New Class of Chemicals Found to Use Marijuana-Like System in Brain

May 4, 2000

Science Daily/University of California, Irvine

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 andother 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.

https://www.sciencedaily.com/releases/2000/05/000503183344.htm

UC Irvine Researchers Demonstrate How Marijuana-Like Chemicals Work in the Brain

March 23, 1999

Science Daily/University of California, Irvine

Findings Could Lead to New Treatments for Schizophrenia, Parkinson's, Other Diseases

Researchers at UC Irvine's College of Medicine have discovered how chemicals in the brain that are related to the active ingredient of marijuana help regulate body movements and other motor activity in rats.

In the April issue of the journal Nature Neuroscience, the researchers also report finding a network of these chemicals within the brain that prevents the overactive motor behavior found in schizophrenia, Parkinson's disease and Tourette's syndrome. The discoveries ultimately could result in new treatments for these and other neurological diseases.

Daniele Piomelli, associate professor of pharmacology, and Andrea Giuffrida, a post-doctoral researcher, found that a marijuana-like chemical called anandamide (the Sanskrit word for "bliss") inhibits the effects of nerve cells that transmit dopamine, which is largely responsible for stimulating movement and other motor behavior in the brain. For years, scientists have linked the uncontrolled production of dopamine to schizophrenia, Tourette's syndrome (which causes severe "nervous tics") and Parkinson's disease.

"This shows for the first time how anandamides work in the brain to produce normal motor activity," Piomelli said. "Patients with schizophrenia and other diseases have reported that marijuana appears to relieve some of their symptoms, but scientists have never found a physiological reason why. By understanding how the anandamide system works similarly to marijuana, we can explore new ways to treat these diseases more effectively."

But Piomelli said his research group will not consider marijuana in future research aimed at developing new treatments, because its chemical activity doesn't produce the effects on dopamine that are useful for treating these diseases. "Marijuana doesn't provide the regulatory effects on dopamine in the brain that we're looking for," he said.

The researchers found that anandamide is part of a network of nerve cells in an area of the brain called the striatum, which coordinates all body movements and other motor behavior. In the striatum, the anandamide network inhibited dopamine's attempts to stimulate the body's motor nerves. Normally, nerve cells regulate this behavior by releasing anandamides at the same time they release dopamine. In order to temper the effects of dopamine, the anandamides bind to nerve cell sites called cannabinoid receptors, so-named because they are targets of tetrahydrocannabinol (marijuana's active ingredient) as well as related chemicals like anandamides. When anandamides were bound to these receptors, body movement in the rats decreased.

But when the researchers prevented the cannabinoid receptors from binding to anandamides, the blocked nerve cells could no longer inhibit dopamine's effects. In such a state, the rats experienced severe nervous tics and other uncontrolled motor activity. In humans, such exaggerated activity brought on by unregulated dopamine production can result in diseases such as schizophrenia, Tourette's and Parkinson's.

By enhancing the nerve cells' sensitivity to anandamide, new medicines could treat these diseases without the side effects of current medicines, Piomelli said. "Current drugs certainly halt the actions of dopamine, but the side effects, including sedation and dizziness, are very severe," he said. "Drugs that exploit the anandamide system can provide a gentler way of reducing the hyperactivity in the brain caused by too much dopamine."

But Piomelli said it will be many years before any drugs will be available on the market. "We're just beginning to map out where this system works in rats' brains. We still are a long way from knowing how anandamides work in humans, and any potential drugs would have to be tested rigorously for their effectiveness and safety."

Piomelli's research group discovered the existence of anandamides in the brain and has spent several years exploring how these chemicals and their nerve-cell receptors work in the central nervous system. Piomelli and Giuffrida were assisted in their research by Loren H. Parsons and Toni Kerr at the Scripps Research Institute, La Jolla, Calif., and Fernando Rodriguez de Fonseca and Miguel Navarro of the Universidad Complutense, Madrid.

https://www.sciencedaily.com/releases/1999/03/990323050735.htm

A new target for marijuana

October 16, 2017

Science Daily/Society for Neuroscience

Cellular-level changes to a part of the brain's reward system induced by chronic exposure to the psychoactive component of marijuana may contribute to the drug's pleasurable and potentially addictive qualities, suggests a study in young mice published in JNeurosci. The results could advance our understanding of marijuana's effects on the developing brain as the drug's rapidly changing legal status increases its recreational and medical use in the United States.

Drugs of abuse impact the ventral tegmental area (VTA) of the brain, which is rich in dopamine neurons. Using juvenile and adolescent mice, Jeffrey Edwards and colleagues investigated the effects of tetrahydrocannabinol (THC), the chemical in marijuana responsible for its effects on cognition and behavior, on VTA GABA cells, an understudied inhibitory cell type in the reward system that regulates dopamine levels.

The authors found that a week of daily THC injections, but not a single injection, blocked the recovery of synapses onto VTA GABA cells in the mice. This finding suggests that persistent THC may alter the inhibitory function of these cells, increasing dopamine levels and the rewarding features of marijuana. These GABA neurons may represent a promising new target for treatment of cannabis use disorder, a common condition on the rise in the United States.

https://www.sciencedaily.com/releases/2017/10/171016132754.htm