Interactions of Tryptophan and Its Catabolites With Melatonin and the Alpha 7 Nicotinic Receptor in Central Nervous System and Psychiatric Disorders: Role of the Aryl Hydrocarbon Receptor and Direct Mitochondria Regulation

George Anderson, Michael Maes, George Anderson, Michael Maes

Abstract

Recent work indicates an intimate interaction of the tryptophan catabolite (TRYCAT) pathways with the melatonergic pathways, primarily via TRYCAT pathway induction taking tryptophan away from the production of serotonin, which is a necessary precursor for the melatonergic pathways. The alpha 7 nicotinic receptor may be significantly modulated by this interaction, given its inactivation by the TRYCAT, kynurenic acid, and its induction by melatonin. Similarly, the aryl hydrocarbon receptor is activated by both kynurenic acid and kynurenine, leading to CYP1A2 and melatonin metabolism, whereas melatonin may act to inhibit the aryl hydrocarbon receptor. These 2 receptors and pathways may therefore be intimately linked, with relevance to a host of intracellular processes of clinical relevance. In this article, these interactions are reviewed. Interestingly, mitochondria may be a site for direct interactions of these pathways and receptors, suggesting that their differential induction may not only be modulating neuronal, glia, and immune cell processes and activity but also be directly acting to regulate mitochondrial functioning. This is likely to have significant consequences as to how an array of diverse central nervous system and psychiatric conditions are conceptualized and treated.

Keywords: CNS; alpha 7 nicotinic; aryl hydrocarbon; glia; gut-brain axis; melatonin; mitochondria; psychiatry; sirtuins; tryptophan catabolites.

Conflict of interest statement

DECLARATION OF CONFLICTING INTERESTS: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. Disclosure This manuscript has been read and approved by all authors. This paper is unique and is not under consideration by any other publication and has not been published elsewhere. The authors and peer reviewers of this paper report no conflicts of interest. The authors confirm that they have permission to reproduce any copyrighted material.

Figures

Figure 1.
Figure 1.
The major components of the kynurenine and serotonergic/melatonergic pathways and their interactions. The initial conversion of tryptophan by tryptophan hydroxylase leads to the synthesis of serotonin and melatonin. When stress and pro-inflammatory cytokines are increased, inducing TDO and IDO, respectively, tryptophan is driven down the kynurenine pathway leading to the increased synthesis of tryptophan catabolites. IDO indicates indoleamine 2,3-dioxygenase; TDO, tryptophan 2,3-dioxygenease.
Figure 2.
Figure 2.
The interactions of the AhR and a7nAChR with the TRYCAT and melatonergic pathways. Pro-inflammatory cytokines and chronic stress increase IDO and TDO, respectively, leading to TRYCAT induction, with differential effects on mitochondrial functioning. TRYCAT activation and stress-induced MAO, by decreasing serotonin availability, decrease melatonergic pathway activation. Increased KYNA may also compete with melatonin via the opposing regulation of the a7nAChR. AhR activation, via IDO induction, may positively feedback on TRYCAT synthesis, as well as decrease the availability of melatonin by increasing its metabolism. Some data indicate that the AhR decreases sirtuins, which may also be mediated by decreased melatonin. Both 3-OHK and 3-OH-ANA can modulate mitochondrial functioning. 3-OH-ANA indicates 3-hydroxyanthranillic acid; 3-OHK, 3-hydroxykynurenine; a7nAChR, alpha 7 nicotinic receptor; AhR, aryl hydrocarbon receptor; IDO, indoleamine 2,3-dioxygenase; KYNA, kynurenic acid; MAO, monoamine oxidase; TDO, tryptophan 2,3-dioxygenase; TRYCATs, tryptophan catabolites.

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