Animal model of dual diagnosis

描述（由申请人提供）：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，其中超过50%的患者滥用某种类型的药物。关于这是否是精神分裂症的另一种症状，由于精神分裂症中功能失调的大脑系统的共同参与，或者试图自我治疗，该领域没有达成一致意见。随着精神分裂症的动物模型变得越来越精致，纳入了发育起源和环境因素，很明显，这些动物中的许多动物也增强了成瘾行为的倾向。新生儿腹侧海马损伤的动物确实表现出可卡因和甲基苯丙胺的自我给药增加。我们将使用这个模型来探索这些动物的成瘾性增加是否可以被描述为自我药物治疗或其病情的另一种表现。此外，我们将使用损伤和假动物来探索与这些动物表现出的可卡因驱动力增加相关的细胞和突触机制，将行为评估与切片、麻醉动物和清醒、自由活动动物的电生理研究相结合。这些实验有望揭示为什么当中皮层边缘回路功能失调时会有成瘾行为的倾向（可能发生在精神分裂症和新生海马损伤的动物中），并可能为这种极难治疗的双重疾病开辟新的治疗方法。该项目有可能揭示存在的药物滥用的潜在机制。在精神分裂症患者中。众所周知，精神分裂症患者滥用药物的可能性增加，这可能是由于大脑奖赏回路参与了这种疾病，或者是自我药物治疗的尝试。我们将进行一系列的实验，旨在区分这两种可能性，在一个完善的精神分裂症发育动物模型。为了了解皮质边缘回路中的细胞和突触机制，这些机制可能有助于增强大脑中对药物的渴望，并在这些回路中发生发育改变，这将促进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性，并可能导致识别新的治疗方法的潜在靶点。

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.