Endocannabinoid system

Endocannabinoid system

The endocannabinoid system refers to a group of neuromodulators (Kreitzer and Regehr, 2001; Maejima "et al", 2001) and their receptors that are involved in a variety of physiological processes including appetite, pain-sensation, mood, and memory. It is named for endocannabinoids, the endogenous lipids that bind cannabinoid receptors (the same receptors that mediate the psychoactive effects of cannibis). Broadly speaking, the endocannabinoid system refers to:
* the cannabinoid receptors CB1 and CB2, 2 G-protein coupled receptors primarily located in the central nervous system and periphery, respectively
* the endogenous arachidonate-based lipids, anandamide ("N"-arachidonoyl ethanolamine or AEA) and 2-arachidonoylglycerol (2-AG), collectively termed the "endocannabinoids," that are ligands for the cannabinoid receptors
* the enzymes that synthesize and degrade the endocannabinoids anandamide and 2-AG. Unlike neurotransmitters, endogenous cannabinoids are not stored in vesicles after synthesis, but are synthesized on demand (Rodriguez de Fonseca "et al", 2004).

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, [cite journal |author=Fortin DA, Levine ES |title=Differential effects of endocannabinoids on glutamatergic and GABAergic inputs to layer 5 pyramidal neurons |journal=Cereb. Cortex |volume=17 |issue=1 |pages=163–74 |year=2007 |pmid=16467564 |doi=10.1093/cercor/bhj133] [cite journal |author=Good CH |title=Endocannabinoid-dependent regulation of feedforward inhibition in cerebellar Purkinje cells |journal=J. Neurosci. |volume=27 |issue=1 |pages=1–3 |year=2007 |pmid=17205618 |doi=] [cite journal |author=Hashimotodani Y, Ohno-Shosaku T, Kano M |title=Presynaptic monoacylglycerol lipase activity determines basal endocannabinoid tone and terminates retrograde endocannabinoid signaling in the hippocampus |journal=J. Neurosci. |volume=27 |issue=5 |pages=1211–9 |year=2007 |pmid=17267577 |doi=10.1523/JNEUROSCI.4159-06.2007] motor learning, [cite journal |author=Kishimoto Y, Kano M |title=Endogenous cannabinoid signaling through the CB1 receptor is essential for cerebellum-dependent discrete motor learning |journal=J. Neurosci. |volume=26 |issue=34 |pages=8829–37 |year=2006 |pmid=16928872 |doi=10.1523/JNEUROSCI.1236-06.2006] synaptic plasticity, [cite journal |author=Brenowitz SD, Regehr WG |title=Associative short-term synaptic plasticity mediated by endocannabinoids |journal=Neuron |volume=45 |issue=3 |pages=419–31 |year=2005 |pmid=15694328 |doi=10.1016/j.neuron.2004.12.045] appetite, [Di Marzo V. et al. "Leptin-regulated endocannabinoids are involved in maintaining food intake." Nature. 2001 Apr 12;410(6830):822-5. PMID 11298451] and pain sensation. [Cravatt, B.F. et al. "Supersensitivity to anandamide and enhanced endogenous cannabinoid signaling in mice lacking fatty acid amide hydrolase." Proc Natl Acad Sci U S A. 2001 Jul 31;98(16):9371-6. PMID 11470906]


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 phosphatidylethanolamine, a membrane-resident phospholipid, into N-acyl-phosphatidylethanolamine (NAPE). Experiments have shown that multiple phospholipases cleave NAPE to yield anandamide (Okamoto et al., 2004; Liu et al, 2006). 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 uptaken via a putative transporter and degraded by fatty acid amide hydrolase (FAAH) which cleaves anandamide and MGLL, which cleaves 2-AG to arachidonic acid & ethanolamine and arachidonic acid & glycerol, respectively (reviewed in 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 by endocannabinoid reuptake.

Endocannabinoid binding & signal transduction

While there have been some papers that have linked concurrent stimulation of dopamine 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 (p38/p42/p44) of MAP kinases 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 RNAs (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).

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-, P/Q- and L-type calcium channels [cite journal |author=Twitchell W, Brown S, Mackie K |title=Cannabinoids inhibit N- and P/Q-type calcium channels in cultured rat hippocampal neurons |journal=J. Neurophysiol. |volume=78 |issue=1 |pages=43–50 |year=1997 |pmid=9242259 |doi=] cite journal |author=Guo J, Ikeda SR |title=Endocannabinoids modulate N-type calcium channels and G-protein-coupled inwardly rectifying potassium channels via CB1 cannabinoid receptors heterologously expressed in mammalian neurons |journal=Mol. Pharmacol. |volume=65 |issue=3 |pages=665–74 |year=2004 |pmid=14978245 |doi=10.1124/mol.65.3.665] In addition to acting on calcium channels, Gi/o and Gs, subunits of G protein-coupled receptors, 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 (Guo and Ikeda, 2004). 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 [cite journal |author=Binzen U, Greffrath W, Hennessy S, Bausen M, Saaler-Reinhardt S, Treede RD |title=Co-expression of the voltage-gated potassium channel Kv1.4 with transient receptor potential channels (TRPV1 and TRPV2) and the cannabinoid receptor CB1 in rat dorsal root ganglion neurons |journal=Neuroscience |volume=142 |issue=2 |pages=527–39 |year=2006 |pmid=16889902 |doi=10.1016/j.neuroscience.2006.06.020] . In the central nervous system, CB1 receptors, for the most part, influence neuronal excitability indirectly, by reducing the impact of incoming synaptic input [cite journal |author=Freund TF, Katona I, Piomelli D |title=Role of endogenous cannabinoids in synaptic signaling |journal=Physiol. Rev. |volume=83 |issue=3 |pages=1017–66 |year=2003 |pmid=12843414 |doi=10.1152/physrev.00004.2003] . 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 [cite journal |author=Chevaleyre V, Heifets BD, Kaeser PS, Südhof TC, Purpura DP, Castillo PE |title=Endocannabinoid-mediated long-term plasticity requires cAMP/PKA signaling and RIM1alpha |journal=Neuron |volume=54 |issue=5 |pages=801–12 |year=2007 |pmid=17553427 |doi=10.1016/j.neuron.2007.05.020] Still, direct effects of CB1 receptors on membrane excitability have been reported, and strongly impact the firing of cortical neurons [cite journal |author=Bacci A, Huguenard JR, Prince DA |title=Long-lasting self-inhibition of neocortical interneurons mediated by endocannabinoids |journal=Nature |volume=431 |issue=7006 |pages=312–6 |year=2004 |pmid=15372034 |doi=10.1038/nature02913] In a series of behavioral experiments, Palazzo et al. demonstrated that NMDA, an ionotropic glutamate receptor, and the metabotropic glutamate receptors (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 about sixty percent leaner and slightly less hungrier than wildtype [cite journal |author=Ravinet Trillou C, Delgorge C, Menet C, Arnone M, Soubrié P |title=CB1 cannabinoid receptor knockout in mice leads to leanness, resistance to diet-induced obesity and enhanced leptin sensitivity |journal=Int. J. Obes. Relat. Metab. Disord. |volume=28 |issue=4 |pages=640–8 |year=2004 |pmid=14770190 |doi=10.1038/sj.ijo.0802583] . Compared to wildtype, CB1 knockout mice exhibit severe deficits in motor learning, memory retrieval, and increased difficulty in completing the Morris water maze [cite journal |author=Varvel SA, Lichtman AH |title=Evaluation of CB1 receptor knockout mice in the Morris water maze |journal=J. Pharmacol. Exp. Ther. |volume=301 |issue=3 |pages=915–24 |year=2002 |pmid=12023519 |doi=] [cite journal |author=Niyuhire F, Varvel SA, Martin BR, Lichtman AH |title=Exposure to marijuana smoke impairs memory retrieval in mice |journal=J. Pharmacol. Exp. Ther. |volume=322 |issue=3 |pages=1067–75 |year=2007 |pmid=17586723 |doi=10.1124/jpet.107.119594] [cite journal |author=Kishimoto Y, Kano M |title=Endogenous cannabinoid signaling through the CB1 receptor is essential for cerebellum-dependent discrete motor learning |journal=J. Neurosci. |volume=26 |issue=34 |pages=8829–37 |year=2006 |pmid=16928872 |doi=10.1523/JNEUROSCI.1236-06.2006] . 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).

ECS changes induced by cannabis consumption


Mice treated with tetrahydrocannabinol show suppression of long-term potentiation in the hippocampus - a process that is essential for the formation and storage of long-term memory [cite journal |author=Hampson RE, Deadwyler SA |title=Cannabinoids, hippocampal function and memory |journal=Life Sci. |volume=65 |issue=6-7 |pages=715–23 |year=1999 |pmid=10462072 |doi=] . These results concur with anecdotal evidence suggesting that smoked preparations of "Cannabis" attenuates short-term memory [cite journal |author=Pertwee RG |title=Cannabinoid receptors and pain |journal=Prog. Neurobiol. |volume=63 |issue=5 |pages=569–611 |year=2001 |pmid=11164622 |doi=] . 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. Interestingly, recent research reported in a 2005 "Journal Of Clinical Investigation" article [cite journal |author=Jiang W, Zhang Y, Xiao L, "et al" |title=Cannabinoids promote embryonic and adult hippocampus neurogenesis and produce anxiolytic- and antidepressant-like effects |journal=J. Clin. Invest. |volume=115 |issue=11 |pages=3104–16 |year=2005 |pmid=16224541 |doi=10.1172/JCI25509] 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.


Those who use cannabis are familiar with its appetite-enhancing effects. Emerging data suggests that THC acts via CB1 receptors on hypothalamic nuclei, thus directly increasing appetite [cite journal |author=Kirkham TC, Tucci SA |title=Endocannabinoids in appetite control and the treatment of obesity |journal=CNS Neurol Disord Drug Targets |volume=5 |issue=3 |pages=272–92 |year=2006 |pmid=16787229 |doi=] . It is thought that hypothalamic neurons tonically produce endocannabinoids that work to tightly regulate hunger. Interestingly, the amount of endocannabinoids produced is inversely correlated with the amount of leptin in the blood [cite journal |author=Di Marzo V, Sepe N, De Petrocellis L, "et al" |title=Trick or treat from food endocannabinoids? |journal=Nature |volume=396 |issue=6712 |pages=636–7 |year=1998 |pmid=9872309 |doi=10.1038/25267] . For example, mice without leptin not only become massively obese but have higher-than-normal levels of hypothalamic endocannabinoidscite journal |author=Di Marzo V, Goparaju SK, Wang L, "et al" |title=Leptin-regulated endocannabinoids are involved in maintaining food intake |journal=Nature |volume=410 |issue=6830 |pages=822–5 |year=2001 |pmid=11298451 |doi=10.1038/35071088] . Similarly, when these mice were treated with an endocannabinoid antagonist, 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 activates a pathway responsible for food-seeking behavior [cite journal |author=Kirkham TC, Tucci SA |title=Endocannabinoids in appetite control and the treatment of obesity |journal=CNS Neurol Disord Drug Targets |volume=5 |issue=3 |pages=272–92 |year=2006 |pmid=16787229 |doi=] .

ECS and multiple sclerosis

Historical records from ancient China and Greece suggest that preparations of "Cannabis Indica" were commonly prescribed to ameloriate multiple sclerosis-like symptoms such as tremors and muscle pain; unfortunately, however, treatment with marinol hasn’t shown the same efficacy as inhaled Cannabis [cite journal |author=Baker D, Pryce G, Croxford JL, "et al" |title=Cannabinoids control spasticity and tremor in a multiple sclerosis model |journal=Nature |volume=404 |issue=6773 |pages=84–7 |year=2000 |pmid=10716447 |doi=10.1038/35003583] [cite journal |author=Baker D, Pryce G, Croxford JL, "et al" |title=Endocannabinoids control spasticity in a multiple sclerosis model |journal=FASEB J. |volume=15 |issue=2 |pages=300–2 |year=2001 |pmid=11156943 |doi=10.1096/fj.00-0399fje] . 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 (reviewed in Pertwee, 2001). 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 oligodendrocytes, 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 microglial cell line by a CB2 receptor dependent mechanism, and the number of microglial cells is increased in multiple sclerosis. [cite web|url=http://molpharm.aspetjournals.org/cgi/content/full/65/4/999|title=Cultured Rat Microglial Cells Synthesize the Endocannabinoid 2-Arachidonylglycerol, Which Increases Proliferation via a CB2 Receptor-Dependent Mechanism 0026-895X/04/6504-999-1007 Mol Pharmacol 65:999-1007, 2004]

Role in human female reproduction

The developing embryo expresses cannabinoid receptors early in development that are responsive to anandamide 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 [cite journal |author=Maccarrone M, Valensise H, Bari M, Lazzarin N, Romanini C, Finazzi-Agrò A |title=Relation between decreased anandamide hydrolase concentrations in human lymphocytes and miscarriage |journal=Lancet |volume=355 |issue=9212 |pages=1326–9 |year=2000 |pmid=10776746 |doi=] . These results suggest that proper intake of exogenous cannabinoids (e.g. marijuana) can decrease the likelihood for pregnancy [cite journal |author=Das SK, Paria BC, Chakraborty I, Dey SK |title=Cannabinoid ligand-receptor signaling in the mouse uterus |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=92 |issue=10 |pages=4332–6 |year=1995 |pmid=7753807 |doi=] [cite journal |author=Paria BC, Das SK, Dey SK |title=The preimplantation mouse embryo is a target for cannabinoid ligand-receptor signaling |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=92 |issue=21 |pages=9460–4 |year=1995 |pmid=7568154 |doi=] .

Role in hippocampal neurogenesis

In the adult brain, the endocannabinoid system facilitates neurogenesis ("birth of new neurons") of hippocampal granule cells [cite journal |author=Aguado T, Monory K, Palazuelos J, "et al" |title=The endocannabinoid system drives neural progenitor proliferation |journal=FASEB J. |volume=19 |issue=12 |pages=1704–6 |year=2005 |pmid=16037095 |doi=10.1096/fj.05-3995fje] [cite journal |author=Jiang W, Zhang Y, Xiao L, "et al" |title=Cannabinoids promote embryonic and adult hippocampus neurogenesis and produce anxiolytic- and antidepressant-like effects |journal=J. Clin. Invest. |volume=115 |issue=11 |pages=3104–16 |year=2005 |pmid=16224541 |doi=10.1172/JCI25509] . 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 [cite journal |author=Christie BR, Cameron HA |title=Neurogenesis in the adult hippocampus |journal=Hippocampus |volume=16 |issue=3 |pages=199–207 |year=2006 |pmid=16411231 |doi=10.1002/hipo.20151] . 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 (Aguado et al., 2005). 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 (Aguada et al., 2005; Jiang et al., 2005).


External links

* [http://www.cannabinoidsociety.org Homepage of the ICRS] - The International Cannabinoid Research Society

* [http://www.endocannabinoid.net Homepage of the ECSN] - The Endocannabinoid System Network

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