Neurokynurenines (Neky) as Common Neurochemical Links of Stress and Anxiety

Abstract

The following NEKY have been studied: 1-kynurenine (KYN), 3-hydroxyKYN (3HKYN), kynurenic (KYNA), anthranilic (ANT), 3-hydroxyANT (3HANT), quinolinic (QUIN), picolinic (PICA), xanthurenic (XAN), nicotinic (NIC) acids, 3-indole-pyruvate (IPA), nicotinamide (NAM). NEKY antagonize the central effects of precursors of serotonin (tryptophan and 5-HTP), and tryptamine as well. Seizures induced by central administration of KYN and QUIN are prevented by centrally injected dopamine and diminished by noradrenaline and adrenaline. KYN, 3HANT, PIC and NIC potentiate oxotremorine hypothermia mediated by acetylcholine. Central administration of GABA, glycine or taurine, as well as proline and melatonin, prevented seizures induced by QUIN and KYN. Behavioral inhibitory effects of these amino acids are diminished by pretreament with KYN, 3HKYN and QUIN. Elevation of concentrations of corticosteroids is resulted in rise of level of NEKY due to hormonal induction of liver tryptophan pyrrolase and brain 2,3 dioxigenase. NEKY, in their turn, activate both enzymes. Thus, a“vicious circle”is formed and it supports an elevated level of NEKY for a long time, hours and days. Long-lasting increased concentrations of NEKY in tissues can lead to significant after-effects and numerous pathogenic consequences. One can not exclude that a rise of the level of some NEKY, e.g. KYNA, IPA, PIC and XAN, may play an “adaptogenic” role in stress antagonizing some pathologic effects of KYN and QUIN, e.g. anxiogenic, neurotoxic and proconvulsive. It has been demonstrated that the excitatory NEKY, KYN, 3HKYN, QUIN, possess an anxiogenic activity in the standard animal models of anxiety. NEKY with opposite neuroactivities, namely KYNA, IPA, PICA and XAN, have a pharmacological profile of anxiolytics and antagonize both anxiogenic NEKY and standard anxiogens, like caffeine, pentylenetetrazole and yohimbine. Major emphasis is made on KYN as a putative endogenous anxiogen. Studies on the interaction of NEKY with other endogenous metabolites involved in anxiety (betaphenylethylamine, cholecystokynine, melatonin) are in progress.