Animal model of dual diagnosis

描述（由申请人提供）：精神病学的双重诊断是指药物滥用与精神疾病共存。这在精神分裂症中非常普遍，超过50%的患者滥用某种药物。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，还是试图自我药物治疗，该领域尚无一致意见。随着精神分裂症的动物模型变得更加精细，包括发育起源和环境因素，很明显，许多这些动物也增加了成瘾行为的责任。新生儿海马腹侧病变的动物确实表现出可卡因和甲基苯丙胺的自我管理增加。我们将使用这个模型来探索这些动物增加的成瘾是否可以被描述为自我药物治疗或他们的病情的另一种表现。此外，我们将使用受损和假动物来探索与这些动物表现出的可卡因驱动增加相关的细胞和突触机制，将行为评估与电生理研究相结合，在切片，麻醉动物和清醒，自由活动的动物中进行。这些实验有望揭示为什么当中皮质边缘回路功能失调时（如精神分裂症和新生儿海马损伤的动物中可能发生的情况）会有上瘾行为的倾向，并可能为这种极难治疗的双重疾病开辟新的治疗方法。该项目有可能通过揭示精神分裂症患者中存在的药物滥用增加的潜在机制。众所周知，精神分裂症患者更容易滥用药物，这很可能是由于这种疾病中奖赏脑回路的参与，或者是由于自我药物治疗的尝试。我们将进行一系列的实验，目的是在一个完善的精神分裂症发育动物模型中区分这两种可能性。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对药物的渴望，并在这些回路中发生发育改变，这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性，并可能导致确定新的治疗方法的潜在目标。

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.