internalization ( reuptake inhibition), but phosphorylation alone induces reverse transporter function (dopamine efflux). Immune system Expression of TAAR1 on lymphocytes is associated with activation of lymphocyte immuno-characteristics. In the immune system, TAAR1 transmits signals through active PKA and PKC phosphorylation cascades. In a 2012 study, Panas et al. observed that methamphetamine had these effects, suggesting that, in addition to brain monoamine regulation, amphetamine-related compounds may have an effect on the immune system. A recent paper showed that, along with TAAR1, TAAR2 is required for full activity of trace amines in PMN cells. Phytohaemagglutinin upregulates mRNA in circulating leukocytes; in these cells, TAAR1 activation mediates leukocyte chemotaxis toward TAAR1 agonists. TAAR1 agonists (specifically, trace amines) have also been shown to induce interleukin 4 secretion in T-cells and immunoglobulin E (IgE) secretion in B cells. Astrocyte-localized TAAR1 regulates EAAT2 levels and function in these cells; this has been implicated in methamphetamine-induced pathologies of the neuroimmune system. Clinical significance Low phenethylamine (PEA) concentration in the brain is associated with major depressive disorder, and high concentrations are associated with schizophrenia. Low PEA levels and under-activation of TAAR1 also appears to be associated with ADHD. It is hypothesized that insufficient PEA levels result in TAAR1 inactivation and overzealous monoamine uptake by transporters, possibly resulting in depression. Some antidepressants function by inhibiting monoamine oxidase (MAO), which increases the concentration of trace amines, which is speculated to increase TAAR1 activation in presynaptic cells. Decreased PEA metabolism has been linked to schizophrenia, a logical finding considering excess PEA would result in over-activation of TAAR1 and prevention of monoamine transporter function. Mutations in region q23.1 of human chromosome 6 – the same chromosome that codes for TAAR1 – have been linked to schizophrenia. Medical reviews from February 2015 and 2016 noted that TAAR1-selective ligands have significant therapeutic potential for treating psychostimulant addictions (e.g., cocaine, amphetamine, methamphetamine, etc.). Despite wide distribution outside of the CNS and PNS, TAAR1 does not affect hematological functions and the regulation of thyroid hormones across different stages of ageing. Such data represent that future TAAR1-based therapies should exert little hematological effect and thus will likely have a good safety profile. Research A large candidate gene association study published in September 2011 found significant differences in TAAR1 allele frequencies between a cohort of fibromyalgia patients and a chronic pain-free control group, suggesting this gene may play an important role in the pathophysiology of the condition; this