Brain's receptors sensitive to pot may 'open door' in treating drug dependence, brain disorders

June 7, 2006

Science Daily/Society of Nuclear Medicine

A team of Johns Hopkins researchers developed a new radiotracer—a radioactive substance that can be traced in the body—to visualize and quantify the brain’s cannabinoid receptors by positron emission tomography (PET), opening a door to the development of new medications to treat drug dependence, obesity, depression, schizophrenia, Parkinson’s disease and Tourette syndrome.

Discovery of the [11C]JHU75528 radioligand, a radioactive biochemical substance that is used to study the receptor systems of the brain, “opens an avenue for noninvasive study of central cannabinoid (CB1) receptors in the human and animal brain,” explained Andrew Horti, assistant professor of radiology at Johns Hopkins Medicine, Baltimore, Md. He explained that there is evidence that CB1 receptors play an essential role in many disorders including schizophrenia, depression and motor function disorders. “Quantitative imaging of the central CB1 using PET could provide a great opportunity for the development of cannabinergic medications and for studying the role of CB1 in these disorders,” added the co-author of “PET Imaging of Cerebral Cannabinoid CB1 Receptors with [11C]JHU75528.”

Cannabinoid receptors are proteins on the surface of brain cells; they are most dense in brain regions involved with thinking and memory, attention and control of movement. The effects of tetrahydrocannabinol (THC), the primary psychoactive compound in marijuana, are due to its binding to specific cannabinoid receptors located on the surface of brain cells. “Blocking CB1 receptors presents the possibility of developing new, emerging medications for treatment of obesity and drug dependence including alcoholism, tobacco and marijuana smoking,” said Horti.

The usefulness of in vivo (in the body) radioligands for studying cerebral receptors by PET depends on the image quality, and a good PET radiotracer must display a high level of specific receptor binding and low non-specific binding (binding with other proteins, cell membranes, etc.), said Horti. “If the non-specific binding is too high and specific binding is too low, the PET images become too ‘noisy’ for quantitative measurements,” he noted. “We developed a PET radiotracer with a unique combination of good CB1 binding affinity and relatively low non-specific binding in mice and baboon brains,” he added. “Previously developed PET radioligands for imaging of CB1 receptors were not suitable for quantitative imaging due to the high level of image ‘noise,’” he added.

“Even though PET methodology was developed 30 years ago, its application for studying cerebral receptors is limited due to the lack of suitable radioligands,” said Horti. “Development of [11C]JHU75528 will allow noninvasive research of CB1 receptor,” he added, indicating that Johns Hopkins researchers need to complete various safety studies and obtain Food and Drug Administration approval before [11C]JHU75528 can be used for PET imaging in people.

“This discovery would not have been possible without involvement of many highly qualified researchers, including the teams of Robert Dannals and Dean Wong and support of Richard Wahl, director of the nuclear medicine department,” said Horti.

https://www.sciencedaily.com/releases/2006/06/060607082641.htm

Role of Cannabinoid Receptors in Alcohol Abuse Examined

September 11, 2005

Science Daily/Brookhaven National Laboratory

A new set of experiments in mice confirms that a brain receptor associated with the reinforcing effects of marijuana also helps to stimulate the rewarding and pleasurable effects of alcohol.

The research, which was conducted at the U.S. Department of Energy’s Brookhaven National Laboratory and was published online September 2, 2005 by the journal Behavioural Brain Research, confirms a genetic basis for susceptibility to alcohol abuse and also suggests that drugs designed to block these receptors could be useful in treatment.

“These findings build on our understanding of how various receptors in the brain’s reward circuits contribute to alcohol abuse, help us understand the role of genetic susceptibility, and move us farther along the path toward successful treatments,” said Brookhaven’s Panayotis (Peter) Thanos, lead author of this study and many others on “reward” receptors and drinking.

Earlier studies in animals and humans have suggested that so-called cannabinoid receptors known as CB1 — which are directly involved in triggering the reinforcing properties of marijuana — might also stimulate reward pathways in response to drinking alcohol. Thanos’ group investigated this association in two experiments.

In the first experiment, they measured alcohol preference and intake in mice with different levels of CB1 receptors: wild type mice with normal levels of CB1; heterozygous mice with approximately 50 percent levels; and so-called knockout (KO) mice that lack the gene for CB1 and therefore have no CB1 receptors. All mice were given a choice of two drinking bottles, one with pure water and one with a 10 percent alcohol solution — approximately equivalent to the alcohol content of wine. Mice with the normal levels of CB1 receptors had a stronger preference for alcohol and drank more than the other two groups, with the CB1-deficient mice showing the lowest alcohol consumption.

After establishing each group’s level of drinking, the scientists treated animals with a drug known to block CB1 receptors (SR141716A) and tested them again. (These animals were also compared with animals injected with plain saline to control for the effect of the injection.) In response to the CB1 receptor-blocking drug, mice with normal and intermediate levels of receptors drank significantly less alcohol compared to their pre-treatment levels, while KO mice showed no change in drinking in response to the treatment.

In the second experiment, the scientists compared the tendency of wild type and KO mice to seek out an environment in which they had previously been given alcohol. Known as “conditioned place preference,” this is an established technique for determining an animal’s preference for a drug.

Animals were first conditioned to “expect” alcohol in a given portion of a three-chambered cage while being given an injection of saline in the opposite end, and then monitored for how much time they spent in the alcohol chamber “seeking” the drug. Wild type animals, with normal levels of CB1, spent more time in the alcohol-associated chamber than the saline chamber, showing a decided preference, while KO mice (with no CB1 receptors) showed no significant preference for one chamber over the other.

“These results support our belief that the cannabinoid system and CB1 receptors play a critical role in mediating the rewarding and pleasurable properties of alcohol, contributing to alcohol dependency and abuse,” Thanos said.

In addition, the fact that the mice with intermediate levels of CB1 exhibited alcohol preference and intake midway between those with high levels of receptors and those with none suggests that the genetic difference between strains quantitatively influences the preference for and the amount of alcohol consumed. “These results provide further evidence for a genetic component to alcohol abuse that includes the CB1 gene — the same gene that is important for the behavioral effects of marijuana,” Thanos said.

While it remains unclear exactly how CB1 triggers the rewarding effects of alcohol, one possibility is that activation of the CB1 receptor somehow blocks the brain’s normal “stop” signals for the production of dopamine, another brain chemical known to play a role in addiction. Without the stop signal, more dopamine is released to produce a pleasure/reward response.

Since blockade of the CB1 receptor with SR141716A appears to effectively reduce alcohol intake and preference, this study also suggests that such CB1 receptor-blocking drugs might play an important role in the future treatment of alcohol abuse.

This study was funded by the Office of Biological and Environmental Research within the U.S. Department of Energy’s (DOE) Office of Science; by the National Institute on Drug Abuse and the Intramural Research Program of the NIH, [National Institute on Alcohol Abuse and Alcoholism]. The DOE has a long-standing interest in research on addiction that builds, as this study does, on the knowledge of brain receptors gained through brain-imaging studies. Brain-imaging techniques such as MRI and PET are a direct outgrowth of DOE’s support of basic physics research.

https://www.sciencedaily.com/releases/2005/09/050908084256.htm