Imaging dopamine transmission in comorbid schizophrenia and cannabis dependence

描述(申请人提供)：多巴胺(DA)在精神分裂症和成瘾的病理生理学中发挥作用。成像研究一直表明，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则变得迟钝。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。这些改进有助于以下观察：在成瘾患者中，DA传递主要在腹侧纹状体(VST)钝化，而在精神分裂症中，DA传递在联合纹状体，更具体地说，在连合前尾状核(PreDCA)增加。由于纹状体内DA传递的这种相反的失调，下一个耐人寻味的问题是关于同时患有精神分裂症和成瘾的双重诊断患者，特别是那些遭受大麻依赖的患者。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(DD用于双重诊断)的受试者将在DA传递中表现出相反的变化，其中VST钝化，而PreDCA增加。这可以解释为什么服用药物(VST中低多巴胺)会导致精神病症状(药物可能失调前DCA中的多巴胺)。抗精神病药物将加剧VST中的低多巴胺基调，导致渴望、吸毒、不坚持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，我们建议提供一小笔同伴赠款，重点放在同时患有大麻依赖和精神分裂症的双重诊断患者。12名DD患者和12名匹配的健康对照(HC)将接受[11C]拉氯普利和D-苯丙胺挑战的PET成像。主要的结果测量将是由于苯丙胺诱导的DA释放或V3“导致的[11C]拉氯必利特定到非特定的平衡分配系数(V3”)的降低。我们预计，与前DCA(SA2)的HC(n=12)相比，DD(n=12)的V3“将增加，而VST(SA1)的V3”将减少。这项研究是朝着更好地了解DD的病理生理学迈出的第一步，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进步，但很少有研究集中在这两种疾病之间的共病领域。药物滥用显然是精神分裂症中一个普遍存在的问题，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规模研究，以测试大麻依赖和精神分裂症患者大脑中多巴胺失调的工作模型，这将导致更好地理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.