Stanford, Calif. -- Marijuana-like chemicals in the brain may point to a treatment for the debilitating condition of Parkinson's disease. In a study to be published in the Feb. 8 issue of Nature, researchers from the Stanford University School of Medicine report that endocannabinoids, naturally occurring chemicals found in the brain that are similar to the active compounds in marijuana and hashish, helped trigger a dramatic improvement in mice with a condition similar to Parkinson's.

"This study points to a potentially new kind of therapy for Parkinson's disease," said senior author Robert Malenka, MD, PhD, the Nancy Friend Pritzker Professor in Psychiatry and Behavioral Sciences. "Of course, it is a long, long way to go before this will be tested in humans, but nonetheless, we have identified a new way of potentially manipulating the circuits that are malfunctioning in this disease." Malenka and postdoctoral scholar Anatol Kreitzer, PhD, the study's lead author, combined a drug already used to treat Parkinson's disease with an experimental compound that can boost the level of endocannabinoids in the brain. When they used the combination in mice with a condition like Parkinson's, the mice went from being frozen in place to moving around freely in 15 minutes. "They were basically normal," Kreitzer said.

But Kreitzer and Malenka cautioned that their findings don't mean smoking marijuana could be therapeutic for Parkinson's disease. (Ed. If these people did not put this statement in they would probably be fired, after all they are working for Big Pharma)

"It turns out the receptors for cannabinoids are all over the brain, but they are not always activated by the naturally occurring endocannabinoids," said Malenka. The treatment used on the mice involves enhancing the activity of the chemicals where they occur naturally in the brain. "That is a really important difference, and it is why we think our manipulation of the chemicals is really different from smoking marijuana."

The researchers began their study by focusing on a region of the brain known as the striatum. They were interested in that region because it has been implicated in a range of brain disorders, including Parkinson's, depression, obsessive-compulsive disorder and addiction.

The activity of neurons in the striatum relies on the chemical dopamine. A shortage of dopamine in the striatum can lead to Parkinson's disease, in which a person loses the ability to execute smooth motions, progressing to muscle rigidity, tremors and sometimes complete loss of movement. The condition affects 1.5 million Americans, according to the National Parkinson Foundation.

"It turns out that the striatum is much more complicated than imagined," said Malenka. The striatum consists of several different cell types that are virtually indistinguishable under the microscope. To uncover the individual contributions of the cell types, Malenka and Kreitzer used genetically modified mice in which the various cell types were labeled with a fluorescent protein that glows vivid green under a microscope. Having an unequivocal way to identify the cells allowed them to tease apart the functions of the different cell types.

Malenka's lab has long studied how the communication between different neurons is modified by experience and disease. In their examination of two types of mouse striatum cells, Kreitzer and Malenka found that a particular form of adaptation occurs in one cell type but not in the other.

Malenka said this discovery was exciting because no one had determined whether there were functional differences between the various cell types. Their study indicated that the two types of cells formed complementary circuits in the brain.

One of the circuits is thought to be involved in activating motion, while the other is thought to be involved in restraining unwanted movement. "These two circuits are critically involved in a push-pull to select the appropriate movement to perform and to inhibit the other," said Kreitzer.

Dopamine appears to modulate these two circuits in opposite ways. When dopamine is depleted, it is thought that the pathway responsible for inhibiting movement becomes overly activated - leading to the difficulty of initiating motion, the hallmark of Parkinson's disease.

Current treatment for Parkinson's includes drugs that stimulate or mimic dopamine. It turns out that the neurons Kreitzer identified as inhibiting motion had a type of dopamine receptor on them that the other cells didn't. The researchers tested a drug called quinpirole, which mimics dopamine, in mice with a condition similar to human Parkinson's disease, resulting in a small improvement in the mice.

"That was sort of expected," said Malenka. "The cool new finding came when we thought to use drugs that boost the activity of endocannabinoids." Based on prior knowledge of endocannabinoids and dopamine, they speculated that the two chemicals were working in concert to keep the inhibitory pathway in check.

When they added a drug that slows the enzymatic breakdown of endocannabinoids in the brain - URB597, being developed by Kadmus Pharmaceuticals in Irvine, Calif. - the results were striking.

"The dopamine drug alone did a little bit but it wasn't great, and the drug that targeted the enzyme that degrades endocannabinoids basically did nothing alone," Kreitzer said. "But when we gave the two together, the animals really improved dramatically."

This work was supported by a Ruth L. Kirchenstein Fellowship, the National Institutes of Health and the National Parkinson Foundation. Neither researcher has financial ties to Kadmus Pharmaceuticals.

Stanford University Medical Center integrates research, medical education and patient care at its three institutions - Stanford University School of Medicine, Stanford Hospital & Clinics and Lucile Packard Children's Hospital at Stanford. For more information, please visit the Web site of the medical center's Office of Communication & Public Affairs at: http://mednews.stanford.edu

Broadcast Media Contact: M.A. Malone at 650 723-6912: mamalone@stanford.edu
Contact: Mitzi Baker: mitzibaker@stanford.edu 650-725-2106 Stanford University Medical Center
Source: EurekAlert (DC) Published: February 7, 2007 Copyright: 2007 American Association for the Advancement of Science Contact: mitzibaker@stanford.edu Website: http://www.eurekalert.org/

Brain 'cannabis' Parkinson's hope

Boosting levels of the brain's natural cannabis-like chemicals could improve the treatment of Parkinson's disease, a US study suggests. Mice with a similar condition could move normally within 15 minutes of having a cocktail including a compound which increases endocannabinoid levels.

But the scientists, writing in Nature, warned smoking cannabis would not have the same effect. (Ed. If these people did not put this statement in they would probably be fired, after all they are working for Big Pharma)

UK experts said the study increased understanding of Parkinson's.

It is a long, long way to go before this will be tested in humans

Dr Robert Malenka, Stanford University

Around one in 500 people in the UK have the disease.

It is a progressive, degenerative, neurological condition for which there is currently no cure.

Sufferers find increasing difficulty in moving their arms and legs. They develop tremors and facial tics, and gradually become more and more immobile.

Treatment combination

The researchers, from Stanford University Medical Center in California, focused on an area of the brain called the striatum which has already been linked to Parkinson's.

The activity of nerve cells in the striatum relies on the chemical dopamine.

If there is too little dopamine in that area, Parkinson's disease can develop.

They used mice genetically modified to have a condition like Parkinson's and marked certain cells with a fluorescent protein that glowed vivid green under a microscope.

Their study indicated that two types of cells formed a "push-pull system" in the brain - one is thought to be involved in activating motion, while the other is likely to stop unwanted movement.

If there is too little dopamine, it is thought that the cells which restrict motion become dominant, making it harder for a person to move.

An existing drug which boosts dopamine levels led to a small improvement in the animals' condition.

But it was only when they added an experimental drug designed to slow the breakdown of endocannabinoids, being developed by Californian firm Kadmus Pharmaceuticals, that the mice showed a dramatic improvement.

The mice went from being unable to move, to moving freely in 15 minutes.

'Greater insight'

Dr Robert Malenka, who led the study, said: "They were basically normal.

"This points to a potentially new kind of therapy for Parkinson's disease."

But he added: "It is a long, long way to go before this will be tested in humans, but nonetheless, we have identified a new way of potentially manipulating the circuits that are malfunctioning in this disease."

And he stressed that the study found the use of specific chemicals made the difference.

"That is a really important difference, and it is why we think our manipulation of the chemicals is really different from smoking marijuana."

Kieran Breen, director of research and development at the UK's Parkinson's Disease Society, said: "The study provides us with a greater insight into how the nerve cells in the area of the brain affected in Parkinson's are connected and how they communicate with one another.

"A greater understanding of this will provide information about the changes that occur when nerve cells die and may ultimately lead to the identification of new targets in the cell at which drugs can act to treat the symptoms of the condition."

Endocannabinoid-mediated rescue of striatal LTD and motor deficits in Parkinson's disease models
Anatol C. Kreitzer1,2 and Robert C. Malenka1
Nature 445, 643-647 (8 February 2007) | doi:10.1038/nature05506; Received 25 August 2006; Accepted 5 December 2006

Department of Psychiatry and Behavioral Sciences, Nancy Pritzker Laboratory, Stanford University Medical School, Palo Alto, California 94305, USA Present address: Gladstone Institute of Neurological Disease and Department of Physiology, University of California, San Francisco, San Francisco, California 94158, USA. Correspondence to: Robert C. Malenka1 Correspondence and requests for materials should be addressed to R.C.M. (Email: malenka@stanford.edu).

1.The striatum is a major forebrain nucleus that integrates cortical and thalamic afferents and forms the input nucleus of the basal ganglia1,

2. Striatal projection neurons target the substantia nigra pars reticulata (direct pathway) or the lateral globus pallidus (indirect pathway). Imbalances between neural activity in these two pathways have been proposed to underlie the profound motor deficits observed in Parkinson's disease and Huntington's disease3,

4. However, little is known about differences in cellular and synaptic properties in these circuits. Indeed, current hypotheses suggest that these cells express similar forms of synaptic plasticity5,

6. Here we show that excitatory synapses onto indirect-pathway medium spiny neurons (MSNs) exhibit higher release probability and larger N-methyl-d-aspartate receptor currents than direct-pathway synapses. Moreover, indirect-pathway MSNs selectively express endocannabinoid-mediated long-term depression (eCB-LTD), which requires dopamine D2 receptor activation. In models of Parkinson's disease, indirect-pathway eCB-LTD is absent but is rescued by a D2 receptor agonist or inhibitors of endocannabinoid degradation.

Administration of these drugs together in vivo reduces parkinsonian motor deficits, suggesting that endocannabinoid-mediated depression of indirect-pathway synapses has a critical role in the control of movement. These findings have implications for understanding the normal functions of the basal ganglia, and also suggest approaches for the development of therapeutic drugs for the treatment of striatal-based brain disorders.

Ed note: Please also read: Long Term Exposure To Cannabis