Deutsch Stephen I, Urbano Maria R, Neumann Serina A, Burket Jessica A, Katz Elionora
Department of Psychiatry and Behavioral Sciences, Eastern Virginia Medical School, Norfolk, VA 23507-1912, USA.
Clin Neuropharmacol. 2010 May;33(3):114-20. doi: 10.1097/WNF.0b013e3181d6f7ad.
The core dysfunctions of autism spectrum disorders, which include autistic disorder, Asperger disorder, and pervasive developmental disorder not otherwise specified, include deficits in socialization and communication and a need for the preservation of "sameness;" intellectual impairment and epilepsy are common comorbidities. Data suggest that pathological involvement of cholinergic nuclei and altered expression of acetylcholine receptors, particularly nicotinic acetylcholine receptors, occur in brain of persons with autistic disorder. However, many of these studies involved postmortem tissue from small samples of primarily adult persons. Thus, the findings may reflect compensatory changes and may relate more closely to intellectual impairment and the confounding effects of seizures and medications, as opposed to the core dysfunctions of autism. Nonetheless, because of the roles played by acetylcholine receptors in general, and nicotinic acetylcholine receptors in particular, in normal processes of attention, cognition, and memory, selective cholinergic interventions should be explored for possible therapeutic effects. Additionally, there are electrophysiological data that complement the clinical observations of frequent comorbid seizure disorders in these patients, suggesting a disturbance in the balance of excitatory and inhibitory tone in the brains of persons with autistic disorders. Conceivably, because the alpha7 nicotinic acetylcholine receptor is located on the surface of gamma-aminobutyric acid inhibitory neurons, selective stimulation of this receptor would promote gamma-aminobutyric acid's release and restore diminished inhibitory tone. The development of agonists and partial agonists for nicotinic acetylcholine receptors and positive allosteric modulators that enhance the efficiency of coupling between the binding of agonist and channel opening should facilitate consideration of clinical trials.
自闭症谱系障碍的核心功能障碍，包括自闭症、阿斯伯格综合征和未特定的广泛性发育障碍，其核心功能障碍包括社交和沟通缺陷以及对保持“一致性”的需求；智力障碍和癫痫是常见的共病。数据表明，胆碱能核团的病理改变以及乙酰胆碱受体，特别是烟碱型乙酰胆碱受体的表达改变，发生在自闭症患者的大脑中。然而，这些研究大多涉及主要为成年人的小样本尸检组织。因此，这些发现可能反映了代偿性变化，并且可能与智力障碍以及癫痫和药物的混杂效应关系更为密切，而非与自闭症的核心功能障碍相关。尽管如此，由于乙酰胆碱受体，特别是烟碱型乙酰胆碱受体在正常的注意力、认知和记忆过程中所起的作用，应探索选择性胆碱能干预措施以寻求可能的治疗效果。此外，有一些电生理数据补充了这些患者频繁合并癫痫障碍的临床观察结果，表明自闭症患者大脑中兴奋性和抑制性张力的平衡受到干扰。可以想象，由于α7烟碱型乙酰胆碱受体位于γ-氨基丁酸抑制性神经元的表面，对该受体的选择性刺激将促进γ-氨基丁酸的释放并恢复减弱的抑制性张力。烟碱型乙酰胆碱受体激动剂、部分激动剂以及增强激动剂结合与通道开放之间偶联效率的正变构调节剂的开发，应有助于考虑开展临床试验。
