Most of the daily dietary tryptophan (Trp) is oxidatively degraded through the kynurenine (Kyn) pathway, and the remaining may be consumed either in serotonin synthesis or in conversion into melatonin through the methoxyindole pathway. Trp degradation products along the Kyn pathway include three neuroactive metabolites: the neuroinhibitory agent kynurenic acid (KA), the free radical generator 3-hydroxykynurenine (3HK), and the excitotoxin quinolinic acid (QA). Kyn is the major metabolite of Trp and is readily transported across the blood-brain barrier into the brain where it can be further metabolized in perivascular macro-phages, microglia, and astrocytes, also to generate neuroactive intermediates. In contrast to Kyn, QA, KA, and 3-hydroxyanthranilic acid (3HAA) penetrate through the blood-brain barrier only poorly due to its polar nature. Although the cytokines do not pass through the blood-brain barrier, their signals reach the brain through humoral, neural, and cellular pathways and stimulate Trp degradation by interacting with a cytokine network in the brain. The induction of Kyn pathway by indoleamine 2,3-dioxygenase (IDO) activity exhausts L-Trp in the medium and produces toxic metabolites. While Kyn to Trp ratio reflects IDO activity, Kyn to KA ratio indicates the neurotoxic challenge. Alpha7 nicotinic acetylcholine receptor (alpha7nAChR) constitutes a crucial link between excessive KA formation and reduction in glutamate. KA-induced reduction in prefrontal glutamate levels emerges as a result of alpha7nAChR inhibition. Changes in the endogenous concentrations of KA, as a potent alpha7nAChR and N-methyl-D-aspartate (NMDA) receptor antagonist, affect extracellular dopamine levels in the brain. The entire monoaminergic neurotransmission involves functional interactions between serotonin, norepinephrine, and dopamine systems (Fig. 1.1). Serotonin transporter (SERT) reuptakes biogenic amine neurotransmitters following release in the nervous systems and terminates the action of serotonin. SERT can be regulated by a membrane-bound G-protein-coupled receptor, and this occurs via nitric oxide (NO) and cyclic guanosine monophosphate (cGMP). Desensitization and re-sensitization of G-protein-coupled receptors (GPCRs) can modulate receptor responsiveness in regulation of many cellular functions. Diet restriction-induced exaggerated feedback control over serotonin synthesis decreases serotonin neurotransmission at postsynaptic sites by reducing availability of Trp. Enterochromaffin (EC) cells of the intestinal mucosa respond to chemical and mechanical stimuli by releasing serotonin. The enteric serotonin transporter plays a critical role in serotonergic neurotransmission and in the initiation of peristaltic and secretory reflexes.