Trace Amines

In addition to the classical monoamines NE, 5HT, and DA, there exists a class of 'trace amines' that are found in very low levels in mammalian tissues, and include tyramine, b-phenylethylamine (b-PEA), tryptamine, and octopamine.74 The rapid turnover of trace amines, as evidenced by the dramatic increases in their levels following treatment with MAOIs or deletion of the MAO genes, suggests that the levels of trace amines at neuronal synapses may be considerably higher than predicted by steady-state measures. Although there is clinical data in the literature that supports a role for trace amines in depression as well as other psychiatric disorders, the role of trace amines as neurotransmitters in mammalian systems has not been thoroughly examined.75 Because they share common structures with the classical amines and can displace other amines from their storage vesicles, trace amines have been referred to as 'false transmitters.' Thus, many of the effects of trace amines are indirect and are caused by the release of endogenous classical amines. However, there is a growing body of evidence suggesting that trace amines function independently of classical amine transmitters and mediate some of their effects via specific receptors. Saturable, high-affinity binding sites for [3H]-tryptamine,^-[3H]-tyramine, and b-[3H]PEA have been reported in rat brain, and both the pharmacology and localization of these sites suggest that they are distinct from the amine transporters. However, although binding sites have been reported no specific receptors for these trace amines have yet been identified conclusively. A family of 15 GPCRs has been described, two members of which are activated by trace amines. TA1 is activated most potently by tyramine and b-PEA, and TA2 by b-PEA. At least 15 distinct receptors have been described to date, along with the orphan receptor (putative neurotransmitter receptor (PNR)) and the pseudogenes GPR58, GPR57 and the 5HT4 pseudogene share a high degree of sequence homology and together form a subfamily of rhodopsin GPCRs distinct from but related to 5HT, NE, and DA receptors. The localization of the TA1 receptor in human and rodent tissues, as well as the chromosomal localization of the human members of this family, has been well characterized. The identification of this family of receptors should facilitate the understanding of the roles of trace amines in the mammalian nervous system and their role in affective disorders.

Clinical studies have examined the levels of PEA in many conditions and discovered significant associations. Patients with depression have decreased PEA levels while levels are increased in schizophrenic and psychopathic subjects. The administration of PEA has been found to reduce depression. Likewise, the administration of its precursor, phenylalanine, has been found to improve depression on its own and the therapy outcome when combined with some antidepressants.76 Trace amines may play a role in the pathophysiology of depression. YKP-10A (R228060) is reported to be a phenylalanine-like molecule.

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