Levin Edward D, Rezvani Amir H
Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC 27710, USA.
EXS. 2006;98:185-205. doi: 10.1007/978-3-7643-7772-4_10.
In summary, neuronal nicotinic systems are important for a variety of aspects of cognitive function impacted by antipsychotic drugs. It has been demonstrated that antipsychotic drugs have memory and attentional impairing effects when given to unimpaired subjects. Nicotine can reduce some of these impairments, but antipsychotic drug administration can also attenuate nicotine effects. We have found that nicotinic agonists selective for alpha7 and alpha4beta2 receptor subtypes significantly improve learning and memory. Serotonergic actions of antipsychotic drugs may decrease efficacy of nicotinic co-treatments. When the antipsychotic drug clozapine and nicotine are administered to subjects with cognitive impairments caused by NMDA glutamate receptor blockade or hippocampal dysfunction they can significantly attenuate the attentional and memory impairments. Nicotine has been shown in our studies to reverse the memory impairment caused by acute clozapine-induced memory improvement. Acute risperidone and haloperidol has been shown to attenuate nicotine-induced memory improvement. We have determined the role of hippocampal alpha7 and alpha4beta2 nicotinic receptors in the neural basis of nicotinic antipsychotic interactions. Local acute and chronic hippocampal infusion of either nicotinic alpha7 or alpha4beta2 antagonists cause significant spatial working memory impairment. Chronic hippocampal nicotinic antagonist infusions have served as a model of persistent decreases in nicotinic receptor level seen in schizophrenia and Alzheimer's disease. Clozapine attenuated the memory deficit caused by chronic suppression of hippocampal alpha4beta2 receptors while the amnestic effects of clozapine were potentiated by chronic suppression of hippocampal alpha7 receptors. Nicotinic co-treatment may be a useful adjunct in the treatment of schizophrenia, to attenuate cognitive impairment of schizophrenia. Nicotine as well as selective nicotinic alpha7 and alpha4beta2 receptor agonists significantly improve working memory and attentional function. Nicotine treatment was found to be effective in attenuating the attentional and memory impairments caused by the psychototmimetic NMDA antagonist dizocilpine (MK-801), a model of the cognitive impairment of schizophrenia. Studies of the interactions of antipsychotic drugs with nicotinic agents provided quite useful information concerning possible co-treatment of people with schizophrenia with nicotinic therapy. Nicotine was found to significantly attenuate the memory impairments caused by the antipsychotic drugs clozapine and olanzapine. Interestingly, nicotine-induced cognitive improvement was significantly attenuated by the antipsychotic drug clozapine. One of the principal effects of clozapine is to block 5HT2 receptors. Ketanserin a 5HT2 antagonist significantly attenuated nicotine-induced improvements in attention and memory. Thus it appears that antipsychotic drugs with actions blocking 5HT2 receptors may limit the efficacy of nicotinic co-treatments for cognitive enhancement.
总之，神经元烟碱系统对于受抗精神病药物影响的认知功能的各个方面都很重要。已经证明，抗精神病药物给予未受损受试者时具有记忆和注意力损害作用。尼古丁可以减轻其中一些损害，但抗精神病药物的给药也可以减弱尼古丁的作用。我们发现，对α7和α4β2受体亚型具有选择性的烟碱激动剂可显著改善学习和记忆。抗精神病药物的5-羟色胺能作用可能会降低烟碱联合治疗的疗效。当将抗精神病药物氯氮平和尼古丁给予由NMDA谷氨酸受体阻断或海马功能障碍引起认知损害的受试者时，它们可以显著减轻注意力和记忆损害。在我们的研究中，尼古丁已被证明可逆转急性氯氮平诱导的记忆改善所引起的记忆损害。急性利培酮和氟哌啶醇已被证明可减弱尼古丁诱导的记忆改善。我们已经确定了海马α7和α4β2烟碱受体在烟碱抗精神病药物相互作用的神经基础中的作用。局部急性和慢性海马注射烟碱α7或α4β2拮抗剂会导致显著的空间工作记忆损害。慢性海马烟碱拮抗剂注射已作为精神分裂症和阿尔茨海默病中所见烟碱受体水平持续下降的模型。氯氮平减轻了慢性抑制海马α4β2受体所引起的记忆缺陷，而慢性抑制海马α7受体则增强了氯氮平的遗忘作用。烟碱联合治疗可能是治疗精神分裂症的有用辅助手段，以减轻精神分裂症的认知损害。尼古丁以及选择性烟碱α7和α4β2受体激动剂可显著改善工作记忆和注意力功能。发现尼古丁治疗可有效减轻由拟精神病性NMDA拮抗剂地佐环平（MK-801）引起的注意力和记忆损害，MK-801是精神分裂症认知损害的模型。抗精神病药物与烟碱类药物相互作用的研究为精神分裂症患者可能的烟碱治疗联合用药提供了非常有用的信息。发现尼古丁可显著减轻抗精神病药物氯氮平和奥氮平引起的记忆损害。有趣的是，抗精神病药物氯氮平显著减弱了尼古丁诱导的认知改善。氯氮平的主要作用之一是阻断5HT2受体。酮色林是一种5HT2拮抗剂，可显著减弱尼古丁诱导的注意力和记忆改善。因此，似乎具有阻断5HT2受体作用的抗精神病药物可能会限制烟碱联合治疗对认知增强的疗效。
