Endocannabinoid system
Encyclopedia
The endocannabinoid system refers to a group of neuromodulatory lipid
s and their receptor
s that are involved in a variety of physiological processes including appetite
, pain-sensation
, mood
, and memory
; it mediates the psychoactive effects of cannabis
and, broadly speaking, includes:
The endocannabinoid system has been studied using genetic and pharmacological methods. These studies have revealed a broad role for endocannabinoid signaling in a variety of physiological processes, including neuromodulator release, motor learning
, synaptic plasticity
, appetite
, and pain
sensation.
, a membrane-resident phospholipid, into N-acyl-phosphatidylethanolamine (NAPE). Experiments have shown that multiple phospholipase
s cleave NAPE to yield anandamide
. In NAPE-phospholipase D (NAPEPLD) knockouts, the PLD
-mediated cleavage of NAPE is reduced, not abolished, in low calcium concentrations, suggesting multiple, distinct pathways are involved in AEA
biosynthesis (Leung et al., 2006). Once released into the extracellular space by a putative endocannabinoid transporter, messengers are vulnerable to glial inactivation. Endocannabinoids are taken up via a putative transporter and degraded by fatty acid amide hydrolase (FAAH), which cleaves anandamide into arachidonic acid
& ethanolamine
or MonoAcylGlycerol Lipase (MAGL or MGLL), which cleaves 2-AG into arachidonic acid & glycerol (for a review, see Pazos et al., 2005). While arachidonic acid is a substrate for leukotriene
and prostaglandin
synthesis, it is unclear whether this degradative byproduct has novel functions in the CNS
(Yamaguchi et al., 2001; Brock, T., 2005). Emerging data in the field also points to FAAH being expressed in the postsynaptic neuron, suggesting it also contributes to the clearance and inactivation of anandamide and 2-AG after endocannabinoid reuptake.
and CB1 receptors to an acute rise in cAMP production, it is accepted that CB1 activation causes an inhibition of cyclic adenosine monophosphate
(or cAMP) when activated alone. This inhibition of cAMP is followed by phosphorylation and subsequent activation of not only a suite of MAP kinases (p38
/p42
/p44) but also the PI3
/PKB and MEK/ERK pathway
(Galve-Roperh et al., 2002; Davis et al., 2005; Jones et al., 2005; Graham et al., 2006). Results from rat hippocampal gene chip data after acute administration of tetrahydrocannabinol
showed an increase in the expression of myelin basic protein
, endoplasmic proteins, cytochrome oxidase, and two cell adhesion molecules: NCAM, and SC1; decreases in expression were seen in both calmodulin
and ribosomal RNA
s (Kittler et al., 2000). In addition, CB1 activation has been demonstrated to increase the activity of transcription factors like c-Fos
and Krox-24 (Graham et al., 2006).
, P
/Q-
and L-type
calcium channel
s. In addition to acting on calcium channels, Gi/o and Gs, activation has also been shown to modulate potassium channel
activity. Recent studies have found that CB1 activation facilitates GIRK
, a potassium channel belonging to the Kir3 family. Corroborating Guo and Ikeda, Binzen et al. performed a series of immunohistochemistry experiments that demonstrated CB1 co-localized with GIRK and Kv1.4
potassium channels, suggesting that these two may interact in physiological contexts.
In the central nervous system, CB1 receptors, for the most part, influence neuronal excitability indirectly, by reducing the impact of incoming synaptic input.
This mechanism ("presynaptic inhibition") is believed to occur when a neuron ("postsynaptic") releases endocannabinoids in a retrograde fashion, binding to CB1 receptors expressed on nerve terminals of an input neuron ("presynaptic"). CB1 receptors then reduce the amount of neurotransmitter released, so that subsequent input from the presynaptic neuron has less of an impact on the postsynaptic neuron. It is likely that presynaptic inhibition uses many of the same ion channel mechanisms listed above, although recent evidence has shown that CB1 receptors can also regulate neurotransmitter release by a non-ion channel mechanism, i.e. through Gi/o mediated inhibition of adenylyl cyclase and Protein Kinase A
Still, direct effects of CB1 receptors on membrane excitability have been reported, and strongly impact the firing of cortical neurons
In a series of behavioral experiments, Palazzo et al. demonstrated that NMDA
, an ionotropic glutamate receptor
, and the metabotropic glutamate receptor
s (mGluRs) work in concert with CB1 to induce analgesia in mice, although the mechanism underlying this effect is unclear. Together, these findings suggest that CB1 influences neuronal excitability by a variety of mechanisms, and these effects are relevant to perception and behavior.
. There is also evidence indicating that these knockout animals have an increased incidence and severity of stroke
and seizure
(Parmentier et al., 2002; Marsicano et al., 2003).
show suppression of long-term potentiation in the hippocampus - a process that is essential for the formation and storage of long-term memory. These results concur with anecdotal evidence suggesting that smoked preparations of Cannabis
attenuates short-term memory Indeed, mice without the CB1 receptor show enhanced memory
and long-term potentiation
indicating that the endocannabinoid system may play a pivotal role in the extinction of old memories. Recent research reported in a 2005 Journal Of Clinical Investigation article indicate that the high-dose treatment of rats with the synthetic cannabinoid, HU-210
over a period of a few weeks resulted in stimulation of neural growth in the rats' hippocampus region, a part of the limbic system playing a part in the formation of declarative
and spatial memories.
acts via CB1 receptors on hypothalamic nuclei, thus directly increasing appetite. It is thought that hypothalamic neurons tonically produce endocannabinoids that work to tightly regulate hunger
. The amount of endocannabinoids produced is inversely correlated with the amount of leptin
in the blood. For example, mice without leptin not only become massively obese but have higher-than-normal levels of hypothalamic endocannabinoids. Similarly, when these mice were treated with an endocannabinoid inverse agonists, such as Rimonabant
, food intake was reduced. When the CB1 receptor is knocked out in mice, these animals tend to be leaner and less hungry than wild-type (or "normal") mice. While there is need for more research, these results (and others) suggest that exogenous cannabinoids (as from smoking marijuana) in the hypothalamus activate a pathway responsible for food-seeking behavior. Recently, however, endocannabinoids have been shown to affect feeding behavior not only at the hypothalamic level, but at the level of taste cells in taste buds At the level of taste cells, endocannabinoids were shown to selectively enhance the strength of neural signaling for sweet taste, whereas leptin decreased the strength of this same response.
-like symptoms such as tremors and muscle pain; unfortunately, however, treatment with marinol has not shown the same efficacy as inhaled Cannabis. Due to the illegality of Cannabis and rising incidence of multiple sclerosis patients who self-medicate with the drug, there has been much interest in exploiting the endocannabinoid system in the cerebellum to provide a legal and effective relief. In mouse models of multiple sclerosis, there is a profound reduction and reorganization of CB1 receptors in the cerebellum (Cabranes et al., 2006). Serial sections of cerebellar tissue subjected to immunohistochemistry
revealed that this aberrant expression occurred during the relapse phase but returned to normal during the remitting phase of the disease (Cabranes et al., 2006). There is recent data indicating that CB1 agonists promote the in vitro survival of oligodendrocyte
s, specialized support glia that are involved in axonal myelination, in the absence of growth and trophic factors; in addition, these agonist have been shown to promote mRNA expression of myelin lipid protein. (Kittler et al., 2000; Mollna-Holgado et al., 2002). Taken together, these studies point to the exciting possibility that cannabinoid treatment may not only be able to attenuate the symptoms of multiple sclerosis but also improve oligodendrocyte function (reviewed in Pertwee, 2001; Mollna-Holgado et al., 2002). 2-arachidonylglycerol stimulates proliferation of a microglia
l cell line by a CB2 receptor dependent mechanism, and the number of microglial cells is increased in multiple sclerosis.
which is secreted in the uterus. This signaling is important in regulating the timing of embryonic implantation and uterine receptivity. In mice, it has been shown that anandamide modulates the probability of implantation to the uterine wall. For example, in humans, the likelihood of miscarriage increases if uterine anandamide levels are too high or low. These results suggest that proper intake of exogenous cannabinoids (e.g. marijuana) can decrease the likelihood for pregnancy for women with high anandamide levels, and alternatively, it can increase the likelihood for pregnancy in women whose anandamide levels were too low.
("birth of new neurons") of hippocampal granule cells. In the subgranular zone
of the dentate gyrus
, multipotent neural progenitors (NP) give rise to daughter cells that, over the course of several weeks, mature into granule cells whose axons project to and synapse onto dendrites on the CA3 region. Very recent data suggests that the maturing granule cells are dependent on a reelin
, a molecular guidance cue, for proper migration through the dentate gyrus (Gong et al., 2007). NPs in the hippocampus have been shown to possess FAAH and express CB1 and utilize 2-AG. Intriguingly, CB1 activation by endogenous or exogenous promote NP proliferation and differentiation; this activation is absent in CB1 knockouts and abolished in the presence of antagonist.
Lipid
Lipids constitute a broad group of naturally occurring molecules that include fats, waxes, sterols, fat-soluble vitamins , monoglycerides, diglycerides, triglycerides, phospholipids, and others...
s and their receptor
Receptor (biochemistry)
In biochemistry, a receptor is a molecule found on the surface of a cell, which receives specific chemical signals from neighbouring cells or the wider environment within an organism...
s that are involved in a variety of physiological processes including appetite
Appetite
The appetite is the desire to eat food, felt as hunger. Appetite exists in all higher life-forms, and serves to regulate adequate energy intake to maintain metabolic needs. It is regulated by a close interplay between the digestive tract, adipose tissue and the brain. Decreased desire to eat is...
, pain-sensation
Nociception
Nociception is defined as "the neural processes of encoding and processing noxious stimuli." It is the afferent activity produced in the peripheral and central nervous system by stimuli that have the potential to damage tissue...
, mood
Mood (psychology)
A mood is a relatively long lasting emotional state. Moods differ from emotions in that they are less specific, less intense, and less likely to be triggered by a particular stimulus or event....
, and memory
Memory
In psychology, memory is an organism's ability to store, retain, and recall information and experiences. Traditional studies of memory began in the fields of philosophy, including techniques of artificially enhancing memory....
; it mediates the psychoactive effects of cannabis
Cannabis (drug)
Cannabis, also known as marijuana among many other names, refers to any number of preparations of the Cannabis plant intended for use as a psychoactive drug or for medicinal purposes. The English term marijuana comes from the Mexican Spanish word marihuana...
and, broadly speaking, includes:
- The cannabinoid receptorCannabinoid receptorThe cannabinoid receptors are a class of cell membrane receptors under the G protein-coupled receptor superfamily. As is typical of G protein-coupled receptors, the cannabinoid receptors contain seven transmembrane spanning domains...
s CB1Cannabinoid receptor type 1The cannabinoid receptor type 1, often abbreviated to CB1, is a G protein-coupled cannabinoid receptor located in the brain. It is activated by endocannabinoid neurotransmitters including anandamide and by the compound THC, found in the psychoactive drug cannabis.-Expression:The CB1 receptor is...
and CB2, two G protein-coupled receptors that are located in the centralCentral nervous systemThe central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
and peripheral nervous systemPeripheral nervous systemThe peripheral nervous system consists of the nerves and ganglia outside of the brain and spinal cord. The main function of the PNS is to connect the central nervous system to the limbs and organs. Unlike the CNS, the PNS is not protected by the bone of spine and skull, or by the blood–brain...
s, respectively. - The endogenous arachidonateArachidonic acidArachidonic acid is a polyunsaturated omega-6 fatty acid 20:4.It is the counterpart to the saturated arachidic acid found in peanut oil, Arachidonic acid (AA, sometimes ARA) is a polyunsaturated omega-6 fatty acid 20:4(ω-6).It is the counterpart to the saturated arachidic acid found in peanut oil,...
-based lipids, anandamideAnandamideAnandamide, also known as N-arachidonoylethanolamide or AEA, is an endogenous cannabinoid neurotransmitter. The name is taken from the Sanskrit word ananda, which means "bliss, delight", and amide. It is synthesized from N-arachidonoyl phosphatidylethanolamine by multiple pathways...
(N-arachidonoylethanolamide, AEA) and 2-arachidonoylglycerol2-Arachidonoylglycerol2-Arachidonoylglycerol is an endocannabinoid, an endogenous agonist of the CB1 receptor. It is an ester formed from the omega-6 fatty acid arachidonic acid and glycerol. It is present at relatively high levels in the central nervous system, with cannabinoid neuromodulatory effects. It has been...
(2-AG); these are known as "endocannabinoids" and are physiological ligandsLigand (biochemistry)In biochemistry and pharmacology, a ligand is a substance that forms a complex with a biomolecule to serve a biological purpose. In a narrower sense, it is a signal triggering molecule, binding to a site on a target protein.The binding occurs by intermolecular forces, such as ionic bonds, hydrogen...
for the cannabinoid receptors. - The enzymes that synthesize and degrade the endocannabinoids. Unlike traditional neurotransmitterNeurotransmitterNeurotransmitters are endogenous chemicals that transmit signals from a neuron to a target cell across a synapse. Neurotransmitters are packaged into synaptic vesicles clustered beneath the membrane on the presynaptic side of a synapse, and are released into the synaptic cleft, where they bind to...
s, endogenous cannabinoids are not stored in vesiclesVesicle (biology)A vesicle is a bubble of liquid within another liquid, a supramolecular assembly made up of many different molecules. More technically, a vesicle is a small membrane-enclosed sack that can store or transport substances. Vesicles can form naturally because of the properties of lipid membranes , or...
after synthesis, but are synthesized on demand (Rodriguez de Fonseca et al. , 2004). However, some evidence suggests that a pool of synthesized endocannabinoids (namely, 2-AG) may exist without the requirement of on-demand synthesis.
The endocannabinoid system has been studied using genetic and pharmacological methods. These studies have revealed a broad role for endocannabinoid signaling in a variety of physiological processes, including neuromodulator release, motor learning
Motor learning
Motor learning is a “relatively permanent” change, resulting from practice or a novel experience, in the capability for responding...
, synaptic plasticity
Synaptic plasticity
In neuroscience, synaptic plasticity is the ability of the connection, or synapse, between two neurons to change in strength in response to either use or disuse of transmission over synaptic pathways. Plastic change also results from the alteration of the number of receptors located on a synapse...
, appetite
Appetite
The appetite is the desire to eat food, felt as hunger. Appetite exists in all higher life-forms, and serves to regulate adequate energy intake to maintain metabolic needs. It is regulated by a close interplay between the digestive tract, adipose tissue and the brain. Decreased desire to eat is...
, and pain
Pain
Pain is an unpleasant sensation often caused by intense or damaging stimuli such as stubbing a toe, burning a finger, putting iodine on a cut, and bumping the "funny bone."...
sensation.
Endocannabinoid synthesis & release
In standard neurotransmission, the pre-synaptic neuron releases neurotransmitter into the synaptic cleft which binds to cognate receptors expressed on the post-synaptic neuron. Upon binding, the neuron depolarizes. This depolarization facilitates the influx of calcium into the neuron; this increase in calcium activates an enzyme called transacylase which catalyzes the first step of endocannabinoid biosynthesis by converting phosphatidylethanolaminePhosphatidylethanolamine
Phosphatidylethanolamine is a lipid found in biological membranes. It is synthesized by the addition of CDP-ethanolamine to diglyceride, releasing CMP. S-adenosyl methionine can subsequently methylate the amine of phosphatidyl ethanolamine to yield phosphatidyl choline.Cephalin is a phospholipid,...
, a membrane-resident phospholipid, into N-acyl-phosphatidylethanolamine (NAPE). Experiments have shown that multiple phospholipase
Phospholipase
A phospholipase is an enzyme that hydrolyzes phospholipids into fatty acids and other lipophilic substances. There are four major classes, termed A, B, C and D, distinguished by the type of reaction which they catalyze:*Phospholipase A...
s cleave NAPE to yield anandamide
Anandamide
Anandamide, also known as N-arachidonoylethanolamide or AEA, is an endogenous cannabinoid neurotransmitter. The name is taken from the Sanskrit word ananda, which means "bliss, delight", and amide. It is synthesized from N-arachidonoyl phosphatidylethanolamine by multiple pathways...
. In NAPE-phospholipase D (NAPEPLD) knockouts, the PLD
Phospholipase D
Phospholipase D is an enzyme which is located in the plasma membrane and catalyzes the hydrolysis of phosphatidylcholine to form phosphatidic acid , releasing the soluble choline headgroup into the cytosol...
-mediated cleavage of NAPE is reduced, not abolished, in low calcium concentrations, suggesting multiple, distinct pathways are involved in AEA
Anandamide
Anandamide, also known as N-arachidonoylethanolamide or AEA, is an endogenous cannabinoid neurotransmitter. The name is taken from the Sanskrit word ananda, which means "bliss, delight", and amide. It is synthesized from N-arachidonoyl phosphatidylethanolamine by multiple pathways...
biosynthesis (Leung et al., 2006). Once released into the extracellular space by a putative endocannabinoid transporter, messengers are vulnerable to glial inactivation. Endocannabinoids are taken up via a putative transporter and degraded by fatty acid amide hydrolase (FAAH), which cleaves anandamide into arachidonic acid
Arachidonic acid
Arachidonic acid is a polyunsaturated omega-6 fatty acid 20:4.It is the counterpart to the saturated arachidic acid found in peanut oil, Arachidonic acid (AA, sometimes ARA) is a polyunsaturated omega-6 fatty acid 20:4(ω-6).It is the counterpart to the saturated arachidic acid found in peanut oil,...
& ethanolamine
Ethanolamine
Ethanolamine, also called 2-aminoethanol or monoethanolamine , is an organic chemical compound that is both a primary amine and a primary alcohol . Like other amines, monoethanolamine acts as a weak base...
or MonoAcylGlycerol Lipase (MAGL or MGLL), which cleaves 2-AG into arachidonic acid & glycerol (for a review, see Pazos et al., 2005). While arachidonic acid is a substrate for leukotriene
Leukotriene
Leukotrienes are fatty signaling molecules. They were first found in leukocytes . One of their roles is to trigger contractions in the smooth muscles lining the trachea; their overproduction is a major cause of inflammation in asthma and allergic rhinitis...
and prostaglandin
Prostaglandin
A prostaglandin is any member of a group of lipid compounds that are derived enzymatically from fatty acids and have important functions in the animal body. Every prostaglandin contains 20 carbon atoms, including a 5-carbon ring....
synthesis, it is unclear whether this degradative byproduct has novel functions in the CNS
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
(Yamaguchi et al., 2001; Brock, T., 2005). Emerging data in the field also points to FAAH being expressed in the postsynaptic neuron, suggesting it also contributes to the clearance and inactivation of anandamide and 2-AG after endocannabinoid reuptake.
Endocannabinoid binding & signal transduction
While there have been some papers that have linked concurrent stimulation of dopamineDopamine
Dopamine is a catecholamine neurotransmitter present in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this substituted phenethylamine functions as a neurotransmitter, activating the five known types of dopamine receptors—D1, D2, D3, D4, and D5—and their...
and CB1 receptors to an acute rise in cAMP production, it is accepted that CB1 activation causes an inhibition of cyclic adenosine monophosphate
Cyclic adenosine monophosphate
Cyclic adenosine monophosphate is a second messenger important in many biological processes...
(or cAMP) when activated alone. This inhibition of cAMP is followed by phosphorylation and subsequent activation of not only a suite of MAP kinases (p38
P38 mitogen-activated protein kinases
P38 mitogen-activated protein kinases are a class of mitogen-activated protein kinases that are responsive to stress stimuli, such as cytokines, ultraviolet irradiation, heat shock, and osmotic shock, and are involved in cell differentiation and apoptosis....
/p42
MAPK1
Mitogen-activated protein kinase 1, also known as MAPK1, p42MAPK, and ERK2, is an enzyme that in humans is encoded by the MAPK1 gene.- Function :The protein encoded by this gene is a member of the MAP kinase family...
/p44) but also the PI3
Phosphoinositide 3-kinase
Phosphatidylinositol 3-kinases are a family of enzymes involved in cellular functions such as cell growth, proliferation, differentiation, motility, survival and intracellular trafficking, which in turn are involved in cancer. In response to lipopolysaccharide, PI3K phosphorylates p65, inducing...
/PKB and MEK/ERK pathway
MAPK/ERK pathway
The MAPK/ERK pathway is a chain of proteins in the cell that communicates a signal from a receptor on the surface of the cell to the DNA in the nucleus of the cell. The signal starts when a growth factor binds to the receptor on the cell surface and ends when the DNA in the nucleus expresses a...
(Galve-Roperh et al., 2002; Davis et al., 2005; Jones et al., 2005; Graham et al., 2006). Results from rat hippocampal gene chip data after acute administration of tetrahydrocannabinol
Tetrahydrocannabinol
Tetrahydrocannabinol , also known as delta-9-tetrahydrocannabinol , Δ1-THC , or dronabinol, is the main chemical psychoactive substance found in the cannabis plant. It was first isolated in 1964. In pure form, it is a glassy solid when cold, and becomes viscous and sticky if warmed...
showed an increase in the expression of myelin basic protein
Myelin basic protein
Myelin basic protein is a protein believed to be important in the process of myelination of nerves in the central nervous system .MBP was initially sequenced in 1971 after isolation from myelin membranes...
, endoplasmic proteins, cytochrome oxidase, and two cell adhesion molecules: NCAM, and SC1; decreases in expression were seen in both calmodulin
Calmodulin
Calmodulin is a calcium-binding protein expressed in all eukaryotic cells...
and ribosomal RNA
Ribosomal RNA
Ribosomal ribonucleic acid is the RNA component of the ribosome, the enzyme that is the site of protein synthesis in all living cells. Ribosomal RNA provides a mechanism for decoding mRNA into amino acids and interacts with tRNAs during translation by providing peptidyl transferase activity...
s (Kittler et al., 2000). In addition, CB1 activation has been demonstrated to increase the activity of transcription factors like c-Fos
C-Fos
In the field of molecular biology and Genetics, c-Fos is a protein encoded by the FOS gene.-Structure and function:c-Fos is a cellular proto-oncogene belonging to the immediate early gene family of transcription factors. c-Fos has a leucine-zipper DNA binding domain, and a transactivation domain at...
and Krox-24 (Graham et al., 2006).
Endocannabinoid binding & alterations in neuronal excitability
The molecular mechanisms of CB1-mediated changes to the membrane voltage have also been studied in detail. CB1 agonists reduce calcium influx by blocking the activity of voltage-dependent N-N-type calcium channel
The N-type calcium channel is a type of voltage-dependent calcium channel. Like the others of this class, the α1 subunit forms the pore through which calcium enters the cell and determines most of the channel's properties...
, P
P-type calcium channel
The p-type calcium channel is a type of voltage-dependent calcium channel. Like the others of this class, the α1 subunit is the one that determines most of the channel's properties....
/Q-
Q-type calcium channel
The Q-type calcium channel is a type of voltage-dependent calcium channel. Like the others of this class, the α1 subunit is the one that determines most of the channel's properties....
and L-type
L-type calcium channel
The L-type calcium channel is a type of voltage-dependent calcium channel. "L" stands for long-lasting referring to the length of activation. Like the others of this class, the α1 subunit is the one that determines most of the channel's properties....
calcium channel
Calcium channel
A Calcium channel is an ion channel which displays selective permeability to calcium ions. It is sometimes synonymous as voltage-dependent calcium channel, although there are also ligand-gated calcium channels.-Comparison tables:...
s. In addition to acting on calcium channels, Gi/o and Gs, activation has also been shown to modulate potassium channel
Potassium channel
In the field of cell biology, potassium channels are the most widely distributed type of ion channel and are found in virtually all living organisms. They form potassium-selective pores that span cell membranes...
activity. Recent studies have found that CB1 activation facilitates GIRK
G protein-coupled inwardly-rectifying potassium channel
The G protein-coupled inwardly-rectifying potassium channels are a family of inward-rectifier potassium ion channels which are activated via a signal transduction cascade starting with ligand-stimulated G protein-coupled receptors . GPCRs in turn release activated G-protein βγ- subunits from...
, a potassium channel belonging to the Kir3 family. Corroborating Guo and Ikeda, Binzen et al. performed a series of immunohistochemistry experiments that demonstrated CB1 co-localized with GIRK and Kv1.4
KCNA4
Potassium voltage-gated channel subfamily A member 4 also known as Kv1.4 is a protein that in humans is encoded by the KCNA4 gene. It contributes to the cardiac transient outward potassium current , the main contributing current to the repolarizing phase 1 of the cardiac action...
potassium channels, suggesting that these two may interact in physiological contexts.
In the central nervous system, CB1 receptors, for the most part, influence neuronal excitability indirectly, by reducing the impact of incoming synaptic input.
This mechanism ("presynaptic inhibition") is believed to occur when a neuron ("postsynaptic") releases endocannabinoids in a retrograde fashion, binding to CB1 receptors expressed on nerve terminals of an input neuron ("presynaptic"). CB1 receptors then reduce the amount of neurotransmitter released, so that subsequent input from the presynaptic neuron has less of an impact on the postsynaptic neuron. It is likely that presynaptic inhibition uses many of the same ion channel mechanisms listed above, although recent evidence has shown that CB1 receptors can also regulate neurotransmitter release by a non-ion channel mechanism, i.e. through Gi/o mediated inhibition of adenylyl cyclase and Protein Kinase A
Still, direct effects of CB1 receptors on membrane excitability have been reported, and strongly impact the firing of cortical neurons
In a series of behavioral experiments, Palazzo et al. demonstrated that NMDA
NMDA
N-Methyl-D-aspartic acid or N-Methyl-D-aspartate is an amino acid derivative which acts as a specific agonist at the NMDA receptor mimicking the action of glutamate, the neurotransmitter which normally acts at that receptor...
, an ionotropic glutamate receptor
Glutamate receptor
Glutamate receptors are synaptic receptors located primarily on the membranes of neuronal cells. Glutamate is one of the 20 amino acids used to assemble proteins and as a result is abundant in many areas of the body, but it also functions as a neurotransmitter and is particularly abundant in the...
, and the metabotropic glutamate receptor
Metabotropic glutamate receptor
The metabotropic glutamate receptors, or mGluRs, are a type of glutamate receptor that are active through an indirect metabotropic process. They are members of the group C family of G-protein-coupled receptors, or GPCRs...
s (mGluRs) work in concert with CB1 to induce analgesia in mice, although the mechanism underlying this effect is unclear. Together, these findings suggest that CB1 influences neuronal excitability by a variety of mechanisms, and these effects are relevant to perception and behavior.
CB1 -/- phenotype
Neuroscientists often utilize transgenic CB1 knockout mice (i.e. the mice have had the gene encoding the CB1 receptor deleted or removed) to discern novel roles for the ECS. While CB1 knockout mice are healthy and live into adulthood, there are some differences among mice without CB1 and wild-type (i.e. "normal" mice with the receptor intact); When under a high-fat diet CB1 knockout mice tend to be about sixty percent leaner and slightly less hungry than wildtype. Compared to wildtype, CB1 knockout mice exhibit severe deficits in motor learning, memory retrieval, and increased difficulty in completing the Morris water mazeMorris water maze
The Morris water navigation task is a behavioral procedure widely used in behavioral neuroscience to study spatial learning and memory. It was developed by neuroscientist Richard G...
. There is also evidence indicating that these knockout animals have an increased incidence and severity of stroke
Stroke
A stroke, previously known medically as a cerebrovascular accident , is the rapidly developing loss of brain function due to disturbance in the blood supply to the brain. This can be due to ischemia caused by blockage , or a hemorrhage...
and seizure
Seizure
An epileptic seizure, occasionally referred to as a fit, is defined as a transient symptom of "abnormal excessive or synchronous neuronal activity in the brain". The outward effect can be as dramatic as a wild thrashing movement or as mild as a brief loss of awareness...
(Parmentier et al., 2002; Marsicano et al., 2003).
Memory
Mice treated with tetrahydrocannabinolTetrahydrocannabinol
Tetrahydrocannabinol , also known as delta-9-tetrahydrocannabinol , Δ1-THC , or dronabinol, is the main chemical psychoactive substance found in the cannabis plant. It was first isolated in 1964. In pure form, it is a glassy solid when cold, and becomes viscous and sticky if warmed...
show suppression of long-term potentiation in the hippocampus - a process that is essential for the formation and storage of long-term memory. These results concur with anecdotal evidence suggesting that smoked preparations of Cannabis
Cannabis
Cannabis is a genus of flowering plants that includes three putative species, Cannabis sativa, Cannabis indica, and Cannabis ruderalis. These three taxa are indigenous to Central Asia, and South Asia. Cannabis has long been used for fibre , for seed and seed oils, for medicinal purposes, and as a...
attenuates short-term memory Indeed, mice without the CB1 receptor show enhanced memory
Memory
In psychology, memory is an organism's ability to store, retain, and recall information and experiences. Traditional studies of memory began in the fields of philosophy, including techniques of artificially enhancing memory....
and long-term potentiation
Long-term potentiation
In neuroscience, long-term potentiation is a long-lasting enhancement in signal transmission between two neurons that results from stimulating them synchronously. It is one of several phenomena underlying synaptic plasticity, the ability of chemical synapses to change their strength...
indicating that the endocannabinoid system may play a pivotal role in the extinction of old memories. Recent research reported in a 2005 Journal Of Clinical Investigation article indicate that the high-dose treatment of rats with the synthetic cannabinoid, HU-210
HU-210
HU-210 is a synthetic cannabinoid that was first synthesized in 1988 from -Myrtenol by the group led by Professor Raphael Mechoulam at the Hebrew University. HU-210 is 100 to 800 times more potent than natural THC from cannabis and has an extended duration of action...
over a period of a few weeks resulted in stimulation of neural growth in the rats' hippocampus region, a part of the limbic system playing a part in the formation of declarative
Declarative memory
Declarative memory is one of two types of long term human memory. It refers to memories which can be consciously recalled such as facts and knowledge. Its counterpart is known as non-declarative or Procedural memory, which refers to unconscious memories such as skills...
and spatial memories.
Appetite
Emerging data suggests that THCTHC
THC commonly refers to tetrahydrocannabinol, the main active chemical compound in Cannabis.THC may also refer to:* Tan Holdings Corporation...
acts via CB1 receptors on hypothalamic nuclei, thus directly increasing appetite. It is thought that hypothalamic neurons tonically produce endocannabinoids that work to tightly regulate hunger
Hunger
Hunger is the most commonly used term to describe the social condition of people who frequently experience the physical sensation of desiring food.-Malnutrition, famine, starvation:...
. The amount of endocannabinoids produced is inversely correlated with the amount of leptin
Leptin
Leptin is a 16 kDa protein hormone that plays a key role in regulating energy intake and energy expenditure, including appetite and metabolism. It is one of the most important adipose derived hormones...
in the blood. For example, mice without leptin not only become massively obese but have higher-than-normal levels of hypothalamic endocannabinoids. Similarly, when these mice were treated with an endocannabinoid inverse agonists, such as Rimonabant
Rimonabant
Rimonabant is an anorectic antiobesity drug that has been withdrawn from the market. It is an inverse agonist for the cannabinoid receptor CB1...
, food intake was reduced. When the CB1 receptor is knocked out in mice, these animals tend to be leaner and less hungry than wild-type (or "normal") mice. While there is need for more research, these results (and others) suggest that exogenous cannabinoids (as from smoking marijuana) in the hypothalamus activate a pathway responsible for food-seeking behavior. Recently, however, endocannabinoids have been shown to affect feeding behavior not only at the hypothalamic level, but at the level of taste cells in taste buds At the level of taste cells, endocannabinoids were shown to selectively enhance the strength of neural signaling for sweet taste, whereas leptin decreased the strength of this same response.
ECS and multiple sclerosis
Historical records from ancient China and Greece suggest that preparations of Cannabis Indica were commonly prescribed to ameloriate multiple sclerosisMultiple sclerosis
Multiple sclerosis is an inflammatory disease in which the fatty myelin sheaths around the axons of the brain and spinal cord are damaged, leading to demyelination and scarring as well as a broad spectrum of signs and symptoms...
-like symptoms such as tremors and muscle pain; unfortunately, however, treatment with marinol has not shown the same efficacy as inhaled Cannabis. Due to the illegality of Cannabis and rising incidence of multiple sclerosis patients who self-medicate with the drug, there has been much interest in exploiting the endocannabinoid system in the cerebellum to provide a legal and effective relief. In mouse models of multiple sclerosis, there is a profound reduction and reorganization of CB1 receptors in the cerebellum (Cabranes et al., 2006). Serial sections of cerebellar tissue subjected to immunohistochemistry
Immunohistochemistry
Immunohistochemistry or IHC refers to the process of detecting antigens in cells of a tissue section by exploiting the principle of antibodies binding specifically to antigens in biological tissues. IHC takes its name from the roots "immuno," in reference to antibodies used in the procedure, and...
revealed that this aberrant expression occurred during the relapse phase but returned to normal during the remitting phase of the disease (Cabranes et al., 2006). There is recent data indicating that CB1 agonists promote the in vitro survival of oligodendrocyte
Oligodendrocyte
Oligodendrocytes , or oligodendroglia , are a type of brain cell. They are a variety of neuroglia. Their main function is the insulation of axons in the central nervous system of some vertebrates...
s, specialized support glia that are involved in axonal myelination, in the absence of growth and trophic factors; in addition, these agonist have been shown to promote mRNA expression of myelin lipid protein. (Kittler et al., 2000; Mollna-Holgado et al., 2002). Taken together, these studies point to the exciting possibility that cannabinoid treatment may not only be able to attenuate the symptoms of multiple sclerosis but also improve oligodendrocyte function (reviewed in Pertwee, 2001; Mollna-Holgado et al., 2002). 2-arachidonylglycerol stimulates proliferation of a microglia
Microglia
Microglia are a type of glial cell that are the resident macrophages of the brain and spinal cord, and thus act as the first and main form of active immune defense in the central nervous system . Microglia constitute 20% of the total glial cell population within the brain...
l cell line by a CB2 receptor dependent mechanism, and the number of microglial cells is increased in multiple sclerosis.
Role in human female reproduction
The developing embryo expresses cannabinoid receptors early in development that are responsive to anandamideAnandamide
Anandamide, also known as N-arachidonoylethanolamide or AEA, is an endogenous cannabinoid neurotransmitter. The name is taken from the Sanskrit word ananda, which means "bliss, delight", and amide. It is synthesized from N-arachidonoyl phosphatidylethanolamine by multiple pathways...
which is secreted in the uterus. This signaling is important in regulating the timing of embryonic implantation and uterine receptivity. In mice, it has been shown that anandamide modulates the probability of implantation to the uterine wall. For example, in humans, the likelihood of miscarriage increases if uterine anandamide levels are too high or low. These results suggest that proper intake of exogenous cannabinoids (e.g. marijuana) can decrease the likelihood for pregnancy for women with high anandamide levels, and alternatively, it can increase the likelihood for pregnancy in women whose anandamide levels were too low.
Role in hippocampal neurogenesis
In the adult brain, the endocannabinoid system facilitates neurogenesisNeurogenesis
Neurogenesis is the process by which neurons are generated from neural stem and progenitor cells. Most active during pre-natal development, neurogenesis is responsible for populating the growing brain with neurons. Recently neurogenesis was shown to continue in several small parts of the brain of...
("birth of new neurons") of hippocampal granule cells. In the subgranular zone
Subgranular zone
The subgranular zone is a brain region in the hippocampus where adult neurogenesis occurs. It is one of the two major sites of adult neurogenesis in the brain, along with the subventricular zone .- Structure :...
of the dentate gyrus
Dentate gyrus
The dentate gyrus is part of the hippocampal formation. It is thought to contribute to new memories as well as other functional roles. It is notable as being one of a select few brain structures currently known to have high rates of neurogenesis in adult rats, .The dentate gyrus cells receive...
, multipotent neural progenitors (NP) give rise to daughter cells that, over the course of several weeks, mature into granule cells whose axons project to and synapse onto dendrites on the CA3 region. Very recent data suggests that the maturing granule cells are dependent on a reelin
Reelin
Reelin is a large secreted extracellular matrix protein that helps regulate processes of neuronal migration and positioning in the developing brain by controlling cell–cell interactions. Besides this important role in early development, reelin continues to work in the adult brain. It modulates the...
, a molecular guidance cue, for proper migration through the dentate gyrus (Gong et al., 2007). NPs in the hippocampus have been shown to possess FAAH and express CB1 and utilize 2-AG. Intriguingly, CB1 activation by endogenous or exogenous promote NP proliferation and differentiation; this activation is absent in CB1 knockouts and abolished in the presence of antagonist.
External links
- Homepage of the ICRS - The International Cannabinoid Research Society
- Homepage of the ECSN - The Endocannabinoid System Network