memory Metabolism Methods Motor Activity Neurons Neurotransmitters Oral Palate Participant Patients Pharmaceutical Preparations Placebo Control Placebos Plasma Play Property Psychostimulant dependence Randomized Rattus Reporting Research Role Safety Sampling Self Administration Self-Administered Serotonin Serotonin Agonists Stimulus Structure Tryptophan United States Veins active method base cocaine use craving disorder later incidence prevention drug abuse prevention drug of abuse drug seeking behavior experience frontal lobe human subject inhibitor/antagonist monoamine motivated behavior novel obesity treatment preclinical study public health relevance raphe nuclei receptor reinforced behavior social sound substance abuse treatment

项目摘要

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.

描述（由申请人提供）：背景5-羟色胺（5-HT）是三种单胺，它们在大脑中广泛分布并在情感和目标指导行为中扮演重要角色。由可口的食物和滥用药物促进的行为构成的边缘结构从脑干血清素能核中获得了密集的预测。在大鼠中，与获得可卡因有关的光线和声音提示强烈刺激寻求药物的行为。 2C型血清素能受体（5-HT2CR）的激动剂减弱了这一反应。药物服用（可卡因自我给药）也以5-HT2CR激动剂剂量减弱，类似于减少食物增强反应并导致运动活性减少的剂量。 Lorcaserin是FDA最近批准用于减肥疗法的5-HT2CR的新颖和选择性激动剂。它以最小的5-HT2AR或5-HT2BR受体的激活方式选择性地以这种受体亚型作用。根据最初的临床研究，劳卡森蛋白的耐受性良好，可能不会引起心脏瓣膜疾病或其他严重的副作用。临床前研究的基本原理，5-HT2CR的激动剂有效地减弱了可卡因的寻求行为。 Lorcaserin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。没有研究报告其对可卡因引起的渴望或药物强化对人类的影响。具体目的：1。确定劳卡塞蛋白预处理是否会减轻可卡因和药物增强行为的积极主观作用。 2。评估主动治疗是否会改变可卡因或脚本引起的渴望。 3。表征劳卡森在个别参与者中的生物利用度并确定它是否修饰可卡因的血浆水平。方法这是一种随机，交叉，双盲，安慰剂对照，研究单位，单中心，多面板评估电位为了使口服劳卡林在实验室环境中修改渴望和可卡因自我管理。总共24个非治疗方法，常规可卡因用户将接受单剂量安慰剂，洛卡塞林10毫克（面板1）或Lorcaserin 20 mg（面板2）的预处理。自传记忆的脚本指导的图像将根据与可卡因的使用，愤怒和中性事件有关的经验来开发。在用Lorcaserin治疗后，将分析脚本引起的情绪状态。采样剂量的可卡因（0.0、0.23和0.46 mg/kg）将被施用，参与者将在自我管理额外的静脉内剂量或接受货币替代方案之间进行选择。还将对静脉输注的负面和积极主观作用进行详细测量。由于对可卡因的非转化输注量，将确定可卡因和劳卡森的药代动力学。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Changes Depression- and Anxiety- like Behaviors following Selective Breeding for Cocaine Reinforcement.

改变可卡因强化选择性育种后的抑郁和焦虑样行为。

DOI：
10.1016/j.psychres.2020.113637
发表时间：
2021
期刊：
Psychiatry research
影响因子：
11.3
作者：
Grasing,MichaelJ;Xu,Haiyang;Idowu,JessicaY;Grasing,Kenneth
通讯作者：
Grasing,Kenneth

Biphasic reward effects are characteristic of both lorcaserin and drugs of abuse: implications for treatment of substance use disorders.

DOI：
10.1097/fbp.0000000000000672
发表时间：
2022-06-01
期刊：
Behavioural pharmacology
影响因子：
1.6
作者：
Grasing KW;Burnell K;De A
通讯作者：
De A

Extracellular dopamine, acetylcholine, and activation of dopamine D1 and D2 receptors after selective breeding for cocaine self-administration in rats.

大鼠选择性繁殖可卡因自我给药后的细胞外多巴胺、乙酰胆碱以及多巴胺 D1 和 D2 受体的激活。

DOI：
10.1007/s00213-017-4640-7
发表时间：
2017
期刊：
Psychopharmacology
影响因子：
3.4
作者：
Xu,Haiyang;Das,Sasmita;Sturgill,Marc;Hodgkinson,Colin;Yuan,Qiaoping;Goldman,David;Grasing,Kenneth
通讯作者：
Grasing,Kenneth