Erhardt Sophie, Schwieler Lilly, Emanuelsson Carolina, Geyer Mark
Department of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden.
Biol Psychiatry. 2004 Aug 15;56(4):255-60. doi: 10.1016/j.biopsych.2004.06.006.
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.
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).
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 haloperidol (.2 mg/kg, IP) or clozapine (7.5 mg/kg, IP).
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.
近期研究表明，精神分裂症患者脑脊液中犬尿喹啉酸（KYNA）的内源性水平升高。听觉惊跳反射的前脉冲抑制（PPI）是一种感觉运动门控的操作性测量指标，在精神疾病如精神分裂症中会降低。先前的研究表明，给予N-甲基-D-天冬氨酸（NMDA）受体拮抗剂，如苯环己哌啶或MK-801，会导致感觉运动门控缺陷，类似于在精神分裂症患者中观察到的情况。
本研究检测了内源性NMDA受体拮抗剂KYNA对大鼠惊跳和PPI的影响。通过腹腔注射（IP）KYNA的前体犬尿氨酸（100mg/kg）或静脉注射PNU 156561A（10mg/kg）来提高大脑中KYNA的内源性水平。
犬尿氨酸或PNU 156561A诱导的大脑KYNA水平增加四倍，显著降低了PPI。对照大鼠和药物处理大鼠之间的惊跳幅度没有差异。给予抗精神病药物氟哌啶醇（0.2mg/kg，IP）或氯氮平（7.5mg/kg，IP）可恢复PPI的破坏。
目前的结果表明，大脑KYNA作为PPI的内源性调节剂，与KYNA参与精神分裂症病理生理学的假设一致。
