Chronic administration of antipsychotics attenuates ongoing and ketamine-induced increases in cortical γ oscillations
Chronic administration of antipsychotics attenuates ongoing and ketamine-induced increases in cortical γ oscillations
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DOI：
10.1017/s1461145714000959
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发表时间：
2014-11-01
影响因子：
4.8
通讯作者：
Jones, Nigel C.
中科院分区：
文献类型：
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作者：
Anderson, Paul M.;Pinault, Didier;Jones, Nigel C.
非竞争性N-甲基-D-天冬氨酸受体（NMDAr）拮抗剂可引起健康人精神分裂症中观察到的许多症状，并诱导动物出现与精神病相关的行为表型。这些化合物还提高伽马（gamma）频率（30-80 Hz）神经振荡的功率和同步性。急性剂量的抗精神病药物已被证明可以降低正在进行的伽马功率，并抑制NMDAr拮抗剂介导的精神病样行为的啮齿动物。本研究旨在研究慢性抗精神病药物给药方案如何影响正在进行的皮质γ振荡，以及由NMDA受体拮抗剂氯胺酮诱导的电生理和行为反应。雄性Wistar大鼠用氟哌啶醇（0.25 mg/kg/d）、氯氮平（5 mg/kg/d）、LY 379268（0.3 mg/kg/d）或媒介物长期处理28天，通过皮下（s.c.）渗透泵每周记录皮层脑电图（ECoG）。在第26天，将氯胺酮（5 mg/kg，s.c.）给予，并同时测量ECoG和自发活动。将这些结果与先前使用这些抗精神病药物进行急性治疗后产生的数据进行比较。持续且显着下降。与溶媒相比，在氟哌啶醇（64%）或氯氮平（43%）的长期给药期间观察到效力，但在LY 379268（增加2%）的长期给药期间未观察到效力。急性氯胺酮注射同时增加溶剂处理大鼠的γ功率和自发活动，这些影响在所有三种抗精神病药物长期处理的大鼠中减弱。急性给药后，未观察到氟哌啶醇或氯氮平抑制氯胺酮诱导的γ功率升高的能力。这些结果表明，γ功率的调制可能是慢性抗精神病药物疗效的有用生物标志物。
Noncompetitive N-methyl-D-aspartate receptor (NMDAr) antagonists can elicit many of the symptoms observed in schizophrenia in healthy humans, and induce a behavioural phenotype in animals relevant to psychosis. These compounds also elevate the power and synchrony of gamma (gamma) frequency (30-80 Hz) neural oscillations. Acute doses of antipsychotic medications have been shown to reduce ongoing gamma power and to inhibit NMDAr antagonist-mediated psychosis-like behaviour in rodents. This study aimed to investigate how a chronic antipsychotic dosing regimen affects ongoing cortical gamma oscillations, and the electrophysiological and behavioural responses induced by the NMDAr antagonist ketamine. Male Wistar rats were chronically treated with haloperidol (0.25 mg/kg/d), clozapine (5 mg/kg/d), LY379268 (0.3 mg/kg/d) or vehicle for 28 d, delivered by subcutaneous (s.c.) osmotic pumps. Weekly electrocorticogram (ECoG) recordings were acquired. On day 26, ketamine (5 mg/kg, s.c.) was administered, and ECoG and locomotor activity were simultaneously measured. These results were compared with data generated previously following acute treatment with these antipsychotics. Sustained and significant decreases in ongoing. power were observed during chronic administration of haloperidol (64%) or clozapine (43%), but not of LY379268 (2% increase), compared with vehicle. Acute ketamine injection concurrently increased gamma power and locomotor activity in vehicle-treated rats, and these effects were attenuated in rats chronically treated with all three antipsychotics. The ability of haloperidol or clozapine to inhibit ketamine-induced elevation in gamma power was not observed following acute administration of these drugs. These results indicate that modulation of gamma power may be a useful biomarker of chronic antipsychotic efficacy.