Shared Neural Circuitry in Comorbid Schizophrenia and Nicotine Addiction

描述（由申请人提供）：严重精神疾病患者与烟草使用相关的健康风险远高于一般人群。其中，精神分裂症患者可能是尼古丁成瘾风险最高的人群。目前对严重精神分裂症-吸烟共病的可能病因的概念包括神经认知缺陷的自我药物治疗，克服抗精神病药物的副作用，以及共享的尼古丁分子途径。然而，这种共病的潜在脑回路尚不清楚。识别大脑共病回路对于开发有效的生物标志物，用于临床治疗开发、个体化治疗选择和结果预测至关重要。最近的数据表明，扣带-腹侧纹状体回路似乎是与尼古丁成瘾相关的关键途径之一。这些相同的区域也是精神分裂症最常涉及的区域之一，另外的初步研究表明，精神分裂症中同样的回路受损。因此，我们假设异常的扣带-腹侧纹状体回路是精神分裂症/尼古丁成瘾共病的关键途径。我们建议验证扣带-腹侧纹状体回路在尼古丁成瘾和精神分裂症中异常的假设，精神分裂症病理破坏了该回路，使患者易患更严重的尼古丁成瘾，导致严重的尼古丁成瘾/精神分裂症共病。我们还将研究该回路在预测长期吸烟行为改变、遗传学及其与假定的成瘾机制的关系方面的临床有效性。在这一高危人群中确定与吸烟相关的关键脑回路将为新的治疗开发提供具体的生物标志物，并最终减少精神分裂症患者吸烟相关的健康负担。此外，由于公共卫生努力减少了吸烟，人口中那些仍然吸烟的人可能更加依赖和更难以治疗。针对最严重的吸烟成瘾人群的努力也可能为治疗普通人群的尼古丁成瘾提供新的视角。

DESCRIPTION (provided by applicant): The health risk associated with tobacco use in people with severe mental illness is much higher than the general population. Among them, patients with schizophrenia are the population with perhaps the highest risk for nicotine addition. Current conceptualizations of the possible etiologies of the severe schizophrenia-smoking comorbidity include self-medication for neurocognition deficits, overcoming antipsychotic medication side effects, and shared nicotinic molecular pathways. However, the underlying brain circuitry for the comorbidity is unknown. Identifying brain comorbidity circuitry is critical for developing valid biomarkers for clinical therapeutic development, individualizing treatment selection and outcome prediction. Recent data suggest that the cingulate-ventral striatum circuit appears to be one of the key pathways associated with nicotine addiction. These same areas are also among the regions most commonly implicated in schizophrenia, and additional preliminary studies suggest that the same circuit is impaired in schizophrenia. Therefore, we hypothesize that abnormal cingulate-ventral striatum circuit is a key path for schizophrenia/nicotine addiction comorbidity. We propose to test the hypotheses that the cingulate-ventral striatum circuit is abnormal in nicotine addiction and in schizophrenia, and that schizophrenia pathology disrupts this circuit and predisposes patients to more severe nicotine addiction, leading to the severe nicotine addiction/schizophrenia comorbidity. We will also examine the clinical validities of the circuit in prediction of long-term smoking behavioral change, in genetics, and in its relationships to putative addiction mechanisms. Identifying the key brain circuits associated with smoking in this high risk population will provide concrete biomarkers for new therapeutic development, and ultimately reducing the smoking related health burden in schizophrenia patients. In addition, as public health efforts have reduced smoking, those who still smoke in the population may be more dependent and more treatment-resistant. An effort targeting the population most addicted to smoking may also yield novel perspectives to treat nicotine addiction in the general population. PUBLIC HEALTH RELEVANCE: People with schizophrenia have high rate of smoking, which is often resistant to available treatment. This study aims to identify the brain circuit responsible for the smoking comorbidity in these patients, which should lead to better treatment strategy for reducing smoking and smoking related health burden in schizophrenia patients and perhaps also in other treatment-resistant smokers in the general population.