Study on modulation of dopaminergic function via manipulation of tryptophan metabolism

Trypotphan代谢产物犬尿酸(KYNA)是α7烟碱型乙酰胆碱受体(α7nAChR)的选择性拮抗剂。在体内，纳米分子KYNA通过阻断α7nAChRs降低脑细胞外多巴胺水平。然而，什么生理状态影响大脑中KYNA的产生却知之甚少。在本研究中，我们研究了几种生理因素，如高血糖和激素变化对KYNA产生和多巴胺能功能的影响。链脲佐菌素诱导的I型糖尿病模型大鼠、甲状腺素灌胃大鼠和乙醇灌胃大鼠均表现为脑组织KYNA含量升高、多巴胺转换率降低。由于我们之前报道过高赖氨酸饮食会抑制大鼠脑内KYNA的产生，所以链脲佐菌素诱导的I型糖尿病模型大鼠被喂养于添加1-3%赖氨酸的饲料中。链脲佐菌素诱导的I型糖尿病模型大鼠脑内KYNA浓度降低，多巴胺转运量增加，呈赖氨酸依赖性。这些结果表明，赖氨酸代谢产物α-氨基己二酸的增加抑制了犬尿氨酸合成犬尿氨酸。目前的结果表明，高赖氨酸饮食抑制KYNA的增加和诱导多巴胺的释放，表明饮食控制KYNA的产生可以调节正常RAGE中的多巴胺释放。

Trypotphan metabolite kynurenic acid (KYNA) is a preferential antagonist of the α7 nicotinic acetylcholine receptor (α7nAChR). In vivo, nanomolar KYNA reduces the extracellular levels of dopamine in the brain via the blockade of α7nAChRs. However, little is known what physiological state affect KYNA production in the brain. In the present study, we examined the effects of several physiological factors such as hyperglycemia and hormone change on the KYNA production and dopaminergic function. Type I diabetes model rats, thyroxin administrated rats and ethanol administrated rats were examined, and the streptozotocin-induced type I diabetes model rats showed the increase of brain KYNA concentration and the decrease of dopamine turnover. Since we previously reported that high lysine diet inhibit KYNA production in the rat brain, streptozotocin-induced type I diabetes model rats were fed on 1-3% lysine added diet. The brain KYNA concentration decreased, and the dopamine turnover increased in lysine-dependent manner in the streptozotocin-induced type I diabetes model rats. Taken together with no change of KYNA precursor kynurenine's concentration, these results suggest that increase of lysine metabolite α-aminoadipic acid inhibited the KYNA synthesis from kynurenine. Present results showing inhibition of KYNA increase and induction of dopamine release by high lysine diet suggest that dietary manipulation of KYNA production can modulate dopamine release in normal rage.