Preclinical Psychopharmacology of Substance Abuse

药物滥用的临床前精神药理学

基本信息

批准号：
10436778
负责人：
Gregory Thomas Collins
金额：
--
依托单位：
SOUTH TEXAS VETERANS HEALTH CARE SYSTEM
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-01-01 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10436778
关键词：
Abstinence Acute Adverse effects Agonist Alcohol abuse Alcohols Behavior Brain region Buspirone Chronic Clinic Clinical Clinical effectiveness Cocaine Combined Modality Therapy Data Disease Dopamine Dose Dose-Limiting Drug Targeting Effectiveness Feeling Female Fentanyl Food Hallucinations Health Human Illicit Drugs Individual Intravenous Knowledge Laboratories Macaca mulatta Mediating Medical Care Costs Methamphetamine Microinjections Motor Activity Nature Neurobiology Nicotine Nociception Nucleus Accumbens Opioid Oxycodone Pathway interactions Personal Satisfaction Pharmaceutical Preparations Pharmacology Pharmacotherapy Population Post-Traumatic Stress Disorders Procedures Psychological reinforcement Psychopharmacology Public Health Rattus Recording of previous events Reinforcement Schedule Reporting Rewards Rhesus Role Schedule Self Administration Serotonin Site Specificity Stimulant Substance Use Disorder Substance abuse problem Testing Therapeutic Therapeutic Effect Time Tobacco Translating United States Food and Drug Administration Ventral Tegmental Area Veterans addiction alcohol use disorder antagonist anxiety-like behavior behavior test comorbidity cost dopamine D3 receptor drug of abuse drug repurposing economic cost effective therapy effectiveness evaluation improved innovation male mesolimbic system nicotine abuse nicotine use novel novel strategies opioid abuse opioid use polysubstance use pre-clinical receptor relative effectiveness sex side effect smoking cessation societal costs stimulant abuse substance use treatment strategy

项目摘要

Substance use disorders are a serious public health problem with medical, societal, and economic costs exceeding $800B annually. Rates of tobacco, alcohol, and illicit drug (e.g., stimulants, and opioids) use among veterans are as high or higher than those observed in civilian populations. Despite long-standing efforts to develop pharmacotherapies to treat substance use disorders, few pharmacotherapies exist for nicotine, opioid, or alcohol use disorders, and there are currently no US Food and Drug Administration (FDA)-approved pharmacotherapies for stimulant abuse. This relative lack of pharmacotherapies for substance use disorders is likely due to a variety of factors; however, the time and costs associated with identifying viable targets and developing effective treatment strategies has discouraged many companies/individuals from entering this space. One strategy to reduce the time and costs required to get candidate medications into the clinic is to leverage knowledge about the neurobiological substrates of addiction to rationally repurpose drugs already approved by the FDA for other indications to treat substance abuse. Given the central role for dopamine (DA) in reward, reinforcement, and addiction, we have focused our efforts on identifying targets, such as 5-HT2C and DA D3 receptor (R)s, that are capable of modulating the activity of the mesolimbic DA system. Indeed, strong preclinical evidence from our laboratory and others suggests that targeting each of these receptors with FDA-approved drugs (lorcaserin [Belviq®], a serotonin [5-HT]2CR agonist; and buspirone [Buspar®], a DA D3R antagonist/5-HT1A agonist) can reduce the abuse-related effects of a variety of drugs (e.g., cocaine, methamphetamine, oxycodone, fentanyl, nicotine, and alcohol). In addition, we have recently shown that the effectiveness of these drugs to reduce drug taking are synergistically enhanced when the drugs are administered in combination (i.e., mixtures of lorcaserin and buspirone are more potent/effective than either drug alone). Although promising, each of these drugs have dose-limiting (off-target) effects that reduce the likelihood that these effects will translate to the clinic. For instance, it is important to note that doses of lorcaserin only slightly larger than those approved/required to produce its therapeutic effects have been reported to producing feelings of “high”, “bad drug effect”, and “hallucination” in humans; effects that are attributed to off-target actions at 5-HT2ARs. In addition to the off-target effects limiting the clinical utility of lorcaserin and buspirone for treating substance use disorder, the relatively “dirty” pharmacology of lorcaserin and buspirone also complicates efforts to isolate the receptor and circuit-level mechanisms that account for these drugs (and drug mixtures) to effectively reduce drug taking behavior. Accordingly, proposed studies will combine intravenous drug self-administration with microinjections aimed at particular brain regions to evaluate the novel hypotheses that acute and repeated administration of fixed dose mixtures of highly selective, but experimental 5-HT2CR agonists (CP809101) and DA D3R antagonist (VK4-116) and partial agonists (BAK4-54) will be produce a synergistic reduction in both stimulant and opioid self-administration (Aim 1), and that these effects are mediated by a combined activation of 5-HT2CRs in the ventral tegmental area (VTA) and inhibition of DA D3Rs in the nucleus accumbens (NAcc) shell (Aim 2). In addition to providing important new information about the neurobiology of substance abuse, because this strategy involves modulation of the mesolimbic DA reward pathway by targeting 5-HT2C and DA D3 Rs, this novel approach will also guide efforts to develop a highly effective and broad-spectrum pharmacotherapy for substance (polysubstance) use disorders. Such a treatment would have significant implications for the health and well-being of millions of veterans.

药物使用障碍是一个严重的公共卫生问题，其医疗、社会和经济成本超过退伍军人每年使用烟草、酒精和非法药物（例如兴奋剂和阿片类药物）的比率同样高。尽管长期努力开发治疗药物，但仍高于在平民中观察到的水平。物质使用障碍，针对尼古丁、阿片类药物或酒精使用障碍的药物疗法很少，并且有目前还没有美国食品和药物管理局（FDA）批准的针对兴奋剂滥用的药物疗法，这相对缺乏。物质使用障碍的药物治疗可能是由于多种因素造成的，但是时间和成本；确定可行的目标和制定有效的治疗策略使许多人望而却步公司/个人进入这个领域。减少将候选药物投入临床所需的时间和成本的一种策略是利用知识关于合理重新利用 FDA 已批准用于其他用途的药物成瘾的神经生物学基础鉴于多巴胺 (DA) 在奖励、强化和成瘾方面的核心作用，我们的重点是确定能够调节的靶标，例如 5-HT2C 和 DA D3 受体 (R) 事实上，来自我们实验室和其他实验室的强有力的临床前证据表明，使用 FDA 批准的药物（氯卡色林 [Belviq®]，一种血清素 [5-HT]2CR 激动剂）针对这些受体中的每一个；以及丁螺环酮 [Buspar®]，一种 DA D3R 拮抗剂/5-HT1A 激动剂）可以减少多种药物（例如，可卡因、甲基苯丙胺、羟考酮、芬太尼、尼古丁和酒精）。当这些药物以不同的方式给药时，这些药物减少吸毒的有效性会得到协同增强。组合（即氯卡色林和丁螺环酮的混合物比单独使用任何一种药物更有效）。有希望的是，这些药物中的每一种都具有剂量限制（脱靶）效应，从而降低了这些效应发生的可能性翻译到诊所。例如，值得注意的是，氯卡色林的剂量仅略大于批准/要求的剂量。据报道，产生其治疗效果会产生“兴奋”、“药效不良”和“幻觉”的感觉在人类中，除了限制 5-HT2AR 的脱靶作用外，还产生了脱靶作用。氯卡色林和丁螺环酮治疗物质使用障碍的临床应用，相对“肮脏”的药理学氯卡色林和丁螺环酮也使分离受体和电路水平机制的工作变得复杂化。因此，拟议的研究将结合这些（和药物混合物）药物来有效减少吸毒行为。通过针对特定脑区域的微注射进行静脉药物自我给药，以评估新颖的药物假设急性和重复施用高度选择性但实验性 5-HT2CR 的固定剂量混合物激动剂（CP809101）和DA D3R拮抗剂（VK4-116）和部分激动剂（BAK4-54）将产生协同作用减少兴奋剂和阿片类药物的自我给药（目标 1），并且这些作用是由联合作用介导的激活腹侧被盖区 (VTA) 中的 5-HT2CR 并抑制伏隔核 (NAcc) 壳中的 DA D3R （目标 2）除了提供有关药物滥用的神经生物学的重要新信息之外，策略涉及通过靶向 5-HT2C 和 DA D3 Rs 来调节中脑边缘 DA 奖励通路，这种新颖的方法还将指导针对物质（多物质）开发高效且广谱的药物疗法的努力这种治疗将对数百万退伍军人的健康和福祉产生重大影响。