Chronic PCP Primate PFC Dopamine Deficit and Schizophrenia

描述(申请人提供)：我们在啮齿动物和灵长类动物身上的研究表明，反复停用苯环利定(PCP)对生物化学和行为的影响形成了一个有用的精神分裂症认知缺陷模型。PCP暴露会导致前额叶皮质(PFC)多巴胺(DA)周转量的持续性和区域性下降，减少PFC锥体神经元上不对称脊突触的数量，并导致执行PFC依赖的认知任务的障碍。综上所述，这些新的数据支持我们的假设，即PFC内树突上的脊髓突触数量是DA依赖的，可能是该区域DA神经传递持续减少所导致的认知障碍的形态基础。由于认知表现和记忆过程似乎与PFC的重塑有关，锥体树突突触可能至少部分地与我们观察到的灵长类PCP模型中的认知功能障碍有关。 这些PCP诱导的DA传递、树突棘形态和认知的变化使人想起精神分裂症患者大脑中报道的变化。在幼年和青春期，灵长类动物的PFC在形态和生化上仍在经历着显著的成熟。对于男性来说，这是精神分裂症症状通常出现的发育阶段，也是对精神活性药物后果的易感性增强的年龄。因此，我们现在急于扩大我们的灵长类动物的工作，以检查五氯酚治疗对幼年和青少年猴子的影响。我们推测，与成年猴相比，幼猴在PFC背外侧区暴露PCP后，将表现出更显著和更持久的影响，表现为DA更替减少、NMDA受体功能低下和不对称脊突触数量减少。我们希望观察到认知表现的缺陷，与DA周转和不对称脊椎突触数量的变化同步。与人类和动物研究腹侧前额叶皮质5-羟色胺在抑制控制和冲动方面的作用的证据一致，我们还预计，在年轻猴子身上，外侧眼眶皮质和伏隔核外壳中的5-羟色胺周转量会在一个与逆转学习任务中的认知缺陷平行的时间过程中放大减少。这项工作将：1)确定非人类灵长类动物PFC的正常突触和单胺发育模式，这对于更好地理解许多疾病，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分裂症药物的脆弱性；III)提供关于NMDA受体功能和PFC完整性之间作为发育函数的洞察力；以及IV)提供精神分裂症PFC认知缺陷的有用的灵长类动物发育模型。 公共卫生相关性：精神分裂症患者的认知缺陷是最难治疗的迹象。反复对猴子进行PCP治疗是精神分裂症认知缺陷的有用模型。由于PFC回路在发育过程中对精神活性药物的脆弱性增加，并且在成年早期典型地出现精神分裂症症状，对反复发生PCP的少年和青少年猴子的治疗有望提供一种更好、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.