Study on modulation of dopaminergic function via manipulation of tryptophan metabolism

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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.