Curbing your enthusiasm for overeating
Mouse study focuses on cannabis-like molecules that augment feeding behavior
June 11, 2019
Science Daily/University of California - Riverside
Signals between our gut and brain control how and when we eat food. But how the molecular mechanisms involved in this signaling are affected when we eat a high-energy diet and how they contribute to obesity are not well understood.
Using a mouse model, a research team led by a biomedical scientist at the University of California, Riverside, has found that overactive endocannabinoid signaling in the gut drives overeating in diet-induced obesity by blocking gut-brain satiation signaling.
Endocannabinoids are cannabis-like molecules made naturally by the body to regulate several processes: immune, behavioral, and neuronal. As with cannabis, endocannabinoids can enhance feeding behavior.
The researchers detected high activity of endocannabinoids at cannabinoid CB1 receptors in the gut of mice that were fed a high-fat and sugar -- or Western -- diet for 60 days. This overactivity, they found, prevented the food-induced secretion of the satiation peptide cholecystokinin, a short chain of amino acids whose function is to inhibit eating. This resulted in the mice overeating. Cannabinoid CB1 receptors and cholecystokinin are present in all mammals, including humans.
Study results appear in the journal Frontiers in Physiology, an open-access journal.
"If drugs could be developed to target these cannabinoid receptors so that the release of satiation peptides is not inhibited during excessive eating, we would be a step closer to addressing the prevalence of obesity that affects millions of people in the country and around the world," said Nicholas V. DiPatrizio, an assistant professor of biomedical sciences in the UCR School of Medicine who led the research team.
DiPatrizio explained that previous research by his group on a rat model showed that oral exposure to dietary fats stimulates production of the body's endocannabinoids in the gut, which is critical for the further intake of high-fat foods. Other researchers, he said, have found that levels of endocannabinoids in humans increased in blood just prior to and after eating a palatable high-energy food, and are elevated in obese humans.
"Research in humans has shown that eating associated with a palatable diet led to an increase in endocannabinoids -- but whether or not endocannabinoids control the release of satiation peptides is yet to be determined," said Donovan A. Argueta, a doctoral student in DiPatrizio's lab and the first author of the research paper.
Previous attempts at targeting the cannabinoid CB1 receptors with drugs such as Rimonabant -- a CB1 receptor blocker -- failed due to psychiatric side effects. However, the DiPatrizio lab's current study suggests it is possible to target only the cannabinoid receptors in the gut for therapeutic benefits in obesity, greatly reducing the negative side effects.
The research team plans to work on getting a deeper understanding of how CB1 receptor activity is linked to cholecystokinin.
"We would also like to get a better understanding of how specific components of the Western diet -- fat and sucrose -- lead to the dysregulation of the endocannabinoid system and gut-brain signaling," DiPatrizio said. "We also plan to study how endocannabinoids control the release of other molecules in the intestine that influence metabolism."
https://www.sciencedaily.com/releases/2019/06/190611081915.htm
How the brain makes, and breaks, a habit
Neuroscience study identifies brain chemicals, neural pathway involved in switching between habitual behavior, deliberate decision-making
May 26, 2016
Science Daily/University of California - San Diego
Not all habits are bad. Some are even necessary. It's a good thing, for example, that we can find our way home on "autopilot" or wash our hands without having to ponder every step. But inability to switch from acting habitually to acting in a deliberate way can underlie addiction and obsessive compulsive disorders.
Working with a mouse model, an international team of researchers demonstrates what happens in the brain for habits to control behavior.
The study is published in Neuron and was led by Christina Gremel, assistant professor of psychology at the University of California San Diego, who began the work as a postdoctoral researcher at the National Institute on Alcohol Abuse and Alcoholism of the National Institutes of Health. Senior authors on the study are Rui Costa, of the Champalimaud Centre for the Unknown in Lisbon, and David Lovinger of the NIAAA/NIH.
The study provides the strongest evidence to date, Gremel said, that the brain's circuits for habitual and goal-directed action compete for control -- in the orbitofrontal cortex, a decision-making area of the brain -- and that neurochemicals called endocannabinoids allow for habit to take over, by acting as a sort of brake on the goal-directed circuit.
Endocannabinoids are a class of chemicals produced naturally by humans and other animals. Receptors for endocannabinoids are found throughout the body and brain, and the endocannabinoid system is implicated in a variety of physiological processes -- including appetite, pain sensation, mood and memory. It is also the system that mediates the psychoactive effects of cannabis.
Earlier work by Gremel and Costa had shown that the orbitofrontal cortex, or OFC, is an important brain area for relaying information on goal-directed action. They found that by increasing the output of neurons in the OFC with a technique called optogenetics -- precisely turning neurons on and off with flashes of light -- they increased goal-directed actions. In contrast, when they decreased activity in the same area with a chemical approach, they disrupted goal-directed actions and the mice relied on habit instead.
"Habit takes over when the OFC is quieted," Gremel said.
In the current study, since endocannabinoids are known to reduce the activity of neurons in general, the researchers hypothesized that endocannabinoids may be quieting or reducing activity in the OFC and, with it, the ability to shift to goal-directed action. They focused particularly on neurons projecting from the OFC into the dorsomedial striatum.
They trained mice to perform the same lever-pressing action for the same food reward but in two different environments that differentially bias the development of goal-directed versus habitual actions. Like humans who don't suffer from neuropsychiatric disorders, healthy mice will readily shift between performing the same action using a goal-directed versus habitual action strategy. To stick with the earlier example of getting home, we can switch the homing autopilot off and shift to goal-directed behavior when we need to get to a new or different location.
To test their hypothesis on the role played by endocannabinoids, the researchers then deleted a particular endocannabinoid receptor, called cannabinoid type 1, or CB1, in the OFC-to-striatum pathway. Mice missing these receptors did not form habits -- showing the critical role played by the neurochemicals as well as that particular pathway.
"We need a balance between habitual and goal-directed actions. For everyday function, we need to be able to make routine actions quickly and efficiently, and habits serve this purpose," Gremel said. "However, we also encounter changing circumstances, and need the capacity to 'break habits' and perform a goal-directed action based on updated information. When we can't, there can be devastating consequences."
The findings may suggest, the authors say, a new therapeutic target for people suffering from OCD or addictions: To stop overreliance on habit and restore the ability to shift from habit to goal-directed action, it may be helpful to treat the brain's endocannabinoid system and so reduce habitual control over behavior. Treatment could be pharmaceutical or might involve behavioral therapy. Further research is needed.
https://www.sciencedaily.com/releases/2016/05/160526185419.htm
Chronic marijuana smoking affects brain chemistry, molecular imaging shows
June 13, 2011
Science Daily/Society of Nuclear Medicine
Definitive proof of an adverse effect of chronic marijuana use revealed at SNM's 58th Annual Meeting could lead to potential drug treatments and aid other research involved in cannabinoid receptors, a neurotransmission system receiving a lot of attention. Scientists used molecular imaging to visualize changes in the brains of heavy marijuana smokers versus non-smokers and found that abuse of the drug led to a decreased number of cannabinoid CB1 receptors, which are involved in not just pleasure, appetite and pain tolerance but a host of other psychological and physiological functions of the body.
"Addictions are a major medical and socioeconomic problem," says Jussi Hirvonen, MD, PhD, lead author of the collaborative study between the National Institute of Mental Health and National Institute on Drug Abuse, Bethesda, Md. "Unfortunately, we do not fully understand the neurobiological mechanisms involved in addiction. With this study, we were able to show for the first time that people who abuse cannabis have abnormalities of the cannabinoid receptors in the brain. This information may prove critical for the development of novel treatments for cannabis abuse. Furthermore, this research shows that the decreased receptors in people who abuse cannabis return to normal when they stop smoking the drug."
According to the National Institute on Drug Abuse, marijuana is the number-one illicit drug of choice in America. The psychoactive chemical in marijuana, or cannabis, is delta-9-tetrahydrocannabinol (THC), which binds to numerous cannabinoid receptors in the brain and throughout the body when smoked or ingested, producing a distinctive high. Cannabinoid receptors in the brain influence a range of mental states and actions, including pleasure, concentration, perception of time and memory, sensory perception, and coordination of movement. There are also cannabinoid receptors throughout the body involved in a wide range of functions of the digestive, cardiovascular, respiratory and other systems of the body. Currently two subtypes of cannabinoid receptors are known, CB1 and CB2, the former being involved mostly in functions of the central nervous system and the latter more in functions of the immune system and in stem cells of the circulatory system.
For this study, researchers recruited 30 chronic daily cannabis smokers who were then monitored at a closed inpatient facility for approximately four weeks. The subjects were imaged using positron emission tomography (PET), which provides information about physiological processes in the body. Subjects were injected with a radioligand, 18F-FMPEP-d2, which is a combination of a radioactive fluorine isotope and a neurotransmitter analog that binds with CB1 brain receptors.
Results of the study show that receptor number was decreased about 20 percent in brains of cannabis smokers when compared to healthy control subjects with limited exposure to cannabis during their lifetime. These changes were found to have a correlation with the number of years subjects had smoked. Of the original 30 cannabis smokers, 14 of the subjects underwent a second PET scan after about a month of abstinence. There was a marked increase in receptor activity in those areas that had been decreased at the outset of the study, an indication that while chronic cannabis smoking causes downregulation of CB1 receptors, the damage is reversible with abstinence.
Information gleaned from this and future studies may help other research exploring the role of PET imaging of CB1 receptors -- not just for drug use, but also for a range of human diseases, including metabolic disease and cancer.
https://www.sciencedaily.com/releases/2011/06/110606131705.htm