Imaging dopamine transmission in comorbid schizophrenia and cannabis dependence

描述（由申请人提供）：多巴胺（DA）在精神分裂症和成瘾的病理生理中起作用。影像学研究一致表明，精神分裂症患者大脑纹状体区域的多巴胺增加，而成瘾患者的多巴胺减少。最近，由于使用了更高分辨率的扫描仪和更好的数据分析方法，这些观测得到了更多的地形特征。这些改进促成了以下观察结果：成瘾患者的DA传递主要在腹侧纹状体（VST）中减弱，而精神分裂症患者的联想纹状体，更具体地说，在交会前尾状体（preDCA）中，DA传递增加。由于纹状体中DA传递的这种相反的失调，下一个有趣的问题是关于患有精神分裂症和成瘾的双重诊断患者，特别是那些患有大麻依赖的患者。大麻的使用与精神分裂症的高风险和更严重的症状有关。我们认为，患有大麻依赖和精神分裂症共病的受试者（双重诊断为DD）将显示相反的DA传递改变，其中VST变钝而前dca增加。这可以解释使用药物的驱动（VST中DA低）导致精神病症状（药物可能失调前dca中的DA）。抗精神病药物会加剧VST中的低多巴胺能张力，导致渴望、吸毒、不遵守和自我延续的恶性循环。我们提交了第一个RO1来评估慢性大麻依赖中的多巴胺传递。在这里，我们提出了一个小的伴侣资助集中在双重诊断患者大麻依赖和精神分裂症的合并症。12名DD患者和12名匹配的健康对照（HC）将接受[11C]raclopride和d -安非他明挑战的PET成像。主要的结局指标将是由于安非他明诱导的DA释放，[11C]氯吡唑啉特异性-非特异性平衡分配系数（V3”）的降低。我们预计在preDCA （SA2）中，与HC （n = 12）相比，DD （n = 12）的V3′将增加，而VST （SA1）的V3′将减少。这项研究是更好地了解DD病理生理学的第一步，最终可能导致更好的检测，预防和治疗。尽管我们对精神分裂症和成瘾的病理生理学的理解有了很大的提高，但很少有研究关注这两种疾病之间的共病。药物滥用显然是精神分裂症中普遍存在的问题，是一个具有挑战性的治疗和管理问题。我们提出了第一个小型研究，以测试大麻依赖和精神分裂症患者大脑多巴胺失调的工作模型，这将有助于更好地了解双重诊断的病理生理学，更好地检测，预防和治疗。

DESCRIPTION (provided by applicant): Dopamine (DA) plays a role in the pathophysiology of schizophrenia and addiction. Imaging studies have shown consistently that dopamine is increased in striatal areas of the brain in schizophrenia, while it is blunted in addiction. Recently these observations received more topographical characterization from use of higher resolution scanners and better data analysis methods. These improvements have contributed to the following observations: DA transmission is predominantly blunted in the ventral striatum (VST) in addiction while, in schizophrenia, DA transmission is increased in the associative striatum, and, more specifically, in the precommissural caudate (preDCA). With this type of opposite dysregulation of DA transmission within the striatum, the intriguing next question is about dual diagnosis patients suffering from both schizophrenia and addiction, and in particular those suffering from cannabis dependence. Cannabis use is associated with higher risk for schizophrenia and more severe symptomatology. We propose that subjects with comorbid cannabis dependence and schizophrenia (DD for dual diagnosis) will display opposite alterations in DA transmission where the VST is blunted while the preDCA is increased. This would explain the drive to use drugs (low DA in VST) leading to psychotic symptoms (drugs may dysregulate DA in preDCA). Antipsychotics will exacerbate the hypodopaminergic tone in the VST leading to craving, drug use, non-adherence and a self-perpetuating vicious circle. We submitted a first RO1 to assess dopamine transmission in chronic cannabis dependence. Here we propose a small companion grant focused on dual diagnosis patients comorbid for cannabis dependence and schizophrenia. Twelve DD patients and 12 matched healthy controls (HC) will undergo PET imaging with [11C]raclopride and the D-amphetamine challenge. The main outcome measure will be the decrease in [11C]raclopride specific-to-nonspecific equilibrium partition coefficient (V3") due to amphetamine induced DA release, or V3". We expect that V3" will be increased in DD (n = 12) compared to HC (n = 12) in preDCA (SA2) and decreased in VST (SA1). This study is a first step towards a better understanding of the pathophysiology of DD, which may ultimately lead to better detection, prevention and treatment. Despite major improvements in our understanding of the pathophysiology of schizophrenia and addiction, very few studies have focused on the area of comorbidity between these two disorders. Substance abuse is clearly a widespread problem in schizophrenia and represents a challenging therapeutic and management problem. We propose a first small study to test a working model of dopamine dysregulation in the brains of patients with cannabis dependence and schizophrenia, which will lead to a better understanding of the pathophysiology of dual diagnosis and better detection, prevention and treatment.