Dewey S L, Smith G S, Logan J, Brodie J D
Department of Chemistry, Brookhaven National Laboratory, Upton, New York 11973.
Neuropsychopharmacology. 1993 Jun;8(4):371-6. doi: 10.1038/npp.1993.37.
The pharmacologic treatment of many neuropsychiatric disorders (Alzheimer's disease, schizophrenia, depressive illness) has been targeted at the central hypothesis that defects in a single neurotransmitter system underlie the pathophysiology of the disease state. With the recognition that such treatments have not been efficacious consistently, recent drug development has been directed at altering other functionally linked neurotransmitters involved in these diseases. Using positron emission tomography, we have noninvasively investigated the effects of two noncholinergic drugs on the release of acetylcholine. By examining the effects of gamma-vinyl gamma-aminobutyric acid (GABA) (a GABA transaminase inhibitor) or altanserin (a serotonergic antagonist) on the regional binding of 11C-benztropine in the primate brain (Papio anubis), we demonstrated that drugs acting upon either GABAergic or serotonergic neurons produce profound regional changes in acetylcholine release. These findings indicate that the mechanisms of action and the subsequent therapeutic efficacy of these centrally acting drugs may be linked to their multitransmitter effects. This application of positron emission tomography represents an extremely promising experimental approach that can be directed towards elucidating abnormalities in neurotransmitter modulation relevant to disease progression and pharmacologic treatment.
许多神经精神疾病（阿尔茨海默病、精神分裂症、抑郁症）的药物治疗一直围绕着这样一个核心假说：单一神经递质系统的缺陷是疾病状态病理生理学的基础。鉴于认识到此类治疗并非始终有效，近期的药物研发方向已转向改变这些疾病中涉及的其他功能相关神经递质。我们利用正电子发射断层扫描技术，对两种非胆碱能药物对乙酰胆碱释放的影响进行了无创研究。通过检测γ-乙烯基γ-氨基丁酸（GABA）（一种GABA转氨酶抑制剂）或阿坦色林（一种5-羟色胺拮抗剂）对灵长类动物大脑（狒狒）中11C-苯海索区域结合的影响，我们证明作用于GABA能或5-羟色胺能神经元的药物会使乙酰胆碱释放产生显著的区域变化。这些发现表明，这些中枢作用药物的作用机制及其后续治疗效果可能与其多递质效应有关。正电子发射断层扫描技术的这种应用代表了一种极有前景的实验方法，可用于阐明与疾病进展和药物治疗相关的神经递质调节异常。
