Endogenous kynurenic acid disrupts prepulse inhibition
Endogenous kynurenic acid disrupts prepulse inhibition
复制标题
DOI：
10.1016/j.biopsych.2004.06.006
复制
发表时间：
2004-08-15
影响因子：
10.6
通讯作者：
Geyer, M
中科院分区：
文献类型：
--
作者：
Erhardt, S;Schwieler, L;Geyer, M
背景最近的研究表明，犬尿烯酸（KYNA）的内源性水平在精神分裂症患者的脑脊液中增加。声惊吓反射的前脉冲抑制（PPI）是感觉运动门控的一种操作措施，在神经精神疾病（如精神分裂症）中减少。以往的研究表明，管理N-甲基-D-天冬氨酸（NMDA）受体拮抗剂，如苯环己哌啶或MK-801，导致赤字的感觉运动门控，模仿那些观察到的精神分裂症patients.Methods：本研究探讨了影响的内源性NMDA受体拮抗剂KYNA惊吓和PPI在大鼠。通过腹腔内（IP）给予KYNA前体犬尿氨酸（100 mg/kg）或静脉内给予PNU 156561 A（10 mg/kg），实现了内源性脑KYNA水平的升高。结果。由犬尿氨酸或PNU 156561 A诱导的脑KYNA水平的四倍增加显著降低了PPI。对照组大鼠和给药组大鼠的惊吓程度无差异。抗精神病药物巴哌啶醇（0.2 mg/kg，IP）或氯氮平（7-5 mg/kg，IP）可恢复PPI的破坏。本研究结果表明，脑KYNA作为PPI的内源性调节剂，并与KYNA有助于精神分裂症的病理生理学的假设是一致的。
Background. Recent studies show that endogenous levels of kynurenic acid (KYNA) are increased in the cerebrospinal fluid of schizophrenic patients. Prepulse inhibition (PPI) of the acoustic startle reflex is an operational measure of sensorimotor gating that is reduced in neuropsychiatric disorders, such as schizophrenia. Previous studies show that administration of N-methyl-D-aspartate (NMDA) receptor antagonists, such as phencyclidine or MK-801, leads to deficits in sensorimotor gating that mimic those observed in schizophrenic patients.Methods: The present study examined the effects of the endogenous NMDA receptor antagonist KYNA on startle and PPI in rats. Elevation of endogenous brain levels of KYNA was achieved through intraperitoneal (IP) administration of kynurenine (100 mg/kg), the precursor of KYNA, or by intravenous administration of PNU 156561A (10 mg/kg).Results. A fourfold increase in brain KYNA levels, as induced by kynurenine or PNU 156561A, significantly reduced PPI. There were no differences in startle magnitudes between control rats and drug-treated rats. The disruption of PPI was restored by administration of the antipsychotic drugs baloperidol (.2 mg/kg, IP) or clozapine (7-5 mg/kg, IP).Conclusions. The present results suggest that brain KYNA serves as an endogenous modulator of PPI and are consistent with the hypothesis that KYNA contributes to the pathophysiology of schizophrenia.