Nicotinic-Antipsychotic Drug Interactions and Cognition

大多数精神分裂症患者都是通过吸烟来自我摄入尼古丁的。尼古丁对认知功能有直接影响，并与抗精神病药物相互作用，显著影响其对认知功能的作用。尼古丁的认知作用可能为改善与精神分裂症相关的认知功能障碍和抗精神病药物引起的认知功能障碍的治疗提供了新的机会。经典的抗精神病药如氟哌啶醇和“非典型”抗精神病药如氯氮平和利培酮具有本质上不同的作用机制，可能以完全不同的方式与尼古丁相互作用。拟议的项目将确定尼古丁系统与抗精神病药物相互作用以影响认知功能的功能机制。经典和非典型抗精神病药物都被发现损害记忆功能。在我们早期对精神分裂症患者和实验鼠的研究中发现，氟哌啶醇引起的工作记忆缺陷可以通过急性剂量的尼古丁来逆转。最近，我们发现氯氮平引起的大鼠工作记忆损伤可以通过尼古丁逆转。这些影响将被用作确定尼古丁与抗精神病药物在控制记忆功能中相互作用的关键神经机制的论坛。我们假设海马体中的尼古丁受体系统是尼古丁减轻精神分裂症相关的注意力障碍和抗精神病药物引起的记忆障碍的关键机制。在我们之前的研究中发现，海马体的尼古丁神经支配对尼古丁对记忆的影响至关重要。重要的是，我们还表明海马DA神经支配对记忆功能也很重要。拟议的项目将明确尼古丁与抗精神病药物对记忆功能的相互作用的机制，包括尼古丁受体亚型及其在海马中对记忆功能重要的解剖位点的参与。选择性尼古丁拮抗剂亚型的剂量反应局部输注研究将用于确定尼古丁系统与基准径向臂迷宫任务和操作性注意任务中记忆表现的关系。这些基础研究将有助于阐明有关尼古丁与经典和非典型抗精神病药物共同治疗对改善记忆和注意力功能的影响的重要治疗问题。这些研究将提供有关神经系统的信息，这些信息可能是我们在系统水平上看到的尼古丁作用的基础，并促进精神分裂症认知功能障碍新药治疗的开发。

Nicotine is self-administered via cigarette smoking by the great majority of patients with schizophrenia. Nicotine has direct effects on cognitive function and interacts with antipsychotic drugs to substantially influence their actions on cognitive function. The cognitive effects of nicotine may present a novel opportunity for improving the treatment of cognitive dysfunction associated with schizophrenia and cognitive dysfunction induced by antipsychotic drugs. Classical neuroleptics such as haloperidol and "atypical" antipsychotics such a clozapine and risperidone have substantially different mechanisms of action and likely interact with nicotine in quite different ways. The proposed project will determine the functional mechanisms by which nicotinic systems interact with antipsychotic drugs to affect cognitive function. Both classical and atypical antipsychotic drugs have been found to impair memory function. Haloperidol-induced working memory deficits have been found in our earlier studies of schizophrenic patients and laboratory rats to be reversed by acute doses of nicotine. Recently, we have found that the working memory impairment caused in rats by clozapine administration can be reversed by nicotine. These effects will be used as a forum in which to determine the critical neural mechanisms by which nicotine interacts with antipsychotic drugs in the control of memory function. We hypothesize that nicotinic receptor systems in the hippocampus are a key mechanism by which nicotine alleviates schizophrenia associated attentional impairment and antipsychotic drug-induced memory impairment. Nicotinic innervation of the hippocampus has been found in our previous studies to be critical for nicotine effects on memory. Importantly, we have also shown that hippocampal DA innervation is also important for memory function. The proposed project will specify the mechanisms underlying nicotinic interactions with antipsychotic effects on memory function, including involvement of nicotinic receptor subtypes and their anatomic loci in hippocampus important for memory function. Dose response local infusion studies with selective nicotinic antagonist subtypes will be used to determine the relationship of nicotinic systems for memory performance in the benchmark radial-arm maze task as well as an operant attention task. These basic studies will help elucidate important therapeutic issues concerning the impact of nicotinic co- treatment with classic and atypical antipsychotic drugs to improve memory and attentional function. These studies will provide information concerning neural systems likely to underlie nicotinic actions we have seen on a systemic level and facilitate the development of new drug therapies for cognitive dysfunction in schizophrenia.