Animal model of dual diagnosis

描述(申请人提供)：精神病学中的双重诊断是指药物滥用与精神疾病并存。这在精神分裂症中相当普遍，超过50%的患者滥用某种药物。对于这是否是这种疾病的另一种症状，该领域还没有达成一致意见，这是因为精神分裂症中常见的大脑系统功能失调，或者是试图自我治疗。随着精神分裂症的动物模型变得更加完善，纳入了发育起源和环境因素，很明显，其中许多动物也增加了成瘾行为的易感性。患有新生腹侧海马区损伤的动物确实表现出自我给药可卡因和甲基苯丙胺增加。我们将使用这个模型来探索这些动物越来越多的成瘾是否可以被描述为自我用药或它们状况的另一种表现。此外，我们将使用受损动物和假动物来探索与这些动物对可卡因的驱动力增加有关的细胞和突触机制，结合切片、麻醉动物和清醒的、自由活动的动物的行为评估和电生理学研究。这些实验有望揭示为什么当中皮质边缘回路功能障碍(很可能发生在精神分裂症和新生的海马区病变的动物中)时，人们会有成瘾行为的倾向，并可能为这种极其困难的双重疾病开辟新的治疗方法。该项目有可能通过潜在的精神分裂症患者存在的物质滥用增加的驱动力来揭示机制。众所周知，精神分裂症患者滥用药物的可能性增加，这可能是由于奖赏脑回路参与了这种障碍，或者是试图自我治疗。我们将进行一系列实验，目的是在一个成熟的精神分裂症动物模型中区分这两种可能性。了解大脑皮质边缘环路的细胞和突触机制可能有助于增强大脑对药物的渴望，这些环路的发育变化将有助于我们理解为什么药物滥用和精神分裂症之间存在强烈的共病，并可能为新的治疗方法确定潜在的靶点。

DESCRIPTION (provided by applicant): Dual-diagnosis in psychiatry refers to the co-existence of drug abuse with a psychiatric condition. This is quite prevalent in schizophrenia, where more than 50% of the patients abuse some type of drug. There is no agreement in the field regarding whether this is another symptom of the disease, due to a common involvement of the brain systems that are dysfunctional in schizophrenia, or an attempt at self-medication. As animal models of schizophrenia have become more refined, incorporating a developmental origin and environmental factors, it has become apparent that many of those animals have also enhanced liability for addictive behaviors. Animals with a neonatal ventral hippocampal lesion do exhibit increased self-administration of cocaine and methamphetamine. We will use this model to explore whether those animals' increased addiction can be described as self-medication or another manifestation of their condition. Also, we will use lesioned and sham animals to explore the cellular and synaptic mechanisms associated with the increased drive for cocaine these animals exhibit, combining behavioral assessments with electrophysiological studies in slices, in anesthetized animals and in awake, freely moving animals. The experiments are expected to shed some light onto why there is propensity for addictive behaviors when mesocorticolimbic circuits are dysfunctional (as likely occurring in schizophrenia and in animals with a neonatal hippocampal lesion), and may open avenues for newer therapeutic approaches for this extremely difficult to treat dual condition This project has the potential for unveiling mechanisms by underlying the increased drive for substance abuse that exists in patients with schizophrenia. It is widely known that schizophrenia patients have increased liability for drug abuse, and this is likely to emerge from an involvement of the reward brain circuits in the disorder or alternatively as an attempt at self-medication. We will conduct a series of experiments aimed at distinguishing these two possibilities in a well-established developmental animal model of schizophrenia. To understand the cellular and synaptic mechanisms in corticolimbic circuits that could contribute to an enhanced craving for drugs in brains with a developmental alteration in these circuits would advance our understanding of why there is a strong comorbidity between drug abuse and schizophrenia, and may result in the identification of potential targets for new therapeutic approaches.