Institute of Neurophysiology, Charité Universitätsmedizin Berlin, Berlin, Germany NeuroCure Research Centre, Charité Universitätsmedizin Berlin, Berlin, Germany.
Br J Pharmacol. 2012 Dec;167(7):1480-91. doi: 10.1111/j.1476-5381.2012.02107.x.
Disturbed cortical gamma band oscillations (30-80 Hz) have been observed in schizophrenia: positive symptoms of the disease correlate with an increase in gamma oscillation power, whereas negative symptoms are associated with a decrease.
Here we investigated the effects of first and second generation antipsychotics (FGAs and SGAs, respectively) on gamma oscillations. The FGAs haloperidol, flupenthixol, chlorpromazine, chlorprothixene and the SGAs clozapine, risperidone, ziprasidone, amisulpride were applied on gamma oscillations induced by acetylcholine and physostigmine in the CA3 region of rat hippocampal slices.
Antipsychotics inhibited the power of gamma oscillations and increased the bandwidth of the gamma band. Haloperidol and clozapine had the highest inhibitory effects. To determine which receptor is responsible for the alterations in gamma oscillations, the effects of the antipsychotics were plotted against their pK(i) values for 19 receptors and analysed for correlation. Our results indicated that 5-HT(3) receptors have an enhancing effect on gamma oscillations whereas dopamine D(3) receptors inhibit them. To test this prediction, m-chlorophenylbiguanide, PD 128907 and CP 809101, selective agonists at 5-HT(3) , D(3) and 5-HT(2C) receptors were applied and revealed that 5-HT(3) receptors indeed enhanced the gamma power whereas D(3) receptors reduced it. As predicted, 5-HT(2C) receptors had no effects on gamma oscillations.
Our data suggest that antipsychotics alter hippocampal gamma oscillations by interacting with 5-HT(3) and dopamine D(3) receptors. Moreover, a correlation of receptor affinities with the biological effects can be used to predict targets for the pharmacological effects of multi-target drugs.
精神分裂症患者的皮质γ波段振荡（30-80Hz）受到干扰：疾病的阳性症状与γ振荡功率增加相关，而阴性症状则与γ振荡功率降低相关。
本文研究了第一代和第二代抗精神病药物（FGAs 和 SGAs）对γ振荡的影响。在大鼠海马切片 CA3 区，应用乙酰胆碱和毒扁豆碱诱导γ振荡，FGAs 氟哌啶醇、氟奋乃静、氯丙嗪、氯普噻吨和 SGAs 氯氮平、利培酮、齐拉西酮、氨磺必利作用于γ振荡。
抗精神病药物抑制γ振荡的功率并增加γ波段的带宽。氟哌啶醇和氯氮平的抑制作用最强。为了确定哪种受体负责γ振荡的改变，将抗精神病药物的作用与它们对 19 种受体的 pK(i)值作图，并进行相关性分析。我们的结果表明，5-HT(3)受体对γ振荡有增强作用，而多巴胺 D(3)受体则抑制它们。为了验证这一预测，应用 5-HT(3)、D(3)和 5-HT(2C)受体的选择性激动剂 m-氯苯大剂量、PD 128907 和 CP 809101，发现 5-HT(3)受体确实增强了γ功率，而 D(3)受体则降低了γ功率。如预测的那样，5-HT(2C)受体对γ振荡没有影响。
我们的数据表明，抗精神病药物通过与 5-HT(3)和多巴胺 D(3)受体相互作用来改变海马γ振荡。此外，受体亲和力与生物学效应的相关性可用于预测多靶药物的药理作用靶点。
