Department of Physiology and Pharmacology, Karolinska Institutet, Nanna Svartz väg 2, 171 77, Stockholm, Sweden.
J Neural Transm (Vienna). 2012 Feb;119(2):155-63. doi: 10.1007/s00702-011-0706-6. Epub 2011 Sep 9.
The neuromodulating tryptophan metabolite kynurenic acid (KYNA) is increased in the brain of patients with schizophrenia. In the present study we investigate the spontaneous locomotor activity as well as the locomotor response to d-amphetamine [5 mg/kg, administered intraperitoneal (i.p.)] after increasing endogenous levels of brain KYNA in mice by acute (10 mg/kg, i.p., 60 min) or subchronic (100 mg/kg i.p., twice daily for 6 days) pretreatment with the blood-brain crossing precursor, L: -kynurenine. We found that an acute increase in the brain KYNA levels caused increased corner time and percent peripheral activity but did not change the d-amphetamine-induced locomotor response. In contrast, subchronic elevation of KYNA did not change the spontaneous locomotor activity but produced an exaggerated d-amphetamine-induced hyperlocomotion. These results cohere with clinical studies of patients with schizophrenia, where a potentiated DA release associated with exacerbation of positive symptoms has been observed following d-amphetamine administration. Present results further underscore KYNA as a possible mediator of the aberrant dopaminergic neurotransmission seen in schizophrenia.
神经调节色氨酸代谢产物犬尿氨酸（KYNA）在精神分裂症患者的大脑中增加。在本研究中，我们研究了在小鼠中通过急性（10mg/kg，ip，60 分钟）或亚慢性（100mg/kg ip，每日两次，持续 6 天）预处理血脑穿越前体 L：-犬尿氨酸增加内源性脑 KYNA 水平后，自发性运动活动以及对 d-安非他命[5mg/kg，腹腔内（ip）给药]的运动反应。我们发现，大脑 KYNA 水平的急性增加导致角落时间和外周活动百分比增加，但不会改变 d-安非他命引起的运动反应。相比之下，KYNA 的亚慢性升高不会改变自发性运动活动，但会产生夸大的 d-安非他命诱导的过度运动。这些结果与精神分裂症患者的临床研究一致，在给予 d-安非他命后，观察到与阳性症状恶化相关的 DA 释放增强。目前的结果进一步强调了 KYNA 作为精神分裂症中异常多巴胺能神经传递的可能介质。
