A recently discovered signaling system in the brain has just been shown to be turned on by methamphetamine, an Oregon Health & Science University study found.
The signaling system could soon become a target for therapies aiming to reverse meth's adverse health effects as well as reduce the craving that drives its abuse.
Working in the recently opened Program in Chemical Biology in the OHSU School of Medicine's Department of Physiology and Pharmacology, scientists demonstrated the new target of meth, and its close relative amphetamine, is a G protein-coupled receptor known as trace amine-associated receptor 1, or TAAR1 for short.
"The Program in Chemical Biology at OHSU is one of the few in the U.S. that allows biologists and chemists to work side-by-side, using their combined skills to identify drug targets and to design new drugs to treat diseases like drug addiction," said David Dawson, Ph.D., OHSU professor and chairman of physiology and pharmacology. "Chemical space , that is, the number of possible drug molecules that could exist , is incredibly large. Our aim is to mine that space in order to uncover novel therapies."
TAAR1 was originally discovered in the laboratory of David K. Grandy, Ph.D., OHSU professor of physiology and pharmacology. Grandy's lab found TAAR1 is activated by chemical relatives of meth known as phenylethylamines. The messenger RNA that codes for TAAR1 is expressed throughout the brain, including areas involved in motivation and drug craving, olfaction , the sense of smell , and temperature regulation, to name a few.
"With this kind of pharmacological profile and brain distribution, we hypothesized TAAR1 could mediate some of meth's metabolic and behavioral effects," explained Grandy, who also directed the groundbreaking research.
"In our most recent article, we provide clear evidence that methamphetamine is a full and potent agonist of TAAR1. In other words, TAAR1 has the necessary features to be considered a real target of methamphetamine and amphetamine in rodents and probably humans, too."
Grandy added that it's his hope that "these findings will eventually lead to the development of new pharmaceuticals that reduce dependence on and craving for methamphetamine."
The study is published in the April edition of the Journal of Pharmacology and Experimental Therapeutics.
Earlier research in the Grandy laboratory demonstrated that meth and amphetamine stimulate the production of an important second messenger known as cyclic adenosine monophosphate, or cAMP, inside cells expressing the rat TAAR1. Encouraged by this observation, Grandy's team explored the effects of these drugs on mouse TAAR1 and a human-rat TAAR1 hybrid and found all three receptors respond in similar ways.