Trace Amines and Their Receptors in the Brain

Trace amines are naturally occurring chemicals that are synthesized in nerve cells. The major trace amines are 2-phenylethylamine, p-tyramine and tryptamine. The thyroid hormone metabolite 3-iodothyronamine and the polyamines spermine, spermidine, and cadaverine may also act as trace amines. The synthetic route of the major trace amines is very similar to that of the classical monoamine neurotransmitters dopamine, noradrenaline and 5-HT. Unlike the neurotransmitters, however, trace amines are only present in very small quantities. A family of proteins (receptors) that are selectively activated by trace amines has been discovered and named Trace Amine-Associated Receptors (TAAR). 

TAAR are found throughout the brain, and one type, TAAR1, appears to
regulate the activity of dopamine, 5-hydroxytryptamine (serotonin; 5-HT), and glutamate receptors. TAAR1 is a direct target for methamphetamine-like drugs of abuse such as methamphetamine. In addition, through its regulation of the dopamine reward system, TAAR1 appears to regulate the susceptibility to self administration of numerous psychotropic agents as well as other addictive compounds such as cocaine, nicotine, alcohol, and maybe even food. TAAR1 is being actively investigated as a novel target for the development of improved therapies for drug abuse/addiction, schizophrenia and other psychiatric disorders. Ulotaront, a TAAR1 agonist, recently received breakthrough approval status from the FDA for the treatment of schizophrenia. This is the first non-dopamine system directed new therapeutic for schizophrenia in over 50 years.

Olfaction and Species-Specific Social Cues

In addition to being present in the brain, TAAR have been validated as a new class of receptor for detecting smell (olfaction). The one exception to this is TAAR1 which is not found in olfactory tissue. There is a large variation between species in the sub-types of TAAR that are present, with some TAAR thought to only occur in an individual species. Studies have identified 2-phenylethylamine as one of the chemical cues in carnivore urine that is detected by prey species. This detection is due to the presence TAAR4 in the olfactory epithelium and induces innate (i.e. hard-wired, not learned) avoidance behaviour in prey species. A number of other naturally occurring compounds have been shown to activate other olfactory TAAR, with some of these also inducing innate behavioural responses, including the classical polyamines such as cadaverine, spermine, and spermidine, and the spoiled fish odour trimethylamine. The role of TAAR in species-specific olfactory-mediated social cues is a growing area of research interest, with suggested involvements in predator detection and avoidance, identification of spoiled food, migratory behaviour, and mate selection.

Trace Amines and TAAR Outside the Brain

The enzymes for the synthesis and degradation of trace amines are also found in a number of tissues outside of the brain. These peripheral tissues often contain one, or more, types of TAAR. In particular TAAR1 (and the trace amine synthetic machinery) is expressed in tissues central to the control of energy metabolism, including insulin secreting pancreatic β-cells, and nutrient detecting cells of the stomach and gastrointestinal tract. TAAR are also present in various types of white blood cells (leukocytes) and emerging evidence suggests they play a role in pro- and anti-inflammatory responses. TAAR have even been suggested to be differentially expressed in some cancer cells. These non-brain functions of trace amines and TAAR are much less well studied and have become a focus of work in the Berry lab.

Trace Amine Work in the Berry Lab

 Updated information in development