Abstract
The evolution of plant metabolic pathways to invent compounds which distract predators, and the history of medicine to find treatments for diseases, often share a common logic. An attractive example to illustrate the rationale behind this is the Cannabis sativa plant, which was exploited for its widespread therapeutic effects for several thousand years, but historical “prescriptions” highlighted its distractive behavioral side-effects if abused. This chapter aims to explain the characteristically wide pharmacological and behavioral profile of the Cannabis plant by pointing to the ubiquitous anatomical distribution of CB1 cannabinoid receptors, its predominant molecular target, throughout the nervous system. However, in contrast to their abundant regional and cellular localization, the subcellular arrangement of CB1 receptors and the enzymes involved in the metabolism of its main endogenous ligand, 2-arachidonoylglycerol (2-AG), are strikingly polarized on the neuronal surface in the adult brain. Though there are still several unresolved issues, the known pieces of the puzzle outline a picture in which the biosynthetic machinery for 2-AG is accumulated in the somatodendritic compartment of neurons, whereas its receptor and degrading enzyme are both found on axon terminals. This molecular architecture suggests that a main physiological role of endocannabinoid signaling is the retrograde regulation of synaptic transmission, and the present chapter aims to summarize compelling evidence that it is an ancient and fundamental component of several distinct types of synapses throughout the nervous system.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Abbreviations
- 2-AG:
-
2-Arachidonoylglycerol
- DGL:
-
Diacylglycerol lipase
- FAAH:
-
Fatty acid amide hydrolase
- MGL:
-
Monoacylglycerol lipase
- NAE:
-
N-Acylethanolamine
- RER:
-
Rough endoplasmic reticulum
- VGCC:
-
Voltage-gated calcium channels
References
Austin CP, Battey JF, Bradley A et al. (2004) The knockout mouse project. Nat Genet 36:921–924
Bacci A, Huguenard JR, Prince DA (2004) Long-lasting self-inhibition of neocortical interneurons mediated by endocannabinoids. Nature 431:312–316
Berghuis P, Rajnicek AM, Morozov YM et al. (2007) Hardwiring the brain: endocannabinoids shape neuronal connectivity. Science (New York, NY) 316:1212–1216
Bisogno T, Howell F, Williams G et al. (2003) Cloning of the first sn1-DAG lipases points to the spatial and temporal regulation of endocannabinoid signaling in the brain. J Cell Biol 163:463–468
Bodor AL, Katona I, Nyiri G et al. (2005) Endocannabinoid signaling in rat somatosensory cortex: laminar differences and involvement of specific interneuron types. J Neurosci 25:6845–6856
Breivogel CS, Griffin G, Di Marzo V et al. (2001) Evidence for a new G protein-coupled cannabinoid receptor in mouse brain. Mol Pharmacol 60:155–163
Buckley NE, McCoy KL, Mezey E et al. (2000) Immunomodulation by cannabinoids is absent in mice deficient for the cannabinoid CB(2) receptor. Eur J Pharmacol 396:141–149
Burns HD, Van Laere K, Sanabria-Bohorquez S et al. (2007) [18F]MK-9470, a positron emission tomography (PET) tracer for in vivo human PET brain imaging of the cannabinoid-1 receptor. Proc Natl Acad Sci USA 104:9800–9805
Cadas H, Gaillet S, Beltramo M et al. (1996) Biosynthesis of an endogenous cannabinoid precursor in neurons and its control by calcium and cAMP. J Neurosci 16:3934–3942
Calignano A, Katona I, Desarnaud F et al. (2000) Bidirectional control of airway responsiveness by endogenous cannabinoids. Nature 408:96–101
Chevaleyre V, Castillo PE (2003) Heterosynaptic LTD of hippocampal GABAergic synapses: a novel role of endocannabinoids in regulating excitability. Neuron 38:461–472
Chevaleyre V, Takahashi KA, Castillo PE (2006) Endocannabinoid-Mediated Synaptic Plasticity in the CNS. Annu Rev Neurosci 29:37–76
Chevaleyre V, Heifets BD, Kaeser PS et al. (2007) Endocannabinoid-mediated long-term plasticity requires cAMP/PKA signaling and RIM1alpha. Neuron 54:801–812
Cope DW, Maccaferri G, Marton LF et al. (2002) Cholecystokinin-immunopositive basket and Schaffer collateral-associated interneurones target different domains of pyramidal cells in the CA1 area of the rat hippocampus. Neuroscience 109:63–80
Cravatt BF, Giang DK, Mayfield SP et al. (1996) Molecular characterization of an enzyme that degrades neuromodulatory fatty-acid amides. Nature 384:83–87
Cravatt BF, Demarest K, Patricelli MP et al. (2001) Supersensitivity to anandamide and enhanced endogenous cannabinoid signaling in mice lacking fatty acid amide hydrolase. Proc Natl Acad Sci USA 98:9371–9376
Dinh TP, Carpenter D, Leslie FM et al. (2002) Brain monoglyceride lipase participating in endocannabinoid inactivation. Proc Natl Acad Sci USA 99:10819–10824
Dudok B, Urban GM, Mackie K et al. (2007) Molecular basis of retrograde endocannabinoid signaling at neocortical glutamatergic synapses. Society for Neuroscience. Abstract 37: 244.7/G19
Egertova M, Elphick MR (2000) Localisation of cannabinoid receptors in the rat brain using antibodies to the intracellular C-terminal tail of CB. J Comp Neurol 422:159–171
Egertova M, Giang DK, Cravatt BF et al. (1998) A new perspective on cannabinoid signalling: complementary localization of fatty acid amide hydrolase and the CB1 receptor in rat brain. Proceedings 265:2081–2085
Egertova M, Simon GM, Cravatt BF et al.(2008) Localization of N-acyl phosphatidylethanolamine phospholipase D (NAPE-PLD) expression in mouse brain: A new perspective on N-acylethanolamines as neural signaling molecules. J Comp Neurol 506:604–615
Freund TF, Buzsaki G (1996) Interneurons of the hippocampus. Hippocampus 6:347–470
Freund TF, Katona I, Piomelli D (2003) Role of endogenous cannabinoids in synaptic signaling. Physiol Rev 83:1017–1066
Fukudome Y, Ohno-Shosaku T, Matsui M et al. (2004) Two distinct classes of muscarinic action on hippocampal inhibitory synapses: M2-mediated direct suppression and M1/M3-mediated indirect suppression through endocannabinoid signalling. Eur J Neurosci 19:2682–2692
Grimsey NL, Goodfellow CE, Scotter EL et al. (2008) Specific detection of CB1 receptors; cannabinoid CB1 receptor antibodies are not all created equal!. J Neurosci Methods 171:78–86
Gulyas AI, Cravatt BF, Bracey MH et al. (2004) Segregation of two endocannabinoid-hydrolyzing enzymes into pre- and postsynaptic compartments in the rat hippocampus, cerebellum and amygdala. Eur J NeuroSci 20:441–458
Hajos N, Katona I, Naiem SS et al. (2000) Cannabinoids inhibit hippocampal GABAergic transmission and network oscillations. Eur J Neurosci 12:3239–3249
Hasegawa K, Martin F, Huang G et al. (2004) PEST domain-enriched tyrosine phosphatase (PEP) regulation of effector/memory T cells. Science (New York, NY) 303:685–689
Hashimotodani Y, Ohno-Shosaku T, Maejima T et al. (2008) Pharmacological evidence for the involvement of diacylglycerol lipase in depolarization-induced endocanabinoid release. Neuropharmacology 54:58–67
Hefft S, Jonas P (2005) Asynchronous GABA release generates long-lasting inhibition at a hippocampal interneuron-principal neuron synapse. Nat Neurosci 8:1319–1328
Herkenham M, Lynn AB, Little MD et al. (1990) Cannabinoid receptor localization in brain. Proc Natl Acad Sci USA 87:1932–1936
Herkenham M, Lynn AB, de Costa BR et al. (1991a) Neuronal localization of cannabinoid receptors in the basal ganglia of the rat. Brain Res 547:267–274
Herkenham M, Lynn AB, Johnson MR et al. (1991b) Characterization and localization of cannabinoid receptors in rat brain: a quantitative in vitro autoradiographic study. J Neurosci 11:563–583
Hohmann AG, Herkenham M (2000) Localization of cannabinoid CB(1) receptor mRNA in neuronal subpopulations of rat striatum: a double-label in situ hybridization study. Synapse (New York, NY) 37:71–80
Johns DG, Behm DJ, Walker DJ et al. (2007) The novel endocannabinoid receptor GPR55 is activated by atypical cannabinoids but does not mediate their vasodilator effects. Br J Pharmacol 152:825–831
Jung KM, Astarita G, Zhu C et al. (2007) A key role for diacylglycerol lipase-alpha in metabotropic glutamate receptor-dependent endocannabinoid mobilization. Mol Pharmacol 72:612–621
Katona I, Sperlagh B, Sik A et al. (1999) Presynaptically located CB1 cannabinoid receptors regulate GABA release from axon terminals of specific hippocampal interneurons. J Neurosci 19:4544–4558
Katona I, Sperlagh B, Magloczky Z et al. (2000) GABAergic interneurons are the targets of cannabinoid actions in the human hippocampus. Neuroscience 100:797–804
Katona I, Rancz EA, Acsady L et al. (2001) Distribution of CB1 cannabinoid receptors in the amygdala and their role in the control of GABAergic transmission. J Neurosci 21:9506–9518
Katona I, Urban GM, Wallace M et al. (2006) Molecular composition of the endocannabinoid system at glutamatergic synapses. J Neurosci 26:5628–5637
Kawamura Y, Fukaya M, Maejima T et al. (2006) The CB1 cannabinoid receptor is the major cannabinoid receptor at excitatory presynaptic sites in the hippocampus and cerebellum. J Neurosci 26:2991–3001
Kim J, Alger BE (2004) Inhibition of cyclooxygenase-2 potentiates retrograde endocannabinoid effects in hippocampus. Nat Neurosci 7:697–698
Klausberger T, Magill PJ, Marton LF et al. (2003) Brain-state- and cell-type-specific firing of hippocampal interneurons in vivo. Nature 421:844–848
Lafourcade M, Elezgarai I, Mato S et al. (2007) Molecular components and functions of the endocannabinoid system in mouse prefrontal cortex. PLoS ONE 2:e709
Ledent C, Valverde O, Cossu G et al. (1999) Unresponsiveness to cannabinoids and reduced addictive effects of opiates in CB1 receptor knockout mice. Science (New York, NY) 283:401–404
Leterrier C, Laine J, Darmon M et al. (2006) Constitutive activation drives compartment-selective endocytosis and axonal targeting of type 1 cannabinoid receptors. J Neurosci 26:3141–3153
Leung D, Saghatelian A, Simon GM et al. (2006) Inactivation of N-acyl phosphatidylethanolamine phospholipase D reveals multiple mechanisms for the biosynthesis of endocannabinoids. Biochemistry 45:4720–4726
Ludanyi A, Eross L, Czirjak S et al. (2008) Downregulation of the CB1 cannabinoid receptor and related molecular elements of the endocannabinoid system in epileptic human hippocampus. J Neurosci 28:2976–2990
Maccarrone M, Rossi S, Bari M et al. (2008) Anandamide inhibits metabolism and physiological actions of 2-arachidonoylglycerol in the striatum. Nat Neurosci 11:152–159
Mailleux P, Vanderhaeghen JJ (1992) Distribution of neuronal cannabinoid receptor in the adult rat brain: a comparative receptor binding radioautography and in situ hybridization histochemistry. Neuroscience 48:655–668
Makara JK, Mor M, Fegley D et al. (2005) Selective inhibition of 2-AG hydrolysis enhances endocannabinoid signaling in hippocampus. Nat Neurosci 8:1139–1141
Marsicano G, Lutz B (1999) Expression of the cannabinoid receptor CB1 in distinct neuronal subpopulations in the adult mouse forebrain. Eur J Neurosci 11:4213–4225
Marsicano G, Wotjak CT, Azad SC et al. (2002) The endogenous cannabinoid system controls extinction of aversive memories. Nature 418:530–534
Marsicano G, Goodenough S, Monory K et al. (2003) CB1 cannabinoid receptors and on-demand defense against excitotoxicity. Science (New York, NY) 302:84–88
Matsuda LA, Lolait SJ, Brownstein MJ et al. (1990) Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature 346:561–564
Matsuda LA, Bonner TI, Lolait SJ (1993) Localization of cannabinoid receptor mRNA in rat brain. J Comp Neurol 327:535–550
Matyas F, Yanovsky Y, Mackie K et al. (2006) Subcellular localization of type 1 cannabinoid receptors in the rat basal ganglia. Neuroscience 137:337–361
Matyas F, Watanabe M, Mackie K et al. (2007) Molecular architecture of the cannabinoid signaling system in the core of the nucleus accumbens. Ideggyogyaszati szemle 60:187–191
Matyas F, Urban GM, Watanabe M et al. (2008) Identification of the sites of 2-arachidonoylglycerol synthesis and action imply retrograde endocannabinoid signaling at both GABAergic and glutamatergic synapses in the ventral tegmental area. Neuropharmacology 54:95–107
McDonald AJ, Mascagni F (2001) Localization of the CB1 type cannabinoid receptor in the rat basolateral amygdala: high concentrations in a subpopulation of cholecystokinin-containing interneurons. Neuroscience 107:641–652
Melis M, Perra S, Muntoni AL et al. (2004) Prefrontal cortex stimulation induces 2-arachidonoyl-glycerol-mediated suppression of excitation in dopamine neurons. J Neurosci 24:10707–10715
Monory K, Massa F, Egertova M et al. (2006) The endocannabinoid system controls key epileptogenic circuits in the hippocampus. Neuron 51:455–466
Mulder J, Aguado T, Keimpema E et al. (2008) Endocannabinoid signaling controls pyramidal cell specification and long-range axon patterning. Proceedings of the National Academy of Sciences of the United States of America
Nyilas R, Dudok B, Urban GM et al. (2008) Enzymatic machinery for endocannabinoid biosynthesis associated with calcium stores in glutamatergic axon terminals. J Neurosci 28:1058–1063
Nyiri G, Cserep C, Szabadits E et al. (2005) CB1 cannabinoid receptors are enriched in the perisynaptic annulus and on preterminal segments of hippocampal GABAergic axons. Neuroscience 136:811–822
Ohno-Shosaku T, Maejima T, Kano M (2001) Endogenous cannabinoids mediate retrograde signals from depolarized postsynaptic neurons to presynaptic terminals. Neuron 29:729–738
Okamoto Y, Morishita J, Tsuboi K et al. (2004) Molecular characterization of a phospholipase D generating anandamide and its congeners. J Biol Chem 279:5298–5305
Palomaki VA, Lehtonen M, Savinainen JR et al. (2007) Visualization of 2-arachidonoylglycerol accumulation and cannabinoid CB1 receptor activity in rat brain cryosections by functional autoradiography. J Neurochem 101:972–981
Pawelzik H, Hughes DI, Thomson AM (2002) Physiological and morphological diversity of immunocytochemically defined parvalbumin- and cholecystokinin-positive interneurones in CA1 of the adult rat hippocampus. J Comp Neurol 443:346–367
Pettit DA, Harrison MP, Olson JM et al. (1998) Immunohistochemical localization of the neural cannabinoid receptor in rat brain. J Neurosci Res 51:391–402
Saper CB, Sawchenko PE (2003) Magic peptides, magic antibodies: guidelines for appropriate controls for immunohistochemistry. J Comp Neurol 465:161–163
Schlicker E, Kathmann M (2001) Modulation of transmitter release via presynaptic cannabinoid receptors. Trends Pharmacol Sci 22:565–572
Simon GM, Cravatt BF (2008) Anandamide biosynthesis catalyzed by the phosphodiesterase GDE1 and detection of glycerophospho-N-acyl ethanolamine precursors in mouse brain. J Biol Chem 283:9341–9349
Stella N, Schweitzer P, Piomelli D (1997) A second endogenous cannabinoid that modulates long-term potentiation. Nature 388:773–778
Straiker A, Mackie K (2007) Metabotropic suppression of excitation in murine autaptic hippocampal neurons. J Physiol 578:773–785
Sugiura T, Kishimoto S, Oka S et al. (2006) Biochemistry, pharmacology and physiology of 2-arachidonoylglycerol, an endogenous cannabinoid receptor ligand. Prog Lipid Res 45:405–446
Terry G, Liow JS, Chernet E et al. (2008) Positron emission tomography imaging using an inverse agonist radioligand to assess cannabinoid CB(1) receptors in rodents. NeuroImage 41:690–698
Tsou K, Brown S, Sanudo-Pena MC et al. (1998) Immunohistochemical distribution of cannabinoid CB1 receptors in the rat central nervous system. Neuroscience 83:393–411
Tsou K, Mackie K, Sanudo-Pena MC et al. (1999) Cannabinoid CB1 receptors are localized primarily on cholecystokinin-containing GABAergic interneurons in the rat hippocampal formation. Neuroscience 93:969–975
Uchigashima M, Narushima M, Fukaya M et al. (2007) Subcellular arrangement of molecules for 2-arachidonoyl-glycerol-mediated retrograde signaling and its physiological contribution to synaptic modulation in the striatum. J Neurosci 27:3663–3676
Van Sickle MD, Duncan M, Kingsley PJ et al. (2005) Identification and functional characterization of brainstem cannabinoid CB2 receptors. Science (New York, NY) 310:329–332
Vizi ES, Katona I, Freund TF (2001) Evidence for presynaptic cannabinoid CB(1) receptor-mediated inhibition of noradrenaline release in the guinea pig lung. Eur J Pharmacol 431:237–244
Westlake TM, Howlett AC, Bonner TI et al. (1994) Cannabinoid receptor binding and messenger RNA expression in human brain: an in vitro receptor autoradiography and in situ hybridization histochemistry study of normal aged and Alzheimer's brains. Neuroscience 63:637–652
Wilson RI, Nicoll RA (2001) Endogenous cannabinoids mediate retrograde signalling at hippocampal synapses. Nature 410:588–592
Wilson RI, Kunos G, Nicoll RA (2001) Presynaptic specificity of endocannabinoid signaling in the hippocampus. Neuron 31:453–462
Yasuno F, Brown AK, Zoghbi SS et al. (2008) The PET radioligand [11C]MePPEP binds reversibly and with high specific signal to cannabinoid CB1 receptors in nonhuman primate brain. Neuropsychopharmacology 33:259–269
Yoshida T, Fukaya M, Uchigashima M et al. (2006) Localization of diacylglycerol lipase-alpha around postsynaptic spine suggests close proximity between production site of an endocannabinoid, 2-arachidonoyl-glycerol, and presynaptic cannabinoid CB1 receptor. J Neurosci 26:4740–4751
Zimmer A, Zimmer AM, Hohmann AG et al. (1999) Increased mortality, hypoactivity, and hypoalgesia in cannabinoid CB1 receptor knockout mice. Proc Natl Acad Sci USA 96:5780–5785
Acknowledgements
This work was supported by ETT 561/2006 and by the János Bolyai scholarship. The author is very grateful to Drs. Tamás F. Freund, Norbert Hájos, Ken Mackie, Daniele Piomelli and Masahiko Watanabe for their long-term collaborative support of his work on the endocannabinoid system. The author is also indebted to Ms. Anikó Ludányi, Rita Nyilas, Gabriella Urbán and Mr. Barna Dudok for their help with the preparation of figures and to Drs. Miles Herkenham, Jarmo Laitinen and Masahiko Watanabe for their kind contribution of figures to this book chapter.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2009 Springer-Verlag Berlin Heidelberg
About this chapter
Cite this chapter
Katona, I. (2009). Endocannabinoid Receptors: CNS Localization of the CB1 Cannabinoid Receptor. In: Kendall, D., Alexander, S. (eds) Behavioral Neurobiology of the Endocannabinoid System. Current Topics in Behavioral Neurosciences, vol 1. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-540-88955-7_3
Download citation
DOI: https://doi.org/10.1007/978-3-540-88955-7_3
Published:
Publisher Name: Springer, Berlin, Heidelberg
Print ISBN: 978-3-540-88954-0
Online ISBN: 978-3-540-88955-7
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)