Preclinical Psychopharmacology of Substance Abuse

物质使用障碍是一个严重的公共卫生问题，医疗，社会和经济成本超过 每年8000元。烟草、酒精和非法药物的比率（例如，兴奋剂和阿片类药物）在退伍军人中的使用率一样高， 或高于在平民中观察到的水平。尽管长期以来一直在努力开发药物治疗， 物质使用障碍，对于尼古丁、阿片样物质或酒精使用障碍存在很少的药物疗法， 目前没有美国食品和药物管理局（FDA）批准的用于兴奋剂滥用的药物疗法。这种相对缺乏 药物治疗物质使用障碍的可能是由于各种因素;然而，时间和成本 与确定可行的目标和制定有效的治疗策略相关的问题使许多人感到沮丧， 公司/个人进入这个领域。 一种减少将候选药物投入临床所需时间和成本的策略是利用知识 关于成瘾的神经生物学底物，合理地重新使用FDA已经批准用于其他药物的药物， 治疗药物滥用的适应症。考虑到多巴胺（DA）在奖赏、强化和成瘾中的核心作用， 我们已经集中精力确定目标，如5-HT 2C和DA D3受体（R），能够调节 中脑边缘DA系统的活性。事实上，来自我们实验室和其他实验室的有力临床前证据表明， 用FDA批准的药物（氯卡色林[Belviq®]，一种血清素[5-HT]2CR激动剂）靶向这些受体中的每一种;以及 丁螺环酮[Buspar®]，一种DAD 3R拮抗剂/5-HT 1A激动剂）可以减少多种药物的滥用相关作用（例如， 可卡因、甲基苯丙胺、羟考酮、芬太尼、尼古丁和酒精）。此外，我们最近表明， 这些药物减少药物服用的有效性在药物联合给药时协同增强， 组合（即，氯卡色林和丁螺环酮的混合物比单独的任一种药物更有效/有效）。虽然 这些药物中的每一种都具有剂量限制（脱靶）效应，降低了这些效应将 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，产生其治疗效果的感觉是“高”，“不良药物效果”和“幻觉” 在人类中;作用归因于5-HT 2AR的脱靶作用。除了脱靶效应限制了 氯卡色林和丁螺环酮用于治疗物质使用障碍的临床效用， 氯卡色林和丁螺环酮也使分离受体和回路水平机制的工作复杂化， 这些药物（和药物混合物），以有效地减少吸毒行为。因此，拟议的研究将联合收割机 静脉内药物自我给药与显微注射针对特定的大脑区域，以评估新的 假设急性和重复施用高选择性但实验性的5-HT 2CR的固定剂量混合物 激动剂（CP 809101）和DA D3 R拮抗剂（VK 4 -116）和部分激动剂（BAK 4 -54）将产生协同作用。 减少兴奋剂和阿片类药物自我给药（目标1），这些作用是由联合 腹侧被盖区（VTA）5-HT 2CRs的激活和中脑核壳（NAcc）DA D3 Rs的抑制 (Aim 2）。除了提供有关药物滥用神经生物学的重要新信息外， 该策略涉及通过靶向5-HT 2C和DA D3 Rs调节中脑边缘DA奖赏通路，这种新方法 还将指导开发高效和广谱药物治疗物质（多物质）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。

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.