Deconstructing Clozapine: Toward Medication for Alcoholism in Schizophrenia

描述（由申请人提供）：精神分裂症患者通常会出现酒精使用障碍，这会加重精神分裂症的病程。虽然典型的抗精神病药物（如氟哌啶醇- HAL）在控制这些患者的酒精使用方面似乎没有什么价值，但非典型抗精神病药物氯氮平（CLOZ）虽然由于其毒性而很少使用，但却大大减少了他们的酒精使用。我们已经提出，在这一人群中，大脑奖励回路的功能障碍是酒精使用的基础，并且：(1)HAL不能减少这一人群的酒精使用，因为它不能恢复奖励回路的正常功能（部分原因是其有效的多巴胺[DA] D2受体拮抗剂）；但(2)CLOZ通过其药理作用（包括弱DA D2受体拮抗作用、强去甲肾上腺素α 2受体拮抗作用和NE再摄取抑制作用）对该回路具有正常化作用。为了进一步阐明CLOZ和HAL对酒精使用的影响，我们在嗜酒啮齿动物中进行了研究。这些啮齿动物研究的初步数据表明：(1)CLOZ比HAL更能减少它们的酒精摄入量；(2)在CLOZ中加入强效DA D2/D3受体拮抗剂raclopride可降低CLOZ对饮酒的影响；(3) HAL与NE 1-2受体拮抗剂或NE再摄取抑制剂联合使用可增加HAL减少饮酒的能力，为我们提出CLOZ和HAL对饮酒的作用提供了支持。在为期两年的“概念验证”应用程序的第二次修订中，我们寻求扩展我们的初步数据。我们的首要假设是CLOZ对嗜酒的啮齿动物的影响，如对精神分裂症和同时发生的酒精使用障碍患者的影响，与其对DA和NE系统的作用有关，这些作用可以通过创造具有CLOZ样药理活性的药物来模仿。本研究旨在更充分地阐明这一假设，并为进一步研究CLOZ对饮酒影响的生物学基础提供数据。我们研究项目的长期目标是为精神分裂症患者的酒精使用障碍开发更好的治疗方法（例如，更安全的cloz样药物）。这项涉及仓鼠研究的提案的具体目的是：(1)扩展并进一步阐明我们的初步数据，表明CLOZ减少饮酒的能力部分与其弱的DA D2受体拮抗剂有关，并评估其强效的NE 1-2受体拮抗剂的作用。(2)扩展并进一步阐明我们的初步数据，表明HAL减少啮齿动物饮酒的能力可以通过将其（低剂量，提供弱DA D2受体阻断）与NE 1-2受体拮抗剂或NE再摄取抑制剂联合使用来增强。(3)探讨DA D2受体拮抗剂、NE 1-2受体拮抗剂和NE再摄取抑制剂联合使用对啮齿动物饮酒的影响。

DESCRIPTION (provided by applicant): Patients with schizophrenia commonly develop alcohol use disorders, which worsen the course of schizophrenia. While typical antipsychotic drugs (e.g., haloperidol -- HAL) appear to be of little value in controlling alcohol use in these patients, the atypical antipsychotic clozapine (CLOZ), although prescribed infrequently because of its toxicity, substantially decreases their alcohol use. We have proposed that a dysfunction in brain reward circuitry underlies alcohol use in this population, and that: (1) HAL does not decrease alcohol use in this population because it does not restore the normal function of the reward circuitry (in part because of its potent dopamine [DA] D2 receptor antagonism); but (2) that CLOZ, through its pharmacologic effects (including its weak DA D2 receptor antagonism, its potent norepinephrine (NE) alpha 2 receptor antagonism, and its NE reuptake inhibition), has a normalizing effect on this circuit. To further elucidate the effects of CLOZ and HAL on alcohol use, we have performed studies in alcohol preferring rodents. Preliminary data from these rodent studies, indicating that (1) CLOZ decreases their alcohol drinking more than HAL; (2) adding the potent DA D2/D3 receptor antagonist raclopride to CLOZ decreases CLOZ's effect on alcohol drinking; and (3) combining HAL with a NE 1-2 receptor antagonist or a NE reuptake inhibitor increases HAL's ability to decrease alcohol drinking, provide support for our proposal about the actions of CLOZ and HAL on alcohol drinking. In this second revision of a two year, "proof of concept" application, we seek to extend our preliminary data. Our overarching hypothesis is that CLOZ's effect in alcohol-preferring rodents, as in patients with schizophrenia and co-occurring alcohol use disorder, relates to its actions on DA and NE systems as noted above, actions that can be mimicked through creation of agents that have CLOZ-like pharmacologic activity. This proposal seeks to more fully elucidate this hypothesis, and to provide data enabling further research related to the biologic basis of CLOZ's effect on alcohol drinking. The long-term goal of our research program is to develop better treatments (e.g., safer CLOZ-like medications) for alcohol use disorder in patients with schizophrenia. The specific aims of this proposal, involving research in hamsters, are: (1) To extend and further elucidate our preliminary data suggesting that CLOZ's ability to decrease alcohol drinking relates in part to its weak DA D2 receptor antagonism and to assess the role of its potent NE 1-2 receptor antagonism. (2) To extend and further elucidate our preliminary data suggesting that HAL's ability to decrease alcohol drinking in rodents can be amplified by combining it (in low dose, to provide a weak DA D2 receptor blockade) with a NE 1-2 receptor antagonist or a NE reuptake inhibitor. (3) To explore the effect of the combination of a DA D2 receptor antagonist, a NE 1-2 receptor antagonist and a NE reuptake inhibitor on alcohol drinking in rodents. PUBLIC HEALTH RELEVANCE: Public health significance: Alcohol use disorder is common in schizophrenia and worsens the course of this severe psychiatric disorder. While most antipsychotics do not lessen alcohol use in schizophrenia, the atypical antipsychotic clozapine does, although the mechanism by which this occurs is uncertain. While clozapine's toxicity severely restricts its use, understanding its mechanism of action, as proposed here, may lead to development of new drugs, safer than clozapine, which could limit alcohol use disorder in patients with schizophrenia.