Preclinical Psychopharmacology of Substance Abuse

药物滥用的临床前精神药理学

• 批准号: 9891589
• 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
• 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/9891589
• 关键词: Abstinence; Acute; Adverse effects; Agonist; Alcohol abuse; Alcohol or Other Drugs use; 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; 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; anxiety-like behavior; behavior test; comorbidity; cost; dopamine D3 receptor; drug of abuse; economic cost; effective therapy; effectiveness evaluation; improved; innovation; male; mesolimbic system; nicotine abuse; nicotine use; novel; novel strategies; opioid abuse; opioid use; pre-clinical; receptor; relative effectiveness; sex; side effect; smoking cessation; societal costs; stimulant abuse; treatment strategy

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 每年$800B。退伍军人中烟草、酒精和非法药物（例如兴奋剂和阿片类药物）的使用率同样高 或高于在平民中观察到的水平。尽管长期以来努力开发药物疗法来治疗 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，美国食品和药物管理局 (FDA) 还没有批准用于治疗兴奋剂滥用的药物疗法。这种相对缺乏 物质使用障碍的药物疗法可能是由于多种因素造成的；然而，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 治疗药物滥用的适应症。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) 中脑边缘 DA 系统的活动。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）。此外，我们最近还表明 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/更有效）。虽然 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，重要的是要注意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；归因于 5-HT2AR 脱靶作用的效应。除了脱靶效应限制 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。 这些药物（和药物混合物）能够有效减少吸毒行为。因此，拟议的研究将结合 针对特定脑区进行静脉内药物自我注射微注射以评估新型药物 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，因为这 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 使用障碍。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。