A rat G-protein coupled receptor sensitive to p-tyramine and b-PEA (the rTAR1) was cloned from rat tumor cell lines (including pancreas and cerrebellum). Tissue distribution was measured by examining freshly dissected rat tissue and detecting presence of the receptor. Distribution of the receptor was found in the rat olfactory tubercle, n. accumbens, prefrontal cortex, substantia nigra, ventral tegmentum, cerebellum and pons/medulla. The highest level of receptor outside the brain was in the liver, with lesser amounts in kidney, gastrointestinal tract, spleen, pancreas and heart. Assays with cAMP and a large variety of drugs were used to test its pharmacological affinities. EC50 values (lower number seems to connote greater potency), p-tyrpamine < b-PEA < tryptamine < synephrine < octopamine < meta-tyramine <= dopamine 5HT < NE, Epi. Other agonists include metabolites of biogenic amines previously believed inactive (like 3-MT, a metabolite of DA). MDMA was among several substances that directly activated cAMP production at the TAR1 receptor (tested in cells expressing receptor). MDMA had 65% +/- 13% maximal stimulation (compare 100% for p-tyramine, 48% +/- 5 for dopamine, 90% +/- 10 for tryptamine.) EC50 for MDMA was 1700 +/- 1200. Fenfluramine and (+)-ethylamphetamine had substantially lower activity at this receptor compared to N-methyl compounds, such as MDMA. DOI, LSD and many ergolines (including ergometrine, dihydroergatamine, bromocriptine and lisuride) activated the TAR1 receptor. Acetylcholine, histamine, GABA, glutamate and morphine did not activate the TAR1 receptor. In HEK293 cells, the TAR1 resided in "intracellular puncta" rather than being on the membrane (like the D1 dopamine receptor), suggesting either that this receptor resides within the cell, perhaps in vesicular membrane, or that it needs another protein to ferry agonists to it. The human gene for this trace amine receptor was also identified; it was found on chromosome 6, in a region sometimes associated with schizophrenia. The authors suggest that the trace amine receptor might be involved in producing behavioral sensitivity to drugs and in the development of psychosis. It is possible that one or more of the physiological, pharmacological or subjective effects are at least in part related to activity at the TAR1 site, but too little is known about this novel receptor to discover the association between the receptor and the effects of MDMA.