the Mental Health Research Institute, Parkville, Victoria, Australia.
CNS Neurol Disord Drug Targets. 2010 Apr;9(2):241-56. doi: 10.2174/187152710791012062.
Cognitive deficits in patients with schizophrenia are the biggest obstacle to achieving an independent and productive lifestyle, with these deficits being refractory to current drug treatments. Significantly, both nicotinic and muscarinic receptors (cholinoceptors) have been shown to have an important role in cognition and are therefore viewed as potential therapeutic targets for drugs designed to lessen cognitive deficits. Importantly, the demonstration that acetylcholinesterase inhibitors, which result in higher synaptic levels of acetylcholine, can reduce the cognitive deficits of schizophrenia suggested that under-stimulation of cholinoceptors could be associated with the cognitive deficits associated with this disorder. This has lead to a focus on the development of receptor agonists, partial agonists and allosteric agonists that can be used to stimulate cholinergic pathways and thus reduce the cognitive deficits of schizophrenia. In addition, muscarinic receptors have now been associated with the modulation of dopamine and may constitute an alternative target for the treatment of psychoses. Given these exciting new therapeutic initiatives, this review will outline current evidence that involves the cholinoceptors in the pathophysiology of schizophrenia and how these data can inform on approaches to more targeted treatments for the disorder.
精神分裂症患者的认知缺陷是实现独立和富有成效的生活方式的最大障碍，而这些缺陷对当前的药物治疗具有抗性。值得注意的是，烟碱和毒蕈碱受体（胆碱能受体）已被证明在认知中具有重要作用，因此被视为设计用于减轻认知缺陷的药物的潜在治疗靶标。重要的是，证明乙酰胆碱酯酶抑制剂可导致突触中乙酰胆碱水平升高，可减少精神分裂症的认知缺陷，这表明胆碱能受体的刺激不足可能与该疾病相关的认知缺陷有关。这导致了对受体激动剂、部分激动剂和变构激动剂的开发的关注，这些激动剂可用于刺激胆碱能途径，从而减少精神分裂症的认知缺陷。此外，毒蕈碱受体现已与多巴胺的调节有关，可能构成治疗精神病的替代靶标。鉴于这些令人兴奋的新治疗策略，本综述将概述涉及精神分裂症病理生理学的胆碱能受体的当前证据，以及这些数据如何为针对该疾病的更有针对性的治疗方法提供信息。
