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Why do we have cannabinoid receptors? What are receptors and how do they work in the body? To understand why do we have cannabinoid receptors we must first understand what receptors are. Receptors are proteins typically found on a cell’s surface which bind to compounds called “ligands.” Ligands can be a neurotransmitter, hormone, or other substance which bind to a receptor. Brain cells, which are also called neurons, have many different types of neurotransmitter receptors. The receptor system that binds cannabinoids that come from marijuana use or from endogenous cannabinoids produced within the body is called the endocannabinoid system. A ligand-receptor interaction can activate many diverse downstream responses. In the brain, the interaction of a receptor with a neurotransmitter can cause a cascade of molecular interactions, ultimately controlling and directing a vast array of cognitive and behavioral responses such as learning, memory, motor control, and decision-making. Cannabinoids can have many diverse effects in the body, both from their direct interactions with cannabinoid receptors and the interactions that can occur downstream of these interactions, which affects the release of other neurotransmitters. While cannabis is a frequently abused drug when used for recreational purposes, medicines including cannabinoids can potentially serve many therapeutic purposes, including the treatment of nausea and vomiting, eating disorders, cancers, and neurodegenerative conditions, due to the complex dynamics of the cannabinoid system and the widespread localization of different types of cannabinoid receptors throughout the body. Visualization of endocannabinoid Signaling System What are cannabinoid receptors? Cannabinoid receptors are a category of receptors located on the cell membrane of cells throughout the body and are involved in various physiological responses including appetite, the sensation and perception of pain, mood, and memory. Cannabinoid receptors also play an important role in immune system modulation, this answers the question of why do we have cannabinoid receptors in the body. What are the different types of cannabinoid receptors and what do they do? Two types of receptors have been identified in the endocannabinoid system and are located throughout the brain, organs, and immune system. These receptors are called CB1 and CB2. Most cannabinoids can bind to both the CB1 and CB2 receptors in the body. In the brain, CB1 can be found on neurons in regions including the basal ganglia, cerebellum, hippocampus, and cerebral cortex. CB2 is primarily found in the immune system. When C1 receptors are activated by a ligand -- such as THC or anandamide -- these receptors can modulate the release of many neurotransmitters including acetylcholine, norepinephrine, dopamine, serotonin, glutamate, and GABA. Unlike most neurotransmitter receptors, CB1 cannabinoid receptors in the brain can bind ligands presynaptically; most other neurotransmitters act postsynaptically (after an action potential has fired). In this way, cannabinoid receptors can have a more modulatory effect on brain function than “traditional” neurotransmitters. The actions of CB1 receptors in the brain can be considered to have a function that is similar to a “dimmer” function on a light switch. Compared to rats, humans have relatively high concentrations of CB1 receptors in the cerebral cortex, which is involved in higher-level reasoning and decision-making, and the amygdala, an important node for fear, anxiety, and emotional processing. CB1 receptors are activated by various compounds including the chemicals anandamide and 2-arachidonoylglycerol (2-AG) that are naturally produced in the body, as well as plant cannabinoids such as the psychoactive compound THC which is found in cannabis. CB1 plays a role in drug-seeking behavior; several studies now indicate that activating the CB1 receptor in addicts restores drug-seeking behavior, likely due to the presence of CB1 receptors in the brain’s limbic system, and particularly due to the interaction between these receptors and the dopamine receptors in the nucleus accumbens. CB1 receptors act as an upstream modulator of dopamine neurons, and CB1 receptor antagonists can reduce drug-seeking behavior in some addicts. CB2 cannabinoid receptors, which were discovered in 1993, are mostly located in the immune system. CB2 receptors have been found on T cells in the body’s immune system and therefore may have a host of largely unexplored therapeutic applications. 2-AG, which is produced in the body naturally, is the primary ligand for 2-AG, but plant-based cannabinoids also bind to and affect the functioning of CB2 receptors. What are CB1 and CB2 Receptors? How does the endogenous cannabinoid, or endocannabinoid, system work? What effects do cannabinoid receptors control in the body? The endocannabinoid receptor system has two main receptor types, and most cannabinoids and endocannabinoids bind to both types. The endocannabinoid system works in two main ways – it can be activated by the production of cannabinoids made by the body or those taken from a plant-based or other sources, such as marijuana or synthetic analogs. The body produces endogenous cannabinoids, or endocannabinoids, such as anandamide. Anandamide is an endocannabinoid which is synthesized in the Purkinje cells of the brain and can inhibit the release of glutamate or GABA in the neocortex. Unlike most neurotransmitters, cannabinoids act on the presynaptic neuron – other neurotransmitters, such as acetylcholine or dopamine, act postsynaptically (after a neuron has fired). The other way that the endocannabinoid system can be stimulated is by the use of marijuana and similar compounds which contain THC, a compound which interacts with receptors of the cannabinoid system. THC has a chemical structure that is very similar to that of the endogenous compound anandamide and therefore can bind at the same receptor sites. The endocannabinoid system is also stimulated when individuals take marijuana or synthetic marijuana analogs, which can stimulate the cannabinoid system. Delta-9-tetrahydrocannabinol, or THC, is an active ingredient in marijuana that gives users a “high” feeling. THC acts on the brain’s endocannabinoid system, interfering with the brain’s natural ability to create and use endocannabinoids that the body makes, e.g., the production of the endocannabinoid anandamide after a hard workout. THC gives a marijuana user a feeling of euphoria due to its interactions with the endocannabinoid system. While these effects may be pleasant or rewarding in the short term, chronic marijuana abuse can heighten the release of dopamine and dysregulate the brain’s reward system with chronic abuse. THC can also act on the brain to dysregulate the natural balance of neurotransmitters, causing behavioral manifestations such as anxiety. People who abuse marijuana or THC can, therefore, experience a vast array of psychological and cognitive symptoms such as hallucinations, delusions, and a loss of the sense of personal identity. Thanks to CB2 receptors, cannabis also plays a role in the modulation of the body’s immune system, and play a role in cytokine release, which is part of the body’s normal immune response. While it was previously thought that CB2 receptors were solely localized to the immune system, recent studies indicate that CB2 receptors may also be located on brain cells as well, leading to a complex neuro immune interaction in this receptor system which could potentially be a novel therapeutic target. We hope this information has helped you answer the question: why do we have cannabinoid receptors to begin with. What are Purkinje cells? Purkinje cells, which are also called Purkinje neurons, were the first neurons identified in the brain. Purkinje cells are neurons (brain cells) located in the brain’s cerebellar cortex. Jan Evangelista Purkyně was the first to discover these cells in sheep brains in 1832. Santiago Ramón y Cajal, who drew detailed maps of neurons in the late 1800s, was awarded the Nobel Prize in Physiology or Medicine in 1906 for his drawings of neurons including Purkinje cells. To understand the function of Purkinje cells, it is important to know about basic neuronal structure. Each neuron in the brain has a cell body, or soma, from which many spinelike processes, called dendrites, originate. Dendrites serve to collect input from nearby firing cells. Each neuron also has an axon, which is an insulated fiber that conducts action potentials to signal to nearby cells. Structurally, Purkinje cells are very distinct, and were famously drawn by Ramón y Cajal in 1899. Each Purkinje cell has many dendrites, or branches, which receive inputs from other neurons that are called granule cells. Each Purkinje cell also has an axon, which is a single projection that transmits signals to the cerebellum, which controls movement and cognition. Purkinje cells are inhibitory, so their activity reduces the activity of adjoining brain cells. Purkinje cells dampen the activity of adjoining neurons by releasing GABA, an inhibitory neurotransmitter which binds to receptors and acts to decrease neuronal activity. Purkinje cells also engage in retrograde signaling, which refers to the backwards transmission of neurotransmitter molecules. Retrograde signaling of Purkinje cells serves as a key modulatory function for these cells. Where are Purkinje cells in the brain? Purkinje cells are located in the brain’s cerebellar cortex, which is the brain’s topmost outer layer. In particular, Purkinje cells are located in the outer layer of the cerebellum. The cerebellum is a structure located at the back of the brain and is responsible for maintenance of balance and posture, coordination of voluntary movement, motor learning, and cognitive functions including language, visuospatial, memory, and task planning and organizing. In the cerebellum, Purkinje cells work to reduce the firing of neurons that receive inputs from them. Purkinje cells inhibit the activity of deep cerebellar nuclei which relay information from the cerebellar cortex to the thalamus. Purkinje cells are the sole output of all motor coordination in the cerebellar cortex. The cerebellum is a key relay in the establishment of fine motor control. What do Purkinje cells do? What might they have an effect on? Purkinje cells themselves are implicated in motor control and learning, and are the only neurons that send signals out of the brain’s cerebellar cortex; as inhibitory GABAergic neurons, Purkinje cells block other neurons from transmitting impulses. Dozens of Purkinje cells converge on a single nucleus in the deep cerebellum; it is thought that the inhibition provided by Purkinje cells serves as a timing signal to modulate downstream behavior and provide precise neuronal control of motor behaviors for the brain’s thalamus, which plays a critical role in the brain’s motor control network. Purkinje cells play a crucial role in the brain in the coordination of complex motor and cognitive processes and disruptions to these cells’ function is associated with many diseases and disorders. Loss of Purkinje cells is associated with other diseases including Niemann Pick disease type C and cerebellar essential tremor. Neurodegenerative diseases including Alzheimer’s disease and Huntington’s disease involve the progressive loss of brain cells including Purkinje cells. Recent work suggests that disruptions to Purkinje cells may be responsible for symptoms of Autism as well (Sudarov, 2013). What type of cannabis plant has an effect on Purkinje cells? All cannabis that contains the psychoactive compound delta-9-tetrohydrocannabinol, or delta-9-THC, affects the brain mainly by activating one of the two known endocannabinoid receptors in the brain. The primary target of cannabinoids and endocannabinoids in the brain is the CB1 receptor. The CB1 receptor is an endocannabinoid receptor primarily localized to the brain and found in the cerebral cortex as well as abundantly in the cerebellum. CB1 is primarily located presynaptically in the most superficial layer of the cerebellar cortex. Endocannabinoids such as 2-arachidonoylglycerol (2-AG) can be released by Purkinje cells and contribute to retrograde signaling of neurons. Retrograde signaling is a process by which the endocannabinoid acts “backwards” to signal from the synapse back to the cell body; typical neuronal signaling travels outward from the cell body to the synapses. Retrograde transmission allows neurons to create feedback loops to enhance neurotransmission rather than actually distribute information; in this way, THC has a modulatory effect on Purkinje cells and in the brain. The endocannabinoids anandamide and 2-AG are thought to play an important role in modulatory retrograde signaling in the formation of new memories. Because THC also binds to endocannabinoid receptors, it is likely that cannabis can impact retrograde signaling in the cerebellar Purkinje cells as well. Over the past 25 years, scientists have learned a lot about the effects of cannabis, and specifically, THC, on neuronal activity. THC has many diverse effects on various brain systems involving reward, cognition, perception, and movement. Subchronic THC exposure was shown to result in impaired eyeblink conditioning and motor control in mice, and the THC-induced behavioral impairments observed were related to a fast downregulation of CB1 receptors in the cerebellum. It is thought that endocannabinoid signaling is disrupted by THC due to changes in neurotransmitter release from the neurons that project to Purkinje cells, rather than due to changes to Purkinje cells themselves. In the cerebellum, CB1 receptors are expressed on the terminals of fibers that project to Purkinje cells, and are thought to regulate synaptic plasticity processes. CB1 receptors inhibit the release of glutamate in the cerebellar cortex, and the decrease in CB1 receptor activity results in overall increase in excitatory, or glutamatergic, activity. Repeated cannabis exposure affects cerebellar-mediated associative learning, but not other types of learning that do not involve the cerebellum. Therefore, research indicates that cerebellar function is highly affected by the consumption of cannabis, and the resulting downregulation of the endocannabinoid receptor CB1. Altered time perception is frequently reported by THC users and this could be linked to temporal disintegration that is linked to an increase in internal clock speed by a mechanism that involves cerebellar function as well. Sources: https://www.nobelprize.org/nobel_prizes/medicine/laureates/1906/cajal-bio.html http://www.sciencedirect.com/science/article/pii/0014488684901626 http://www.sciencedirect.com/topics/neuroscience/purkinje-cell https://embryo.asu.edu/pages/purkinje-cells https://www.ncbi.nlm.nih.gov/books/NBK10865/ http://serendip.brynmawr.edu/bb/kinser/Structure1.html#cerebrum https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3795842/ https://www.ncbi.nlm.nih.gov/pubmed/11976437 https://www.ncbi.nlm.nih.gov/pubmed/25520276 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3967658/ http://www.sciencedirect.com/topics/neuroscience/purkinje-cell https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3967658/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4604191/ [Note: I don’t know how open source this photo is, but you may consider using Ramon y Cajal’s original drawings on your website – this is from Wikipedia, so I think it is Public Domain, but I don’t know about fair use for images on commercial blogs. Anyway, here is the link, in case it is useful for your blog: https://en.wikipedia.org/wiki/Neuron#/media/File:PurkinjeCell.jpg] Sources used to write the article on "why do we have Cannabinoid receptors?": http://www.journals.uchicago.edu/doi/abs/10.2307/1543648?journalCode=bbl, http://www.sinobiological.com/what-are-receptors-sinobio.html, http://ir.uiowa.edu/cgi/viewcontent.cgi?article=5279&context=etd, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2219532/, https://www.drugabuse.gov/publications/research-reports/marijuana/how-does-marijuana-produce-its-effects

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