Antipsychotics and Alcohol Drinking in Rodents

描述（由申请人提供）：精神分裂症（SCH）患者通常会出现酒精使用障碍。虽然典型的抗精神病药物（如氟哌啶醇- HAL）不能控制这些患者的酒精使用，但最近的数据表明，非典型抗精神病药物氯氮平（CLOZ）可以。我们最近提出了一个神经生物学的表述，表明：(a)嗜酒性精神障碍患者的多巴胺（DA）介导的中脑皮质边缘奖赏通路存在功能障碍；(b)大多数抗精神病药物（如HAL）不能减少该人群的酒精使用，因为它们不能恢复这些通路的正常功能；但(c) CLOZ通过其对多种神经递质系统的作用，特别是其对α 2去甲肾上腺素能受体的有效阻断，以及对DA D2受体的弱阻断，对这些通路的信号检测能力具有正常化作用。为了进一步阐明HAL和CLOZ的不同作用，我们最近在叙利亚金仓鼠（一种饮用大量酒精的近亲繁殖动物）中开展了一项研究。我们的初步数据表明CLOZ而不是HAL显著减少仓鼠饮酒。在这个R03提案中，我们寻求扩大我们的调查，并准备提交R01提案。我们将继续对仓鼠的研究，但也将扩大到包括“P”大鼠，一种遗传育种的菌株，已被提议作为酒精中毒的优秀动物模型。我们的首要假设是，CLOZ对嗜酒动物的影响，如对SCH和共病酒精使用障碍患者的影响，与其在da介导的中脑边缘回路中的作用有关。主要的具体目的是：(1)确定CLOZ是否会比HAL更能减少P大鼠的饮酒，P大鼠是一种已知的da介导的中脑边缘系统功能障碍的啮齿动物。另一个目的是进一步了解CLOZ（而不是HAL）在仓鼠和P大鼠中限制酒精使用的神经生物学基础：(2)探索在长期使用CLOZ治疗期间是否会丧失对饮酒的抑制；(3)开始探索(a)向CLOZ添加强效D2拮抗剂是否会降低CLOZ抑制饮酒的能力，以及(b)向HAL添加强效α 2拮抗剂是否会使HAL抑制饮酒。我们研究的长期目标是创造更好的治疗酒精中毒的患者有SCH（甚至可能没有SCH）。

DESCRIPTION (provided by applicant): Patients with schizophrenia (SCH) commonly develop alcohol use disorders. While typical antipsychotic drugs (e.g., haloperidol - HAL) do not control alcohol use in these patients, recent data suggest that the atypical antipsychotic clozapine (CLOZ) does. We recently presented a neurobiologic formulation suggesting: (a) that persons with SCH have a dysfunction in their dopamine (DA) mediated mesocorticolimbic reward pathways underlying alcohol use; (b) that most antipsychotic drugs (e.g., HAL) do not decrease alcohol use in this population because they do not restore the normal function of these pathways; but (c) that CLOZ, through its actions on multiple neurotransmitter systems, particularly its potent blockade of alpha 2 noradrenergic receptors, as well as its weak blockade of DA D2 receptors, has a normalizing effect on the signal detection capability of these pathways. To further elucidate the differential effects of HAL and CLOZ, we recently initiated a study in Syrian golden hamsters, an outbred animal that drinks large amounts of alcohol. Our initial data indicate that CLOZ but not HAL substantially decreases hamster alcohol drinking. In this R03 proposal, we seek to expand our investigations and prepare for submission of an R01 proposal. We will continue studies of the hamster, but will also expand to include the "P" rat, a genetically- bred strain that has been proposed as an excellent animal model for alcoholism. Our overarching hypothesis is that CLOZ's effect in alcohol-preferring animals, as in patients with SCH and comorbid alcohol use disorder, relates to its action in DA-mediated mesolimbic circuits. The primary specific aim seeks: (1) To determine whether CLOZ will decrease alcohol drinking more than HAL does in the P rat, a rodent with known dysfunction in the DA-mediated mesolimbic system. The other aims are designed to further inform the neurobiologic basis by which CLOZ, but not HAL, limits alcohol use in the hamster and, potentially, in the P rat: (2) To explore whether loss of suppression of alcohol drinking develops during long-term treatment with CLOZ; and (3) to begin to explore (a) whether addition of a potent D2 antagonist to CLOZ will lessen the CLOZ's ability to suppress alcohol drinking, and (b) whether addition of a potent alpha 2 antagonist to HAL will allow HAL to suppress alcohol drinking. The long-term goal of our research is to create better treatments for alcoholism in patients with SCH (and possibly even in those without SCH).