Natural 'high' could avoid chronic marijuana use

December 1, 2014

Science Daily/Vanderbilt University Medical Center

Replenishing the supply of a molecule that normally activates cannabinoid receptors in the brain could relieve mood and anxiety disorders and enable some people to quit using marijuana, a Vanderbilt University study suggests.

Cannabinoid receptors are normally activated by compounds in the brain called endocannabinoids, the most abundant of which is 2-AG. They also are "turned on" by the active ingredient in marijuana.

Sachin Patel, M.D., Ph.D., and his colleagues developed a genetically modified mouse with impaired ability to produce 2-AG in the brain. The mice exhibited anxiety-like behaviors, and female mice also displayed behaviors suggestive of depression.

When an enzyme that normally breaks down 2-AG was blocked, and the supply of the endocannabinoid was restored to normal levels, these behaviors were reversed, the researchers reported on Nov. 26 in the online edition of the journal Cell Reports.

If further research confirms that some people who are anxious and depressed have low levels of 2-AG, this method of "normalizing 2-AG deficiency could represent a viable ... therapeutic strategy for the treatment of mood and anxiety disorders," they concluded.

However, this approach has not been tested in humans, they cautioned.

Relief of tension and anxiety is the most common reason cited for chronic marijuana use. Thus, restoring depleted levels of 2-AG also "could be a way to help people using marijuana," added Patel, the paper's senior author and professor of Psychiatry and of Molecular Physiology and Biophysics.

Chronic use of marijuana down-regulates cannabinoid receptors, and thus paradoxically increases anxiety. This can lead to a "vicious cycle" of increasing marijuana use that in some cases leads to addiction.

Patel and his colleagues previously have found cannabinoid receptors in the central nucleus of the amygdala of the mouse. The amygdala is a key emotional hub in the brain involved in regulating anxiety and the flight-or-fight response.

They also have found that chemically modified inhibitors of the COX-2 enzyme they developed relieve anxiety behaviors in mice by activating natural "endocannabinoids" without gastrointestinal side effects. Clinical trials of some of these potential drugs could begin in the next several years.

Cyclooxygenase (COX) enzymes produce pro-inflammatory prostaglandins and are the target of aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs), used to relieve pain and inflammation. It has been known for several years that COX-2 inhibition also activates endocannabinoids.

https://www.sciencedaily.com/releases/2014/12/141201113253.htm

Marijuana's anxiety relief effects: Receptors found in emotional hub of brain

March 6, 2014

Science Daily/Vanderbilt University Medical Center

An international group led by Vanderbilt University researchers has found c, through which marijuana exerts its effects, in a key emotional hub in the brain involved in regulating anxiety and the flight-or-fight response.

This is the first time cannabinoid receptors have been identified in the central nucleus of the amygdala in a mouse model, they report in the current issue of the journal Neuron.

The discovery may help explain why marijuana users say they take the drug mainly to reduce anxiety, said Sachin Patel, M.D., Ph.D., the paper's senior author and professor of Psychiatry and of Molecular Physiology and Biophysics.

Led by first author Teniel Ramikie, a graduate student in Patel's lab, the researchers also showed for the first time how nerve cells in this part of the brain make and release their own natural "endocannabinoids."

The study "could be highly important for understanding how cannabis exerts its behavioral effects," Patel said. As the legalization of marijuana spreads across the country, more people -- and especially young people whose brains are still developing -- are being exposed to the drug.

Previous studies at Vanderbilt and elsewhere, Patel said, have suggested the following:

·     The natural endocannabinoid system regulates anxiety and the response to stress by dampening excitatory signals that involve the neurotransmitter glutamate.

·     Chronic stress or acute, severe emotional trauma can cause a reduction in both the production of endocannabinoids and the responsiveness of the receptors. Without their "buffering" effect, anxiety goes up.

·     While marijuana's "exogenous" cannabinoids also can reduce anxiety, chronic use of the drug down-regulates the receptors, paradoxically increasing anxiety. This can trigger "a vicious cycle" of increasing marijuana use that in some cases leads to addiction.

In the current study, the researchers used high-affinity antibodies to "label" the cannabinoid receptors so they could be seen using various microscopy techniques, including electron microscopy, which allowed very detailed visualization at individual synapses, or gaps between nerve cells.

"We know where the receptors are, we know their function, we know how these neurons make their own cannabinoids," Patel said. "Now can we see how that system is affected by … stress and chronic (marijuana) use? It might fundamentally change our understanding of cellular communication in the amygdala."

https://www.sciencedaily.com/releases/2014/03/140306142803.htm

Insight into the proteins in the brain that detect cannabis

April 30, 2019

Science Daily/University of Bristol

Researchers at the University of Bristol have made new progress in understanding how cannabinoid receptors (CB1Rs), the proteins that detect the active components of marijuana, are controlled in the brain.

The brain contains about 100 billion nerve cells that are constantly communicating with one another at specialised junctions called synapses. Nerve cells possess extensions called axons, which send signals to synapses, and dendrites, which receive information from synapses.

At the synapse, the electrical 'firing' of a nerve cell causes the release of chemicals called neurotransmitters from the presynaptic terminals of its axon. These neurotransmitters cross the synapse and pass on the signal by binding to receptors at postsynaptic sites on the dendrites of the next nerve cell.

CB1Rs help control information flow in the brain by binding molecules made in the brain called endocannabinoids, which influence brain functions such as pain, appetite, mood and memory. Unusually, endocannabinoid signalling goes in the reverse direction compared to most other neurotransmitters. The 'receiving' CB1Rs are located at presynaptic sites on axons, whereas the release sites are at postsynaptic sites on dendrites.

This reverse or 'retrograde' signalling that activates presynaptic CB1Rs 'dampens down' presynaptic release of other neurotransmitters resulting in a slowing of brain activity. Moreover, the active components of cannabis bind to CB1Rs in a similar manner to endocannabinoids, resulting in the 'mellow' sensation caused by the recreational use of cannabis.

For CB1Rs to regulate brain function properly, it is essential that they are sent to the right place on the surface of the axon. However, very little is known about exactly how this occurs. The research published today [Tuesday 30 April] in eLife investigated how this process happens.

The Bristol group showed that a specific part of the CB1R protein plays a key role in the getting CB1R into axons. The research team tracked newly made CB1Rs in nerve cells grown in a dish and found that a short region of CB1R is crucial for sending CB1R to the axon and preventing it from going to the dendrites. They also discovered that this region stabilises CB1R at the surface of the axon, making it more available to receive signals from endocannabinoids.

Jeremy Henley, Professor of Molecular Neuroscience in Bristol's School of Biochemistry, said: "In recent years there has been tremendous interest in -- and controversy about -- activation of CB1R by medical marijuana. It is becoming increasingly apparent that activation of CB1Rs could be therapeutically useful for a wide range of diseases such as chronic pain, epilepsy, or multiple sclerosis. Understanding the fundamental properties of CB1R is an important basis for future studies exploring the efficacy and optimisation of these targeted approaches."

It is hoped that this increased understanding of how CB1Rs behave in nerve cells will pave the way for future studies aimed at examining the possible medical uses of marijuana, or other drugs that target CB1Rs, in treating a wide range of disorders.

https://www.sciencedaily.com/releases/2019/04/190430103457.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

Go for a run or eat chocolate: A choice dictated by the cannabinoid receptors

March 19, 2019

INSERM (Institut national de la santé et de la recherche médicale)

Physical inactivity is a common factor in lifestyle diseases -- and one that is often linked to the excessive consumption of fatty and/or sugary foods. The opposite scenario of excessive physical activity at the expense of caloric intake can also be harmful, as cases of anorexia nervosa illustrate. These data therefore point to the crucial need to research the neurobiological processes that control the respective motivations for exercise and food intake. A study by Inserm and CNRS researchers published on March 7, 2019 in JCI Insight reveals that the cannabinoid type 1 (CB1) receptors play an essential role in the choice between running and eating chocolatey food.

The authors of this paper had previously reported that the cannabinoid type-1 (CB1) receptors, present on several types of neurons, play a key role in performance during physical activity in mice. A conclusion based on the performances achieved by animals with free access to an exercise wheel -- a model in which it was not possible to distinguish the mechanism involved (motivation, pleasure...). Given that the motivation for a reward can only be estimated by measuring the efforts that the individual -- whether human or animal -- is prepared to make to get that reward, the researchers devised a model in which each access to the wheel was conditional on a prior effort. This involved the animal repeatedly introducing its snout into a recipient, an essential prerequisite for unlocking the wheel. After a training period during which the level of effort required to unlock the wheel remained the same, the mice were confronted with a test in which the effort required was gradually increased. When exposed to this test, the mice lacking CB1 receptors showed an 80 % deficit in the maximum effort they were prepared to make to unlock the wheel, and without a decrease in performance during their access to it. This finding indicates that the CB1 receptors play a major role in controlling motivation for exercise. The use of other genetically-modified mice also enabled the researchers to demonstrate that these CB1 receptors controlling motivation for exercise are located on GABAergic neurons.

The researchers then examined whether the CB1 receptors in the GABAergic neurons control the motivation for another reward: chocolatey food (like humans, mice love it even when they are otherwise well-fed). While the CB1 receptors also play a role in motivation for food -- albeit to a lesser extent than in motivation for exercise -- the CB1 receptors located on the GABAergic neurons are not implicated in the motivation for eating chocolatey food.

In our daily life, we are faced with an ongoing choice between various rewards. A fact which has encouraged the researchers to develop a model in which following a learning period the mice had the choice -- in return for the efforts described above -- between exercise and chocolatey food. The motivation for exercise was greater than that for chocolatey food, with the exception of the mice lacking CB1 -- whether generally or just on GABAergic neurons -- whose preference was for the food.

In addition to these findings indicating that the cannabinoid receptor is essential for the motivation for exercise, this study opens up avenues for researching the neurobiological mechanisms behind pathological increases in this motivation. One illustration is provided by anorexia nervosa which often combines the decreased motivation to eat with an increased motivation to exercise.

https://www.sciencedaily.com/releases/2019/03/190319121721.htm

Perception of marijuana as a 'safe drug' is scientifically inaccurate, finds review of teen brain studies

August 27, 2013

Science Daily/Universite de Montreal

The nature of the teenage brain makes users of cannabis amongst this population particularly at risk of developing addictive behaviors and suffering other long-term negative effects, according to researchers at the University of Montreal and New York's Icahn School of Medicine at Mount Sinai.

"Of the illicit drugs, cannabis is most used by teenagers since it is perceived by many to be of little harm. This perception has led to a growing number of states approving its legalization and increased accessibility. Most of the debates and ensuing policies regarding cannabis were done without consideration of its impact on one of the most vulnerable population, namely teens, or without consideration of scientific data," wrote Professor Didier Jutras-Aswad of the University of Montreal and Yasmin Hurd, MD, PhD, of Mount Sinai. "While it is clear that more systematic scientific studies are needed to understand the long-term impact of adolescent cannabis exposure on brain and behavior, the current evidence suggests that it has a far-reaching influence on adult addictive behaviors particularly for certain subsets of vulnerable individuals."

The researchers reviewed over 120 studies that looked at different aspects of the relationship between cannabis and the adolescent brain, including the biology of the brain, chemical reaction that occurs in the brain when the drug is used, the influence of genetics and environmental factors, in addition to studies into the "gateway drug" phenomenon. "Data from epidemiological studies have repeatedly shown an association between cannabis use and subsequent addiction to heavy drugs and psychosis (i.e. schizophrenia). Interestingly, the risk to develop such disorders after cannabis exposure is not the same for all individuals and is correlated with genetic factors, the intensity of cannabis use and the age at which it occurs. When the first exposure occurs in younger versus older adolescents, the impact of cannabis seems to be worse in regard to many outcomes such as mental health, education attainment, delinquency and ability to conform to adult role," Dr Jutras-Aswad said.

Although it is difficult to confirm in all certainty a causal link between drug consumption and the resulting behavior, the researchers note that rat models enable scientists to explore and directly observe the same chemical reactions that happen in human brains. Cannabis interacts with our brain through chemical receptors (namely cannabinoid receptors such as CB1 and CB2.) These receptors are situated in the areas of our brain that govern our learning and management of rewards, motivated behavior, decision-making, habit formation and motor function. As the structure of the brain changes rapidly during adolescence (before settling in adulthood), scientists believe that the cannabis consumption at this time greatly influences the way these parts of the user's personality develop. In adolescent rat models, scientists have been able to observe differences in the chemical pathways that govern addiction and vulnerability -- a receptor in the brain known as the dopamine D2 receptor is well known to be less present in cases of substance abuse.

Only a minority (approximately one in four) of teenage users of cannabis will develop an abusive or dependent relationship with the drug. This suggests to the researchers that specific genetic and behavioral factors influence the likelihood that the drug use will continue. Studies have also shown that cannabis dependence can be inherited through the genes that produce the cannabinoid receptors and an enzyme involved in the processing of THC. Other psychological factors are also likely involved. "Individuals who will develop cannabis dependence generally report a temperament characterized by negative affect, aggressivity and impulsivity, from an early age. Some of these traits are often exacerbated with years of cannabis use, which suggests that users become trapped in a vicious cycle of self-medication, which in turn becomes a dependence," Jutras-Aswad said.

The researchers stress that while a lot remains unknown about the mechanics of cannabis abuse, the body of existing research has clear implications for society. "It is now clear from the scientific data that cannabis is not harmless to the adolescent brain, specifically those who are most vulnerable from a genetic or psychological standpoint. Identifying these vulnerable adolescents, including through genetic or psychological screening, may be critical for prevention and early intervention of addiction and psychiatric disorders related to cannabis use. The objective is not to fuel the debate about whether cannabis is good or bad, but instead to identify those individuals who might most suffer from its deleterious effects and provide adequate measures to prevent this risk" Jutras-Aswad said. "Continuing research should be performed to inform public policy in this area. Without such systematic, evidenced-based research to understand the long-term effects of cannabis on the developing brain, not only the legal status of cannabis will be determined on uncertain ground, but we will not be able to innovate effective treatments such as the medicinal use of cannabis plant components that might be beneficial for treating specific disorders," Dr Hurd said.

https://www.sciencedaily.com/releases/2013/08/130827091401.htm