Ichikawa Junji, Dai Jin, O'Laughlin Ian A, Fowler Wiley L, Meltzer Herbert Y
Departments of Psychiatry and Pharmacology, The Psychiatric Hospital at Vanderbilt, Vanderbilt University School of Medicine, 1601 23rd Avenue South, Nashville, TN 37212, USA.
Neuropsychopharmacology. 2002 Mar;26(3):325-39. doi: 10.1016/S0893-133X(01)00312-8.
The role of acetylcholine (ACh) in the action of antipsychotic drugs (APDs) was studied by microdialysis, without AChesterase inhibition, to facilitate the interpretation of any observed drug effects. The atypical APDs, clozapine (2.5-20 mg/kg), olanzapine (10 mg/kg), risperidone (1 mg/kg), and ziprasidone (3 mg/kg) significantly increased ACh release in rat medial prefrontal cortex (mPFC), whereas the typical APDs, haloperidol (0.1-1 mg/kg), S(-)-sulpiride (10-25 mg/g), and thioridazine (5-20 mg/kg) did not. None of seven APDs increased ACh release in the nucleus accumbens or striatum at the doses effective in the mPFC. Thus, atypical and typical APDs may differ in the ability to increase cortical ACh release, a possible factor contributing to cognitive improvement in schizophrenia. After perfusion with neostigmine, an AChesterase inhibitor, clozapine, but not haloperidol, increased ACh release in all three aforementioned brain regions with an enhanced effect in the mPFC, indicating the importance of studying ACh release in the absence of AChesterase inhibition. Clozapine, and perhaps other atypical APDs, alone or in combination with an AChesterase inhibitor, may improve cognition in schizophrenia, and perhaps other cognitive disorders, e.g., early Alzheimer's disease, by enhancing cortical cholinergic transmission.
通过微透析研究了乙酰胆碱（ACh）在抗精神病药物（APD）作用中的角色，且未抑制乙酰胆碱酯酶，以便于解释观察到的任何药物效应。非典型抗精神病药物氯氮平（2.5 - 20毫克/千克）、奥氮平（10毫克/千克）、利培酮（1毫克/千克）和齐拉西酮（3毫克/千克）显著增加大鼠内侧前额叶皮质（mPFC）中的ACh释放，而典型抗精神病药物氟哌啶醇（0.1 - 1毫克/千克）、S（-）-舒必利（10 - 25毫克/克）和硫利达嗪（5 - 20毫克/千克）则没有。在对mPFC有效的剂量下，七种抗精神病药物中没有一种能增加伏隔核或纹状体中的ACh释放。因此，非典型和典型抗精神病药物在增加皮质ACh释放的能力上可能存在差异，这可能是有助于改善精神分裂症认知功能的一个因素。在用乙酰胆碱酯酶抑制剂新斯的明灌注后，氯氮平而非氟哌啶醇能增加上述所有三个脑区的ACh释放，且在mPFC中作用增强，这表明在不抑制乙酰胆碱酯酶的情况下研究ACh释放的重要性。氯氮平，或许还有其他非典型抗精神病药物，单独使用或与乙酰胆碱酯酶抑制剂联合使用，可能通过增强皮质胆碱能传递来改善精神分裂症以及或许其他认知障碍，如早期阿尔茨海默病的认知功能。
