Chronic PCP Primate PFC Dopamine Deficit and Schizophrenia

描述（由申请人提供）：我们在啮齿动物和灵长类动物中的工作表明，从重复苯环己哌啶（PCP）中戒断的生化和行为效应形成了精神分裂症认知缺陷的有用模型。五氯苯酚暴露会导致前额叶皮层（PFC）多巴胺（DA）周转率持续和区域特异性下降，PFC锥体神经元上的不对称棘突触数量减少，以及执行PFC依赖性认知任务的缺陷。这些新的数据一起支持我们的假设，在PFC树突上的棘突触的数量是DA依赖性的，可能是一个形态学基板的认知功能障碍引起的持续减少DA神经传递在这个地区。由于认知性能和记忆过程似乎与PFC的重塑相结合，锥体树突棘突触可能，至少部分地，有助于观察到的认知功能障碍，在我们的灵长类动物PCP模型。 这些PCP诱导的DA传输，树突棘形态和认知的变化让人想起精神分裂症患者大脑中报告的改变。在幼年和青少年时期的发展过程中，灵长类动物的PFC仍在经历显着的成熟，无论是形态和生化。在人类中，这是精神分裂症症状典型出现的发育时期，也是对精神活性药物后果的脆弱性增强的年龄。因此，我们现在渴望扩大我们的灵长类动物工作，以检查五氯苯酚治疗对少年和青少年猴子的影响。我们假设，与成年人相比，年轻的猴子将显示更明显和更持久的PCP暴露减少DA营业额，NMDA受体功能减退和减少不对称的脊柱突触数量与成年人相比，在背外侧PFC的影响。我们期望观察到认知能力的缺陷，平行DA营业额和不对称的脊柱突触数量的变化。与人类和动物研究中关于腹侧前额叶皮层中5-羟色胺对抑制控制和冲动性的作用的证据一致，在年轻的猴子中，我们还预计在与逆转学习任务中的认知缺陷平行的时间过程中，外侧眶皮层和背核壳中的5-羟色胺周转率会放大降低。这项工作将i）确定非人灵长类PFC的正常突触和单胺发育的模式，这对于更好地理解许多疾病至关重要，例如精神分裂症，被认为与突触发育不良有关，ii）揭示PFC认知回路在发育过程中对拟精神病药物的脆弱性，iii）提供关于NMDA受体功能和PFC完整性作为发育的函数之间的关系的见解，以及iv）提供精神分裂症中PFC认知缺陷的有用的灵长类发育模型。 公共卫生相关性：精神分裂症的认知缺陷是最难治疗的症状。对猴子重复PCP治疗是精神分裂症认知缺陷的有用模型。由于PFC电路在发育过程中对精神活性药物的脆弱性增加，以及成年早期精神分裂症症状的典型出现，用重复PCP治疗青少年和青春期猴子有望提供更好和更相关的精神分裂症认知缺陷模型。

DESCRIPTION (provided by applicant): Our work in both rodents and primates has indicated that the biochemical and behavioral effects of withdrawal from repeated phencyclidine (PCP) form a useful model of the cognitive deficits of schizophrenia. PCP exposure imparts a lasting and regionally-specific decrease in dopamine (DA) turnover in the prefrontal cortex (PFC), a decreased number of asymmetric spine synapses on PFC pyramidal neurons, and deficits in performing PFC-dependent cognitive tasks. Together these novel data support our hypothesis that the number of spine synapse on dendrites in the PFC is DA-dependent and may be a morphological substrate of the cognitive deficits induced by sustained reductions in DA neurotransmission in this region. Because cognitive performance and memory processes seem to be coupled with the remodeling of PFC, pyramidal dendritic spine synapses may, at least partly, contribute to observed cognitive dysfunction in our primate PCP model. These PCP-induced changes in DA transmission, dendritic spine morphology and cognition are reminiscent of alterations reported in brains from schizophrenic patients. During juvenile and adolescent periods of development the PFC in primates is still undergoing significant maturation, both morphologically and biochemically. In man, this is the time in development when signs of schizophrenia typically emerge and also is the age at which the vulnerability to the consequences of psychoactive drugs is enhanced. Thus, we are now eager to extend our primate work to examine the effects of PCP treatment in juvenile and adolescent monkeys. We hypothesize that compared to adults, young monkeys will display more pronounced and longer lasting effects of PCP exposure on diminished DA turnover, NMDA receptor hypofunction and reduced asymmetric spine synapse number in the dorsolateral PFC compared with adults. We expect to observe deficits in cognitive performance that parallel the changes in DA turnover and asymmetric spine synapse number. Consistent with evidence from human and animal studies on the role of serotonin in the ventral prefrontal cortex on inhibitory control and impulsivity, in young monkeys we also expect a magnified reduction in serotonin turnover in the lateral orbital cortex and nucleus accumbens shell in a time-course that parallels the cognitive deficit in the reversal learning task. This work will i) identify the pattern of normal synaptic and monoamine development of the non-human primate PFC, which is critical for a better understanding of the many diseases, such as schizophrenia, thought to be related to synaptic maldevelopment, ii) reveal the vulnerability of PFC cognitive circuits to psychotomimetic agents during development, iii) provide insight concerning the relationship between NMDA receptor function and PFC integrity as a function of development, and iv) provide a useful primate developmental model of PFC cognitive deficits in schizophrenia. PUBLIC HEALTH RELEVANCE: The cognitive deficit in schizophrenia is the most treatment resistant sign. Repeated PCP treatment of monkeys is a useful model of schizophrenic cognitive deficits. Due to the increased vulnerability of PFC circuitry to psychoactive drugs during development, and the typical emergence of schizophrenic symptoms in early adulthood, the treatment of juvenile and adolescent monkeys with repeated PCP promises to provide a better and more relevant model of schizophrenic cognitive deficits.