Celada Pau, Puig M Victoria, Díaz-Mataix Llorenç, Artigas Francesc
Department of Neurochemistry and Neuropharmacology, Institut d'Investigacions Biomèdiques de Barcelona, Consejo Superior de Investigaciones Científicas, IDIBAPS, Centro de Investigación Biomédica en Red de Salud Mental, Barcelona, Spain.
Biol Psychiatry. 2008 Sep 1;64(5):392-400. doi: 10.1016/j.biopsych.2008.03.013. Epub 2008 Apr 23.
Perceptual and psychic alterations and thought disorder are fundamental elements of schizophrenia symptoms, a pathology associated with an abnormal macro- and microcircuitry of several brain areas including the prefrontal cortex (PFC). Alterations in information processing in PFC may partly underlie schizophrenia symptoms.
The 5-HT(2A/2C) agonist DOI and antipsychotic drugs were administered to anesthetized rats. Single unit and local field potential (LFP) extracellular recordings were made in medial PFC (mPFC). Electrolytic lesions were performed in the thalamic nuclei.
DOI markedly disrupts cellular and network activity in rat PFC. DOI altered pyramidal discharge in mPFC (39% excited, 27% inhibited, 34% unaffected; n = 51). In all instances, DOI concurrently reduced low-frequency oscillations (.3-4 Hz; power spectrum: .25 +/- .02 and .14 +/- .01 microV(2) in basal conditions and after 50-300 microg/kg intravenous (i.v.) DOI, respectively; n = 51). Moreover, DOI disrupted the temporal association between the active phase of LFP and pyramidal discharge. Both effects were reversed by M100907 (5-HT(2A) receptor antagonist) and were not attenuated by thalamic lesions, supporting an intracortical origin of the effects of DOI. The reduction in low-frequency oscillations induced by DOI was significantly reversed by the antipsychotic drugs haloperidol (.1-.2 mg/kg i.v.) and clozapine (1 mg/kg i.v.).
DOI disorganizes network activity in PFC, reducing low-frequency oscillations and desynchronizing pyramidal discharge from active phases of LFP. These effects may underlie DOI's psychotomimetic action. The reversal by clozapine and haloperidol indicates that antipsychotic drugs may reduce psychotic symptoms by normalizing an altered PFC function.
感知和心理改变以及思维紊乱是精神分裂症症状的基本要素，精神分裂症是一种与包括前额叶皮质（PFC）在内的多个脑区的宏观和微观回路异常相关的病理学疾病。PFC中信息处理的改变可能部分是精神分裂症症状的基础。
将5-HT(2A/2C)激动剂DOI和抗精神病药物给予麻醉大鼠。在内侧前额叶皮质（mPFC）进行单单位和局部场电位（LFP）细胞外记录。在丘脑核进行电解损伤。
DOI显著破坏大鼠PFC中的细胞和网络活动。DOI改变了mPFC中的锥体放电（39%兴奋，27%抑制，34%未受影响；n = 51）。在所有情况下，DOI同时降低了低频振荡（0.3 - 4 Hz；功率谱：基础条件下为0.25±0.02 μV²，静脉注射（i.v.）50 - 300 μg/kg DOI后为0.14±0.01 μV²；n = 51）。此外，DOI破坏了LFP活动期与锥体放电之间的时间关联。这两种效应均被M100907（5-HT(2A)受体拮抗剂）逆转，并且未因丘脑损伤而减弱，支持DOI效应的皮质内起源。DOI诱导的低频振荡减少被抗精神病药物氟哌啶醇（0.1 - 0.2 mg/kg i.v.）和氯氮平（1 mg/kg i.v.）显著逆转。
DOI扰乱PFC中的网络活动，降低低频振荡并使锥体放电与LFP的活动期不同步。这些效应可能是DOI拟精神病作用的基础。氯氮平和氟哌啶醇的逆转作用表明抗精神病药物可能通过使改变的PFC功能正常化来减轻精神病症状。
