Psychoactive Compound Activates Mysterious Receptor

Thursday, February 12, 2009

A hallucinogenic compound found in a plant indigenous to South
America and used in shamanic rituals regulates a mysterious protein
that is abundant throughout the body, University of Wisconsin-
Madison researchers have discovered.

The finding, reported in the Feb. 13 issue of Science, may
ultimately have implications for treating drug abuse and/or
depression. Many more experiments will be needed, the researchers
say.

Scientists have been searching for years for naturally occurring
compounds that trigger activity in the protein, the sigma-1
receptor. In addition, a unique receptor for the hallucinogen,
called dimethyltryptamine (DMT), has never been identified.

The UW-Madison researchers made the unusual pairing by doing their
initial work the "old-fashioned," yet still effective, way. They
diagrammed the chemical structure of several drugs that bind to the
sigma-1 receptor, reduced them to their simplest forms and then
searched for possible natural molecules with the same features.
Biochemical, physiological and behavioral experiments proved that
DMT does, in fact, activate the sigma-1 receptor.

"We have no idea at present if or how the sigma-1 receptor may be
connected to hallucinogenic activity," says senior author Arnold
Ruoho, chair of pharmacology at the UW-Madison School of Medicine
and Public Health. "But we believe that the National Institute on
Drug Abuse (NIDA) may be interested in biological mechanisms
underlying psychoactive and addictive drug action."

In addition to being a component of psychoactive snuffs and
sacramental teas used in native religious practices in Latin
America, DMT is known to be present in some mammalian tissues, and
it has also been identified in mammalian blood and spinal fluid.
Elevated levels of DMT and a related molecule have been found in
the urine of schizophrenics.

Ruoho speculates that the hallucinogen's involvement may mean that
the sigma-1 receptor is connected in some fashion to psychoactive
behavior. When his team injected DMT into mice known to have the
receptor, the animals became hyperactive; mice in which the
receptor had been genetically removed did not.

"Hyperactive behavior is often associated with drug use or
psychiatric problems," says Ruoho. "It's possible that new, highly
selective drugs could be developed to inhibit the receptor and
prevent this behavior."

The study revealed an additional neurologic link by confirming that
the sigma-1 receptor and some compounds that bind to it inhibit ion
channels, which are important for nerve activity. Work by many
researchers - including some from UW-Madison - initially showed
this relationship in earlier studies.

Some studies have also linked the receptor to the action of
antidepressant drugs, and National Institutes of Health (NIH)
scientists recently found that it appears to serve as a "chaperon,"
helping proteins to fold properly.

The Wisconsin researchers found that DMT is derived from the
naturally occurring amino acid tryptophan and is structurally
related to the neurotransmitter serotonin. This finding, Ruoho
says, illustrates the mantra often used in the biological
processing of natural molecules: Nothing goes to waste.

"Our findings support the idea that biochemical alterations of
molecules such as tryptophan can produce simple compounds such as
DMT that may target other regulatory pathways served by sigma-1
receptors," he says.

DMT may also reflect the presence of an even larger family of
natural compounds that arise from other structurally related amino
acids that may further regulate the receptor, Ruoho adds.

"It may well be that these different, naturally derived chemical
forms regulate the sigma-1 receptor in tissue and organ-specific
ways," he says.