New Class of Chemicals Found to Use Marijuana-like System in Brain to Treat Mental Disorders

Drugs eventually may treat schizophrenia,
Parkinson's, attention-deficit disorder, autism

Irvine, Calif., May 1, 2000 — Researchers at UC Irvine's College of Medicine have developed a chemical that could form the basis of a new class of drugs to treat a number of psychiatric disorders, including schizophrenia, Parkinson's disease, autism and attention-deficit hyperactivity disorder.
     The chemical, which has been tested on rats, affects brain cells that use chemicals similar to marijuana to counteract the actions of a neurotransmitter called dopamine. Dopamine has been implicated in schizophrenia, Parkinson's disease, Tourette's syndrome and many other psychiatric disorders. The researchers' findings appear in the May issue of the Journal of Neuroscience.
     Daniele Piomelli, professor of pharmacology, led a team that found that a chemical called AM404 reversed the normal inactivation of a naturally occurring chemical in the brain called anandamide, which is related to marijuana's active ingredient and opposes the actions of dopamine. By reversing the inactivation of anandamide, AM404 is able to gently curb the exaggerated movements and other disorders caused by too much dopamine activity in nerve cells.
     "We were excited to find this action of AM404 in the brain. It's very encouraging to see it work in a very subtle and effective way to counteract the effects of too much dopamine-induced activity," said Piomelli. "With further testing, we hope this eventually will result in new treatments that don't have the side effects of many current psychiatric drugs."
     Piomelli and his colleagues found that AM404 targeted nerves that produced unusually high levels of dopamine and caused exaggerated movements and other problems in rats. Instead of directly encouraging the production of dopamine-curbing anandamide, AM404 was found to discourage the disintegration of existing anandamide. More anandamide was then available to bind to receptors on nerve cells and reduce the stimulation of nerve cells by dopamine.
     If further research proves successful, the chemical could be used to treat schizophrenia, Tourette's, Parkinson's, autism and attention-deficit disorder, all of which are currently treated by drugs that attack the dopamine system in the brain.
     Piomelli warns that their research on cannabinoid receptors has shown consistently that smoking marijuana may actually make these disorders worse. "Although AM404 helps to manipulate cannabinoid receptors, we think that using marijuana directly creates too severe a reaction and can create adverse reactions among people suffering from these diseases," he said.
     The researchers, who have been working for several years on detailing the cannabinoid nerve cell system in the brain, are now looking at how AM404 selects the nerve cells it affects in the brain.
     "AM404's selection of nerve cells may mean that treatments may not have the side effects of many current drugs, which aren't as selective about the nerve cells they impact," Piomelli said. "Once we see how the drug actually works in the brain, we'll have a better idea of what disorders it may be most effective at treating. Using brain scans and analyzing the uptake of AM404 in rats and other animals, we can have a better idea of where it's working."
     Piomelli's colleagues in this study were Massimo Beltramo and Andrea Giuffrida at UCI; Fernando Rodriguez de Fonseca, Miguel A. Gorriti and Miguel Navarro at the Complutense University, Madrid, Spain, and Antonio Calignano, Gerasimos Grammatikopoulos and Antonio G. Sadile at the University of Naples, Italy.
     The researchers' work was supported by a grant from the National Institute of Drug Abuse.

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