Preclinical Psychopharmacology of Substance Abuse

物质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8000亿美元。退伍军人中烟草、酒精和非法药物(如兴奋剂和阿片类药物)的使用率也很高 或者比在平民人口中观察到的更高。尽管长期以来一直努力开发药物疗法来治疗 物质使用障碍，针对尼古丁、阿片或酒精使用障碍的药物疗法很少，而且有 目前还没有美国食品和药物管理局(FDA)批准的兴奋剂滥用药物疗法。这种相对的缺乏 药物治疗药物使用障碍可能是由于各种因素；然而，时间和成本 与确定可行的靶点和开发有效的治疗策略相关联，已经使许多人望而却步 禁止公司/个人进入此领域。 减少候选药物进入临床所需时间和成本的一个策略是利用知识 关于成瘾的神经生物学基础，以便合理地重新使用FDA已经批准的用于其他药物的药物 治疗药物滥用的适应症。鉴于多巴胺(DA)在奖赏、强化和成瘾中的核心作用， 我们已经集中精力寻找能够调节的靶点，如5-HT2C和DA D3受体(R)S 中脑边缘多巴胺系统的活性。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 用FDA批准的药物(5-羟色胺[5-羟色胺]2CR激动剂氯卡斯林[Belviq®])靶向这些受体； 丁螺环酮[Buspar®]，一种DA D3R拮抗剂/5-HT1A激动剂)可以减少各种药物的滥用相关效应(例如， 可卡因、甲基苯丙胺、羟考酮、芬太尼、尼古丁和酒精)。此外，我们最近已经表明， 这些药物减少吸毒的效果在给药后协同增强。 联合用药(即氯酪蛋白和丁螺环酮的混合物比任何一种药物单独更有效/有效)。虽然 前景看好的是，这些药物中的每一种都具有剂量限制(靶外)效应，降低了这些效应将 转到诊所去。 例如，必须指出的是，氯卡斯宁的剂量仅略大于批准/要求的剂量。 据报道，产生“快感”、“不良药物效应”和“幻觉”的感觉。 在人类中；被归因于5-HT2ARs的偏离目标的行为的影响。除了偏离目标的影响限制了 氯卡瑞林和丁螺环酮治疗物质使用障碍的临床应用 氯卡瑟林和丁螺环酮也使分离受体和电路水平的机制的努力复杂化，这些机制解释了 这些药物(和药物混合物)能有效减少吸毒行为。因此，拟议的研究将结合 针对特定脑区的微量注射静脉给药自我给药以评估这一创新 假设急性重复给药的固定剂量混合物具有高度选择性，但具有实验性的5-HT2CR 激动剂(CP809101)和多巴胺D3R拮抗剂(VK4-116)与部分激动剂(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)，这些影响是通过联合 腹侧被盖区5-HT2CRs的激活和伏核外壳多巴胺D3Rs的抑制 (目标2)。除了提供有关物质滥用的神经生物学的重要新信息外，因为这 策略包括通过靶向5-HT2C和DA D3受体来调节中脑边缘DA奖赏通路，这一新方法 还将指导努力开发一种高效和广谱的物质(多物质)药物疗法 使用障碍。这样的治疗将对数百万退伍军人的健康和福祉产生重大影响。

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.