Brain
Expert Pharmacologist
- Joined
- Jul 6, 2021
- Messages
- 240
- Reaction score
- 269
- Points
- 63
The compulsive desire to eat, eat and eat again after consuming cannabis, even if the stomach does not agree with it, is both a curse and a salvation. It all depends on the purpose of using this plant. And the newly discovered mechanism of cannabinoid action on the brain turned out to be paradoxical: the indomitable appetite is caused by the stimulation of hypothalamic neurons which usually form the feeling of satiety. Here, too, the "bacterial invaders" - the mitochondria - were involved.
This effect of cannabis, popularly described as "the munchies", is well known and is even used in medicine to increase the appetite of patients suffering from weight loss due to painful anorexia or particularly toxic cancer treatment. The psychoactive substances in cannabis, cannabinoids, cause this effect. The most active and studied of these is the terpenoid delta-9-tetrahydrocannabinol, or THC. It is this cannabinoid - synthetically under the generic name dronabinol - that is approved for medical use in the United States, Canada and some European countries. Since its advantages over other antiemetics and painkillers are questionable, dronabinol is prescribed only in cases of intolerance to standard therapy.
In 2015, researchers from Yale University (USA) led by Tamas Horvath uncovered the paradoxicality of these mechanisms: appetite is awakened by activation of brain circuits, whose normal function is to create the feeling of satiety, but not uncontrollable hunger at all. However, the paradox turned out to be only external: a study conducted on a special line of genetically modified mice shed light on the "hacking" of the sense of satiety system. It was explained by a complex mode of operation of a special group of hypothalamic neurons producing proopiomelanocortin, a precursor of a number of hormones, including adrenocorticotropic hormone, melanocyte-stimulating hormones, and the endogenous opioid β-endorphin.
In 2015, researchers from Yale University (USA) led by Tamas Horvath uncovered the paradoxicality of these mechanisms: appetite is awakened by activation of brain circuits, whose normal function is to create the feeling of satiety, but not uncontrollable hunger at all. However, the paradox turned out to be only external: a study conducted on a special line of genetically modified mice shed light on the "hacking" of the sense of satiety system. It was explained by a complex mode of operation of a special group of hypothalamic neurons producing proopiomelanocortin, a precursor of a number of hormones, including adrenocorticotropic hormone, melanocyte-stimulating hormones, and the endogenous opioid β-endorphin.
The central link in the regulation of appetite
The central regulation of appetite is carried out by the hypothalamic, predominantly arcuate nucleus, signaling pathways. The hypothalamus, due to the local absence of the blood-brain barrier, integrates hormonal signals from the digestive system, adipose tissue, and brain reward system, and in accordance with them generates "commands" that weaken or enhance metabolism, intestinal motility, and appetite. The arcuate nucleus cells transmit signals to II-order neurons in other parts of the hypothalamus, especially in the paraventricular nucleus, where hormones regulating sympathetic nervous system activity and thyroid and adrenal gland function are produced.
Within the arc-shaped nucleus of the hypothalamus there are two populations of neurons that act in different directions and thus maintain energy balance of the body (the image shows the molecular mechanism of maintaining such balance and appetite regulation).
The image shows the molecular mechanism of maintaining this balance and regulating appetite. Within the arc-shaped nucleus of the hypothalamus there are two populations of neurons that act in different directions and thus maintain the energy balance of the body:
The central regulation of appetite is carried out by the hypothalamic, predominantly arcuate nucleus, signaling pathways. The hypothalamus, due to the local absence of the blood-brain barrier, integrates hormonal signals from the digestive system, adipose tissue, and brain reward system, and in accordance with them generates "commands" that weaken or enhance metabolism, intestinal motility, and appetite. The arcuate nucleus cells transmit signals to II-order neurons in other parts of the hypothalamus, especially in the paraventricular nucleus, where hormones regulating sympathetic nervous system activity and thyroid and adrenal gland function are produced.
Within the arc-shaped nucleus of the hypothalamus there are two populations of neurons that act in different directions and thus maintain energy balance of the body (the image shows the molecular mechanism of maintaining such balance and appetite regulation).
The image shows the molecular mechanism of maintaining this balance and regulating appetite. Within the arc-shaped nucleus of the hypothalamus there are two populations of neurons that act in different directions and thus maintain the energy balance of the body:
- Neurons that produce orexigenic peptides that stimulate appetite and decrease metabolic rate and energy expenditure are agouti-like protein and neuropeptide Y (the predominant peptide of the CNS);
- Neurons that produce anorexigenic appetite-suppressing neuropeptides are proopiomelanocortin and cocaine-amphetamine-regulated transcript. Little is yet known about the cocaine-amphetamine-regulated transcript. It appears to be an endogenous psychostimulant, similar in effect to amphetamine and cocaine, and a potential target for addiction therapy. Mutations of the CARTPT gene have been linked to a propensity for alcoholism. CARTPT is thought to play a key role in modulating the activity of the mesolimbic dopamine pathway of the brain reward system. It has been shown that this peptide reduces appetite and the rate of fat accumulation, and a decrease in its activity in the hypothalamus of animals (in depression, for example) leads to gluttony and obesity.
Peripheral link in appetite regulation
It is believed that the main peripheral modulators of eating behavior are the hormones insulin, leptin and ghrelin, which have differently directed influence on the activity of hypothalamic neurons.
Leptin - is secreted by cells of adipose tissue when food is ingested, in proportion to the amount of fat in the body, and reduces appetite.
Insulin - is secreted by the β-cells of the islets of Langerhans pancreas after a meal. Peripheral action of insulin is anabolic and anti-catabolic: it increases synthesis of fats and proteins, increases entry of glucose into cells (decreasing its level in blood), stimulates formation of glycogen from glucose and inhibits breakdown of glycogen and fats. The central effect of insulin, on the contrary, is catabolic - it reduces appetite, shifting the energy balance to the "expenditure" side.
Both leptin and insulin interact with both neuronal populations: they inhibit ourexigenic NP-y/APB cells and activate conditionally anorexigenic POMC/CART cells (see figure with molecular diagram). Leptin, in addition, reduces the output of the inhibitory mediator GABA from axons in contact with POMC neurons. All this usually leads to an anorexigenic effect - suppressing appetite.
GI cells synthesize a number of anorexigenic hormones and only one appetite-stimulating peptide, ghrelin (hunger hormone). It is produced by the walls of the stomach and small intestine during starvation and in the brain it interacts with the growth hormone receptors (GHSR1a) and stimulates its secretion, for which it was named: growth hormone release-inducing (ghrelin). In the arcuate nucleus of the hypothalamus ghrelin excites NP-y/APB neurons, pushing people to eat, and also mediates the pleasure of alcohol and delicious food.
Cannabinoid application points in this scheme
As we found out, the consequence of stimulation of POMC neurons is a decrease in appetite, and that of APB neurons is an increase in appetite. Therefore, it would be logical to explain the phenomenon of "the munchies" after marijuana use by the inhibition of the first cell population and/or activation of the second. However, a recent study conducted by Tamas Horvath's group found that in reality cannabis acts exactly the opposite: hunger in well-fed people is provoked by the activation of POMC neurons, while APB cells are «silent».
On the basis of the collected evidence, the authors of the work proposed a scheme of POMC neuron excitation by cannabinoids, including two pathways:
It is believed that the main peripheral modulators of eating behavior are the hormones insulin, leptin and ghrelin, which have differently directed influence on the activity of hypothalamic neurons.
Leptin - is secreted by cells of adipose tissue when food is ingested, in proportion to the amount of fat in the body, and reduces appetite.
Insulin - is secreted by the β-cells of the islets of Langerhans pancreas after a meal. Peripheral action of insulin is anabolic and anti-catabolic: it increases synthesis of fats and proteins, increases entry of glucose into cells (decreasing its level in blood), stimulates formation of glycogen from glucose and inhibits breakdown of glycogen and fats. The central effect of insulin, on the contrary, is catabolic - it reduces appetite, shifting the energy balance to the "expenditure" side.
Both leptin and insulin interact with both neuronal populations: they inhibit ourexigenic NP-y/APB cells and activate conditionally anorexigenic POMC/CART cells (see figure with molecular diagram). Leptin, in addition, reduces the output of the inhibitory mediator GABA from axons in contact with POMC neurons. All this usually leads to an anorexigenic effect - suppressing appetite.
GI cells synthesize a number of anorexigenic hormones and only one appetite-stimulating peptide, ghrelin (hunger hormone). It is produced by the walls of the stomach and small intestine during starvation and in the brain it interacts with the growth hormone receptors (GHSR1a) and stimulates its secretion, for which it was named: growth hormone release-inducing (ghrelin). In the arcuate nucleus of the hypothalamus ghrelin excites NP-y/APB neurons, pushing people to eat, and also mediates the pleasure of alcohol and delicious food.
Cannabinoid application points in this scheme
As we found out, the consequence of stimulation of POMC neurons is a decrease in appetite, and that of APB neurons is an increase in appetite. Therefore, it would be logical to explain the phenomenon of "the munchies" after marijuana use by the inhibition of the first cell population and/or activation of the second. However, a recent study conducted by Tamas Horvath's group found that in reality cannabis acts exactly the opposite: hunger in well-fed people is provoked by the activation of POMC neurons, while APB cells are «silent».
On the basis of the collected evidence, the authors of the work proposed a scheme of POMC neuron excitation by cannabinoids, including two pathways:
- Presynaptic pathway: When cannabinoids interact with CB1R-receptors of axons that form synapses with POMC neurons, the release of the inhibitory neurotransmitter GABA from presynaptic neurons (e.g., APB cells) is blocked. As a result, POMC neurons can become excited.
- Mitochondrial pathway (new and basic): when cannabinoids interact with CB1R-receptors of mitochondrial POMC neurons, mitochondrial respiration is stimulated, reactive oxygen species (ROS) are produced and expression of mitochondrial uncoupling protein 2 (RB2, UCP2) increases. It is this protein that is involved in the regulation of AFC production and eating behavior.
But why, in this case, do cells secrete β-endorphin? The fact is that the oppositely acting α-MSH and β-endorphin are encoded by the same Pomc gene, since they are formed by posttranslational conversions from the same POMC peptide. The gene expression levels of the two convertases that carry out this formation do not differ when cannabinoids bind to CB1R receptors.
Apparently, α-MSH and β-endorphin are also produced in equal amounts in this case, but are secreted selectively by POMC neurons. Tamas Horvath and his colleagues showed that about 35% of the POMC neuronal buds that form synapses with neurons of the paraventricular nucleus contain secretory vesicles with either α-MSH or β-endorphin. That is, these peptides are produced synchronously and in equal amounts, but are stored separately, and most importantly, secreted by POMC neurons under the control of different signals. RB2 under the influence of cannabinoids "switches the arrow" from the pathway of secretion of appetite-reducing α-MSH to the pathway of secretion of β-endorphin, which causes irresistible gorge (and possibly obesity).
It is not yet known whether the described effect of PB2 is unique to the POMC population of neurons, because it has previously been shown that this protein is also produced by many other cells in the nervous system. It is also unknown whether neurons in other brain regions respond to cannabinoids in exactly the same way. The Yale team focused specifically on CB1R-mediated uncontrolled eating of satiated animals, which is exactly what cannabinoid lovers do. It is possible that hypothalamic POMC neurons are also involved in the development of other symptoms associated with marijuana use.
Conclusion
Thus, paradoxically, the neurons which normally induce a feeling of satiety become the driving force behind food consumption under the influence of THC. Cannabis activates the olfactory bulb in the brain (the department responsible for recognizing odors), which leads to better and stronger smelling food. THC also acts on receptors in an area of the brain called the adjoining nucleus, which increases the release of the neurotransmitter dopamine. The release of dopamine increases the feeling of pleasure from eating high. The brain naturally releases dopamine when we eat pleasurable foods, but when THC is present, your body gets an additional dopamine release from what you eat.
THC also interacts with CB1 receptors in the hypothalamus to release a hormone called ghrelin, an appetite-stimulating hormone that speeds up digestion. Not only does THC stimulate this hormone, ghrelin is also responsible for creating feelings of hunger, which plays a role in carbohydrate metabolism, which scientists hypothesize is why THC makes you feel hungry and crave carbohydrate-rich substances.
Apparently, α-MSH and β-endorphin are also produced in equal amounts in this case, but are secreted selectively by POMC neurons. Tamas Horvath and his colleagues showed that about 35% of the POMC neuronal buds that form synapses with neurons of the paraventricular nucleus contain secretory vesicles with either α-MSH or β-endorphin. That is, these peptides are produced synchronously and in equal amounts, but are stored separately, and most importantly, secreted by POMC neurons under the control of different signals. RB2 under the influence of cannabinoids "switches the arrow" from the pathway of secretion of appetite-reducing α-MSH to the pathway of secretion of β-endorphin, which causes irresistible gorge (and possibly obesity).
It is not yet known whether the described effect of PB2 is unique to the POMC population of neurons, because it has previously been shown that this protein is also produced by many other cells in the nervous system. It is also unknown whether neurons in other brain regions respond to cannabinoids in exactly the same way. The Yale team focused specifically on CB1R-mediated uncontrolled eating of satiated animals, which is exactly what cannabinoid lovers do. It is possible that hypothalamic POMC neurons are also involved in the development of other symptoms associated with marijuana use.
Conclusion
Thus, paradoxically, the neurons which normally induce a feeling of satiety become the driving force behind food consumption under the influence of THC. Cannabis activates the olfactory bulb in the brain (the department responsible for recognizing odors), which leads to better and stronger smelling food. THC also acts on receptors in an area of the brain called the adjoining nucleus, which increases the release of the neurotransmitter dopamine. The release of dopamine increases the feeling of pleasure from eating high. The brain naturally releases dopamine when we eat pleasurable foods, but when THC is present, your body gets an additional dopamine release from what you eat.
THC also interacts with CB1 receptors in the hypothalamus to release a hormone called ghrelin, an appetite-stimulating hormone that speeds up digestion. Not only does THC stimulate this hormone, ghrelin is also responsible for creating feelings of hunger, which plays a role in carbohydrate metabolism, which scientists hypothesize is why THC makes you feel hungry and crave carbohydrate-rich substances.