Study on modulation of dopaminergic function via manipulation of tryptophan metabolism

Trypotphan代谢产物犬尿烯酸（KYNA）是α7烟碱乙酰胆碱受体（α 7 nAChR）的优先拮抗剂。在体内，纳摩尔KYNA通过阻断α 7 nAChR降低脑中多巴胺的细胞外水平。然而，很少有人知道什么样的生理状态会影响大脑中KYNA的产生。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生产和多巴胺能功能的影响。对I型糖尿病模型大鼠、甲状腺素给药大鼠和乙醇给药大鼠进行了检查，链脲佐菌素诱导的I型糖尿病模型大鼠显示脑KYNA浓度增加和多巴胺周转减少。由于我们先前报道了高赖氨酸饮食抑制大鼠脑中KYNA的产生，因此链脲佐菌素诱导的I型糖尿病模型大鼠饲喂添加1-3%赖氨酸的饮食。链脲佐菌素诱导的I型糖尿病模型大鼠脑内KYNA浓度降低，多巴胺周转率升高，呈赖氨酸依赖性。结合KYNA前体犬尿氨酸的浓度没有变化，这些结果表明赖氨酸代谢物α-氨基己二酸的增加抑制了犬尿氨酸合成KYNA。目前的结果表明，抑制KYNA增加和诱导多巴胺释放的高赖氨酸饮食表明，饮食操纵KYNA生产可以调节多巴胺释放在正常范围内。

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.