在海马-前额叶皮层连接的神经元可塑性表型筛选中发现一种具有新型特征的抗精神病药。

Phenotypical Screening on Neuronal Plasticity in Hippocampal-Prefrontal Cortex Connectivity Reveals an Antipsychotic with a Novel Profile.

机构信息

Institut de Recherches Internationales Servier, 92284 Suresnes, France.

Spedding Research Solutions SAS, 78110 Le Vésinet, France.

出版信息

Cells. 2022 Mar 31;11(7):1181. doi: 10.3390/cells11071181.

Dysfunction in the hippocampus-prefrontal cortex (H-PFC) circuit is a critical determinant of schizophrenia. Screening of pyridazinone-risperidone hybrids on this circuit revealed EGIS 11150 (S 36549). EGIS 11150 induced theta rhythm in hippocampal slice preparations in the stratum lacunosum molecular area of CA1, which was resistant to atropine and prazosin. EGIS 11150 enhanced H-PFC coherence, and increased the 8−9 Hz theta band of the EEG power spectrum (from 0.002 mg/kg i.p, at >30× lower doses than clozapine, and >100× for olanzapine, risperidone, or haloperidol). EGIS 11150 fully blocked the effects of phencyclidine (PCP) or ketamine on EEG. Inhibition of long-term potentiation (LTP) in H-PFC was blocked by platform stress, but was fully restored by EGIS 11150 (0.01 mg/kg i.p.), whereas clozapine (0.3 mg/kg ip) only partially restored LTP. EGIS 11150 has a unique electrophysiological profile, so phenotypical screening on H-PFC connectivity can reveal novel antipsychotics.

海马-前额皮质（H-PFC）回路功能障碍是精神分裂症的关键决定因素。在该回路中对哒嗪酮-利培酮杂化物进行筛选，发现了 EGIS 11150（S 36549）。EGIS 11150 在 CA1 分子层的海马切片制备物中诱导了海马 theta 节律，该节律对阿托品和普萘洛尔具有抗性。EGIS 11150 增强了 H-PFC 的相干性，并增加了 EEG 频谱的 8-9 Hz theta 波段（从 0.002 mg/kg 腹腔内给药开始，其剂量比氯氮平低 30 倍以上，比奥氮平、利培酮或氟哌啶醇高 100 倍以上）。EGIS 11150 完全阻断了苯环利定（PCP）或氯胺酮对 EEG 的影响。平台应激抑制了 H-PFC 中的长时程增强（LTP），但 EGIS 11150（0.01 mg/kg 腹腔内给药）完全恢复了 LTP，而氯氮平（0.3 mg/kg 腹腔内给药）仅部分恢复了 LTP。EGIS 11150 具有独特的电生理特征，因此 H-PFC 连接性的表型筛选可以揭示新型抗精神病药。