DMT was shown to be endogenously present in the human brain and in other tissues of the body, however the exact physiological role of this tryptamine has not been identified yet (Frecska et al., 2013). Tryptamines are naturally occurring monoamine alkaloids sharing a common biochemical – tryptamine – backbone.
Tryptaminergic trace amines ( e.g., N,N-dimethyltryptamine DMT) as well as neurosteroids ( e.g., dehydroepiandrosterone) are endogenous ligands of the Sig-1R (Fontanilla et al., 2009). Based on its central localization and function, pivotal physiological activities of the Sig-1R have been described such as indispensable role in neuronal differentiation, neuronal signaling, cellular survival in hypoxia, resistance against oxidative stress, and mitigating unfolded protein response (Pal et al., 2012). Neuroprotection by Sig-1R activation can be attained by preventing elevations of intracellular calcium-mediated cell death signaling (Ruscher and Wieloch, 2015). At the MAM, Sig-1Rs are involved in the regulation and mobilization of calcium from endoplasmic reticulum stores.
The molecular chaperone Sig-1R is located at the endoplasmic reticulum-mitochondrion interface and has an important role in the fine-tuning of cellular metabolism and energetics under stressful conditions (Hayashi, 2015). Both 5-HTRs and the Sig-1R use G protein-coupled (GPCR) pathways thereby modulating a plethora of cellular functions, such as cytokine/neurotransmitter release, proliferation, differentiation, and apoptosis. 5-HTRs and Sig-1R have been shown to be expressed ubiquitously in higher vertebrate tissues and mediate various processes, including the regulation of cognition and behavior, body temperature, as well as immune functions (Szabo, 2015). Recently another receptor has been added to the greater picture: the orphan receptor sigma-1 (Sig-1R). It has been known for decades that immunomodulation through serotonin/5-hydroxytryptamine receptors (5-HTRs) has the potential to regulate inflammation and prevent damage of the nervous tissue (Shajib and Khan, 2015). During inflammation of the central nervous system, polarization towards the T helper 1 and 17 (Th1, Th17) subsets is especially important as these T cells play a major role in the development of chronic inflammation and brain tissue damage in infectious diseases and autoimmunity (Kothur et al., 2016). Macrophages and dendritic cells are also capable of antigen-presentation so they can initiate adaptive immune responses by priming naive T-cells. Pattern recognition receptors couple to nuclear factor kappaB (NF-κB), the master transcription regulator of inflammatory cytokines ( e.g., IL-1β, IL-6, TNFα) and chemokines ( e.g., IL-8/CXCL8) (Szabo and Rajnavolgyi, 2013). Once a DAMP or PAMP has been recognized by a pattern recognition receptor various downstream signaling pathways are initiated, which eventually leads to the secretion of inflammatory cytokines and many other soluble factors important in the elimination of e.g. They act as ‘gatekeepers’ continuously monitoring the tissue microenvironment for potential ‘danger signals’ by means of their pattern recognition receptors, such as Toll-like receptors or RIG-I-like receptors. Recognition of self-derived damage-associated molecular patterns (DAMPs) or pathogen-associated molecular pattern molecules (PAMPs) is usually leading to the activation of tissue resident immune cells including macrophages (microglia) and dendritic cells. Unwanted and excess inflammation is most typically the result of dysregulated innate immune responses. Various immune mechanisms – mainly via the activity of microglia – may contribute to the etiology and symptomatology of diseases, such as schizophrenia, bipolar disorder, depression, or Alzheimer's disease (Deleidi et al., 2015 Khandaker et al., 2015). The inflammatory theory of many neuropsychiatric illnesses has become an emerging trend in modern medicine.