Endocannabinoids are endogenous lipid messengers that act on the same receptors that are activated by the active component of cannabis. The most well-understood are anandamide and 2-arachidonoylglycerol (2-AG), the synthetic pathways of which have been elucidated. Other putative ligands include noladin ether and virodhamine.
Endocannabinoids are synthesized in neurons, but it is unclear how they are released. In some cases, they might diffuse within the membrane to activate receptors on the cells in which they are generated, but there is evidence that they are also released to act on neighbouring cells.
Endocannabinoid signalling is attenuated by transport and hydrolysis. Transport of endocannabinoids into neurons is rapid and selective, although the transporter has not been identified and transport might be mediated by facilitated diffusion. Once inside cells, anandamide is broken down by fatty acid amide hydrolase, whereas 2-AG is hydrolysed by two less well-characterized enzymatic activities.
The cannabinoid receptor CB1 is the most abundant G-protein-coupled receptor in the brain, and mediates most of the behavioural actions of cannabinoid drugs. The signalling events initiated by this receptor include closure of Ca2+ channels, opening of K+ channels, inhibition of adenylyl cyclase activity and stimulation of protein kinases. These signalling pathways can modulate synaptic communication and neuronal gene expression.
Cannabinoids do have some effect on CB1-null mice, and it has been proposed that another brain cannabinoid receptor might exist. However, the evidence is contradictory.
An important function of cannabinoid receptors is the regulation of GABA (γ-aminobutyric acid) transmission. In the hippocampus, cannabinoids can modulate plasticity, and so might influence learning and memory. In the amygdala, CB1 inactivation causes anxiety-like and aggressive behaviour. In the basal ganglia, cannabinoids might modulate motor function. And in the hindbrain, cannabinoid agonists can influence the central processing of pain. All of these functions seem to involve depression of GABA release.
Endocannabinoids can also suppress the release of glutamate at excitatory synapses in the hippocampus, cerebellum and other brain areas, although the function of this suppression is unclear. Cannabinoid agonists also seem to influence the release of other neurotransmitters such as acetylcholine and amines.
Endocannabinoid-dependent long-term depression (LTD) in the striatum and nucleus accumbens might be involved in habit learning and addiction. Endocannabinoids seem also to be involved in inhibitory LTD in the hippocampus.
The endocannabinoids are a family of lipid messengers that engage the cell surface receptors that are targeted by Δ9-tetrahydrocannabinol, the active principle in marijuana (Cannabis). They are made on demand through cleavage of membrane precursors and are involved in various short-range signalling processes. In the brain, they combine with CB1 cannabinoid receptors on axon terminals to regulate ion channel activity and neurotransmitter release. Their ability to modulate synaptic efficacy has a wide range of functional consequences and provides unique therapeutic possibilities.
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Rouyer, M. Sur les medicaments usuels des Egyptiens. Bull. Pharmacie 2, 25 (1810).
O'Shaugnessy, W. B. On the Cannabis indica or Indian hemp. Pharmacol. J. Trans. 2, 594 (1843).
Moreau, J. J. Du Hachisch et de l'Aliénation Mentale (Fortin, Masson & Co., Paris, 1845).
Christison, R. in A Dispensatory, or Commentary on the Pharmacopoeias of Great Britain (and the United States) 971–974 (Lea and Blanchard, Philadelphia, 1848).
Adams, R. Marihuana. Harvey Lect. 37, 168 (1941).
Gaoni, Y. & Mechoulam, R. Isolation, structure and partial synthesis of an active constituent of hashish. J. Am. Chem. Soc. 86, 1646–1647 (1964).
Melvin, L. S. & Johnson, M. R. Structure–activity relationships of tricyclic and nonclassical bicyclic cannabinoids. NIDA Res. Monogr. 79, 31–47 (1987).
Devane, W. A., Dysarz, F. A., Johnson, M. R., Melvin, L. S. & Howlett, A. C. Determination and characterization of a cannabinoid receptor in rat brain. Mol. Pharmacol. 34, 605–613 (1988). This paper describes the original discovery of selective cannabinoid sites in the rat brain and outlines their pharmacological properties.
Matsuda, L. A., Lolait, S. J., Brownstein, M. J., Young, A. C. & Bonner, T. I. Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature 346, 561–564 (1990).
Munro, S., Thomas, K. L. & Abu-Shaar, M. Molecular characterization of a peripheral receptor for cannabinoids. Nature 365, 61–65 (1993). References 9 and 10 report on the molecular cloning and structural characterization of CB 1 and CB 2 , the two cannabinoid receptors identified in mammalian tissues.
Devane, W. A. et al. Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science 258, 1946–1949 (1992). This paper outlines the ground-breaking isolation of anandamide from pig brain and the ability of this lipid derivative to activate cannabinoid receptors.
Piomelli, D. & Greengard, P. Lipoxygenase metabolites of arachidonic acid in neuronal transmembrane signalling. Trends Pharmacol. Sci. 11, 367–373 (1990).
Kempe, K., Hsu, F. F., Bohrer, A. & Turk, J. Isotope dilution mass spectrometric measurements indicate that arachidonylethanolamide, the proposed endogenous ligand of the cannabinoid receptor, accumulates in rat brain tissue post mortem but is contained at low levels in or is absent from fresh tissue. J. Biol. Chem. 271, 17287–17295 (1996).
Di Marzo, V. et al. Formation and inactivation of endogenous cannabinoid anandamide in central neurons. Nature 372, 686–691 (1994).
Giuffrida, A. et al. Dopamine activation of endogenous cannabinoid signaling in dorsal striatum. Nature Neurosci. 2, 358–363 (1999).
Walker, J. M., Huang, S. M., Strangman, N. M., Tsou, K. & Sañudo-Peña, M. C. Pain modulation by release of the endogenous cannabinoid anandamide. Proc. Natl Acad. Sci. USA 96, 12198–12203 (1999). By showing that anandamide is produced in and released from brain neurons under physiological conditions, references 14–16 established the role of this compound as an endogenous ligand for cannabinoid receptors.
Sugiura, T. et al. 2-Arachidonoylglycerol: a possible endogenous cannabinoid receptor ligand in brain. Biochem. Biophys. Res. Commun. 215, 89–97 (1995).
Mechoulam, R. et al. Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors. Biochem. Pharmacol. 50, 83–90 (1995).
Hanus, L. et al. 2-Arachidonyl glyceryl ether, an endogenous agonist of the cannabinoid CB1 receptor. Proc. Natl Acad. Sci. USA 98, 3662–3665 (2001).
Porter, A. C. et al. Characterization of a novel endocannabinoid, virodhamine, with antagonist activity at the CB1 receptor. J. Pharmacol. Exp. Ther. 301, 1020–1024 (2002).
Huang, S. M. et al. An endogenous capsaicin-like substance with high potency at recombinant and native vanilloid VR1 receptors. Proc. Natl Acad. Sci. USA 99, 8400–8405 (2002).
Chapman, K. D. Emerging physiological roles for N-acylphosphatidylethanolamine metabolism in plants: signal transduction and membrane protection. Chem. Phys. Lipids 108, 221–229 (2000).
Sugiura, T. et al. Transacylase-mediated and phosphodiesterase-mediated synthesis of N-arachidonoylethanolamine, an endogenous cannabinoid-receptor ligand, in rat brain microsomes. Comparison with synthesis from free arachidonic acid and ethanolamine. Eur. J. Biochem. 240, 53–62 (1996).
Cadas, H., di Tomaso, E. & Piomelli, D. Occurrence and biosynthesis of endogenous cannabinoid precursor, N-arachidonoyl phosphatidylethanolamine, in rat brain. J. Neurosci. 17, 1226–1242 (1997).
Kodaki, T. & Yamashita, S. Cloning, expression, and characterization of a novel phospholipase D complementary DNA from rat brain. J. Biol. Chem. 272, 11408–11413 (1997).
Cadas, H., Gaillet, S., Beltramo, M., Venance, L. & Piomelli, D. Biosynthesis of an endogenous cannabinoid precursor in neurons and its control by calcium and cAMP. J. Neurosci. 16, 3934–3942 (1996).
Ferrer, B., Asbrock, N., Kathuria, S., Piomelli, D. & Giuffrida, A. Effects of levodopa on endocannabinoid levels in rat basal ganglia: implications for the treatment of levodopa-induced dyskinesias. Eur. J. Neurosci. 18, 1607–1614 (2003).
Varma, N., Carlson, G. C., Ledent, C. & Alger, B. E. Metabotropic glutamate receptors drive the endocannabinoid system in hippocampus. J. Neurosci. 21, RC188 (2001).
Kim, J., Isokawa, M., Ledent, C. & Alger, B. E. Activation of muscarinic acetylcholine receptors enhances the release of endogenous cannabinoids in the hippocampus. J. Neurosci. 22, 10182–10191 (2002).
Senogles, S. E. The D2s dopamine receptor stimulates phospholipase D activity: a novel signaling pathway for dopamine. Mol. Pharmacol. 58, 455–462 (2000).
Hernández-López, S. et al. D2 dopamine receptors in striatal medium spiny neurons reduce L-type Ca2+ currents and excitability via a novel PLCβ1-IP3-calcineurin-signaling cascade. J. Neurosci. 20, 8987–8995 (2000).
Stella, N., Schweitzer, P. & Piomelli, D. A second endogenous cannabinoid that modulates long-term potentiation. Nature 388, 773–778 (1997).
Kanoh, H., Yamada, K. & Sakane, F. Diacylglycerol kinases: emerging downstream regulators in cell signaling systems. J. Biochem. 131, 629–633 (2002).
Farooqui, A. A., Rammohan, K. W. & Horrocks, L. A. Isolation, characterization, and regulation of diacylglycerol lipases from the bovine brain. Ann. NY Acad. Sci. 559, 25–36 (1989).
Higgs, H. N. & Glomset, J. A. Identification of a phosphatidic acid-preferring phospholipase A1 from bovine brain and testis. Proc. Natl Acad. Sci. USA 91, 9574–9578 (1994).
Pete, M. J., Ross, A. H. & Exton, J. H. Purification and properties of phospholipase A1 from bovine brain. J. Biol. Chem. 269, 19494–19500 (1994).
Stella, N. & Piomelli, D. Receptor-dependent formation of endogenous cannabinoids in cortical neurons. Eur. J. Pharmacol. 425, 189–196 (2001).
Oka, S. et al. Ether-linked analogue of 2-arachidonoylglycerol (noladin ether) was not detected in the brains of various mammalian species. J. Neurochem. 85, 1374–1381 (2003).
Song, Z. H. & Bonner, T. I. A lysine residue of the cannabinoid receptor is critical for receptor recognition by several agonists but not WIN55212-2. Mol. Pharmacol. 49, 891–896 (1996).
Xie, X. Q., Melvin, L. S. & Makriyannis, A. The conformational properties of the highly selective cannabinoid receptor ligand CP-55,940. J. Biol. Chem. 271, 10640–10647 (1996).
Wilson, R. I. & Nicoll, R. A. Endogenous cannabinoids mediate retrograde signalling at hippocampal synapses. Nature 410, 588–592 (2001).
Kreitzer, A. C. & Regehr, W. G. Retrograde inhibition of presynaptic calcium influx by endogenous cannabinoids at excitatory synapses onto Purkinje cells. Neuron 29, 717–727 (2001).
Ohno-Shosaku, T., Maejima, T. & Kano, M. Endogenous cannabinoids mediate retrograde signals from depolarized postsynaptic neurons to presynaptic terminals. Neuron 29, 729–738 (2001). References 41–43 provided the first unequivocal demonstration that endocannabinoids regulate synaptic transmission in the brain.
Gerdeman, G. L., Ronesi, J. & Lovinger, D. M. Postsynaptic endocannabinoid release is critical to long-term depression in the striatum. Nature Neurosci. 5, 446–451 (2002).
Robbe, D., Kopf, M., Remaury, A., Bockaert, J. & Manzoni, O. J. Endogenous cannabinoids mediate long-term synaptic depression in the nucleus accumbens. Proc. Natl Acad. Sci. USA 99, 8384–8388 (2002).
Chevaleyre, V. & Castillo, P. E. Heterosynaptic LTD of hippocampal GABAergic synapses. A novel role of endocannabinoids in regulating excitability. Neuron 38, 461–472 (2003).
Beuckmann, C. T. et al. Cellular localization of lipocalin-type prostaglandin D synthase (β-trace) in the central nervous system of the adult rat. J. Comp. Neurol. 428, 62–78 (2000).
Bojensen, I. N. & Hansen, H. S. Binding of anandamide to bovine serum albumin. J. Lipid Res. 44, 1790–1794 (2003).
Beltramo, M. et al. Functional role of high-affinity anandamide transport, as revealed by selective inhibition. Science 277, 1094–1097 (1997). Together with reference 50, this paper identifies facilitated transport as the first step in anandamide deactivation and introduces the first anandamide transport inhibitor, AM404.
Hillard, C. J., Edgemond, W. S., Jarrahian, A. & Campbell, W. B. Accumulation of N-arachidonoylethanolamine (anandamide) into cerebellar granule cells occurs via facilitated diffusion. J. Neurochem. 69, 631–638 (1997).
Abumrad, N., Coburn, C. & Ibrahimi, A. Membrane proteins implicated in long-chain fatty acid uptake by mammalian cells: CD36, FATP and FABPm. Biochim. Biophys. Acta 1441, 4–13 (1999).
Piomelli, D. et al. Structural determinants for recognition and translocation by the anandamide transporter. Proc. Natl Acad. Sci. USA 96, 5802–5807 (1999).
Beltramo, M. et al. Reversal of dopamine D2 receptor responses by an anandamide transport inhibitor. J. Neurosci. 20, 3401–3407 (2000).
Lopez-Rodriguez, M. L. et al. Design, synthesis and biological evaluation of novel arachidonic acid derivatives as highly potent and selective endocannabinoid transporter inhibitors. J. Med. Chem. 44, 4505–4508 (2001).
De Petrocellis, L., Bisogno, T., Davis, J. B., Pertwee, R. G. & Di Marzo, V. Overlap between the ligand recognition properties of the anandamide transporter and the VR1 vanilloid receptor: inhibitors of anandamide uptake with negligible capsaicin-like activity. FEBS Lett. 483, 52–56 (2000).
Schmid, P. C., Zuzarte-Augustin, M. L. & Schmid, H. H. Properties of rat liver N-acylethanolamine amidohydrolase. J. Biol. Chem. 260, 14145–14149 (1985). Published long before the discovery of anandamide, this paper describes a membrane-associated enzyme activity that breaks down fatty acid ethanolamides. This enzyme, which also catalyses the hydrolysis of anandamide, is now called fatty acid amide hydrolase.
Hillard, C. J., Wilkison, D. M., Edgemond, W. S. & Campbell, W. B. Characterization of the kinetics and distribution of N-arachidonylethanolamine (anandamide) hydrolysis by rat brain. Biochim. Biophys. Acta 1257, 249–256 (1995).
Ueda, N., Kurahashi, Y., Yamamoto, S. & Tokunaga, T. Partial purification and characterization of the porcine brain enzyme hydrolyzing and synthesizing anandamide. J. Biol. Chem. 270, 23823–23827 (1995).
Cravatt, B. F. et al. Molecular characterization of an enzyme that degrades neuromodulatory fatty-acid amides. Nature 384, 83–87 (1996). The first of an elegant series of papers (including references 60 and 64) that unveils the molecular properties of fatty acid amide hydrolase.
Bracey, M. H., Hanson, M. A., Masuda, K. R., Stevens, R. C. & Cravatt, B. F. Structural adaptations in a membrane enzyme that terminates endocannabinoid signaling. Science 298, 1793–1796 (2002).
Fu, J. et al. Oleylethanolamide regulates feeding and body weight through activation of the nuclear receptor PPAR-α. Nature 425, 90–93 (2003).
Mazzari, S., Canella, R., Petrelli, L., Marcolongo, G. & Leon, A. N-(2-hydroxyethyl)hexadecanamide is orally active in reducing edema formation and inflammatory hyperalgesia by down-modulating mast cell activation. Eur. J. Pharmacol. 300, 227–236 (1996).
Calignano, A., La Rana, G., Giuffrida, A. & Piomelli, D. Control of pain initiation by endogenous cannabinoids. Nature 394, 277–281 (1998).
Cravatt, B. F. et al. Supersensitivity to anandamide and enhanced endogenous cannabinoid signaling in mice lacking fatty acid amide hydrolase. Proc. Natl Acad. Sci. USA 98, 9371–9376 (2001).
Kathuria, S. et al. Modulation of anxiety through blockade of anandamide hydrolysis. Nature Med. 9, 76–81 (2003). Selective and systemically active inhibitors of fatty acid amide hydrolase activity reveal a crucial role for anandamide in the regulation of emotion.
Tsou, K. et al. Fatty acid amide hydrolase is located preferentially in large neurons in the rat central nervous system as revealed by immunohistochemistry. Neurosci. Lett. 254, 137–140 (1998).
Egertová, M., Cravatt, B. F. & Elphick, M. R. Comparative analysis of fatty acid amide hydrolase and CB1 cannabinoid receptor expression in the mouse brain: evidence of a widespread role for fatty acid amide hydrolase in regulation of endocannabinoid signaling. Neuroscience 119, 481–496 (2003).
Goparaju, S. K., Ueda, N., Taniguchi, K. & Yamamoto, S. Enzymes of porcine brain hydrolyzing 2-arachidonoylglycerol, an endogenous ligand of cannabinoid receptors. Biochem. Pharmacol. 57, 417–423 (1999).
Dinh, T. P. et al. Brain monoglyceride lipase participating in endocannabinoid inactivation. Proc. Natl Acad. Sci. USA 99, 10819–10824 (2002).
Herkenham, M. et al. Cannabinoid receptor localization in brain. Proc. Natl Acad. Sci. USA 87, 1932–1936 (1990).
Adams, I. B. & Martin, B. R. Cannabis: pharmacology and toxicology in animals and humans. Addiction 91, 1585–1614 (1996). A comprehensive review of the pharmacology of Cannabis derivatives.
Ledent, C. et al. Unresponsiveness to cannabinoids and reduced addictive effects of opiates in CB1 receptor knockout mice. Science 283, 401–404 (1999).
Zimmer, A., Zimmer, A. M., Hohmann, A. G., Herkenham, M. & Bonner, T. I. Increased mortality, hypoactivity, and hypoalgesia in cannabinoid CB1 receptor knockout mice. Proc. Natl Acad. Sci. USA 96, 5780–5785 (1999).
Mackie, K. & Hille, B. Cannabinoids inhibit N-type calcium channels in neuroblastoma-glioma cells. Proc. Natl Acad. Sci. USA 89, 3825–3829 (1992).
Caulfield, M. P. & Brown, D. A. Cannabinoid receptor agonists inhibit Ca current in NG108-15 neuroblastoma cells via a pertussis toxin-sensitive mechanism. Br. J. Pharmacol. 106, 231–232 (1992).
Twitchell, W., Brown, S. & Mackie, K. Cannabinoids inhibit N- and P/Q-type calcium channels in cultured rat hippocampal neurons. J. Neurophysiol. 78, 43–50 (1997).
Wilson, R. I. & Nicoll, R. A. Endocannabinoid signaling in the brain. Science 296, 678–682 (2002).
Hoffman, A. F. & Lupica, C. R. Mechanisms of cannabinoid inhibition of GABAA synaptic transmission in the hippocampus. J. Neurosci. 20, 2470–2479 (2000).
Gerdeman, G. & Lovinger, D. M. CB1 cannabinoid receptor inhibits synaptic release of glutamate in rat dorsolateral striatum. J. Neurophysiol. 85, 468–471 (2001).
Huang, C. C., Lo, S. W. & Hsu, K. S. Presynaptic mechanisms underlying cannabinoid inhibition of excitatory synaptic transmission in rat striatal neurons. J. Physiol. 532, 731–748 (2001).
Wilson, R. I., Kunos, G. & Nicoll, R. A. Presynaptic specificity of endocannabinoid signaling in the hippocampus. Neuron 31, 1–20 (2001).
Mu, J., Zhuang, S. Y., Kirby, M. T., Hampson, R. E. & Deadwyler, S. A. Cannabinoid receptors differentially modulate potassium A and D currents in hippocampal neurons in culture. J. Pharmacol. Exp. Ther. 291, 893–902 (1999).
Kreitzer, A. C., Carter, A. G. & Regehr, W. G. Inhibition of interneuron firing extends the spread of endocannabinoid signaling in the cerebellum. Neuron 34, 787–796 (2002).
Daniel, H. & Crepel, F. Control of Ca2+ influx by cannabinoid and metabotropic glutamate receptors in rat cerebellar cortex requires K+ channels. J. Physiol. 537, 793–800 (2001).
Robbe, D., Alonso, G., Duchamp, F., Bockaert, J. & Manzoni, O. J. Localization and mechanisms of action of cannabinoid receptors at the glutamatergic synapses of the mouse nucleus accumbens. J. Neurosci. 21, 109–116 (2001).
Azad, S. C. et al. Activation of the cannabinoid receptor type 1 decreases glutamatergic and GABAergic synaptic transmission in the lateral amygdala of the mouse. Learn. Mem. 10, 116–128 (2003).
Adams, J. P. & Sweatt, J. D. Molecular psychology: roles for the ERK MAP kinase cascade in memory. Annu. Rev. Pharmacol. Toxicol. 42, 135–163 (2002).
Derkinderen, P. et al. Regulation of a neuronal form of focal adhesion kinase by anandamide. Science 273, 1719–1722 (1996).
Derkinderen, P. et al. Regulation of extracellular signal-regulated kinase by cannabinoids in hippocampus. J. Neurosci. 23, 2371–2382 (2003).
Hoffman, A. F., Oz, M., Caulder, T. & Lupica, C. R. Functional tolerance and blockade of long-term depression at synapses in the nucleus accumbens after chronic cannabinoid exposure. J. Neurosci. 23, 4815–4820 (2003).
Katona, I. et al. Presynaptically located CB1 cannabinoid receptors regulate GABA release from axon terminals of specific hippocampal interneurons. J. Neurosci. 19, 4544–4558 (1999).
Marsicano, G. & Lutz, B. Expression of the cannabinoid receptor CB1 in distinct neuronal subpopulations in the adult mouse forebrain. Eur. J. Neurosci. 11, 4213–4225 (1999).
Tsou, K., Brown, S., Sañudo-Peña, M. C., Mackie, K. & Walker, J. M. Immunohistochemical distribution of cannabinoid CB1 receptors in the rat central nervous system. Neuroscience 83, 393–411 (1998).
Katona, I. et al. Distribution of CB1 cannabinoid receptors in the amygdala and their role in the control of GABAergic transmission. J. Neurosci. 21, 9506–9518 (2001).
McDonald, A. J. & Mascagni, F. 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 (2001).
Hohmann, A. G. & Herkenham, M. Localization of cannabinoid CB1 receptor mRNA in neuronal subpopulations of rat striatum: a double-label in situ hybridization study. Synapse 37, 71–80 (2000).
Herkenham, M., Lynn, A. B., de Costa, B. R. & Richfield, E. K. Neuronal localization of cannabinoid receptors in the basal ganglia of the rat. Brain Res. 547, 267–274 (1991).
Hohmann, A. G. & Herkenham, M. Cannabinoid receptors undergo axonal flow in sensory nerves. Neuroscience 92, 1171–1175 (1999).
Price, T. J., Helesic, G., Parghi, D., Hargreaves, K. M. & Flores, C. M. The neuronal distribution of cannabinoid receptor type 1 in the trigeminal ganglion of the rat. Neuroscience 120, 155–162 (2003).
Breivogel, C. S., Griffin, G., Di Marzo, V. & Martin, B. R. Evidence for a new G protein-coupled cannabinoid receptor in mouse brain. Mol. Pharmacol. 60, 155–163 (2001).
Hájos, N., Ledent, C. & Freund, T. F. Novel cannabinoid-sensitive receptor mediates inhibition of glutamatergic synaptic transmission in the hippocampus. Neuroscience 106, 1–4 (2001). Together with reference 100, this study provided the first indication that an additional brain cannabinoid receptor remains to be cloned.
Rouach, N. & Nicoll, R. A. Endocannabinoids contribute to short-term but not long-term mGluR-induced depression in the hippocampus. Eur. J. Neurosci. 18, 1017–1020 (2003).
Hájos, N. & Freund, T. F. Pharmacological separation of cannabinoid sensitive receptors on hippocampal excitatory and inhibitory fibers. Neuropharmacology 43, 503–510 (2002).
Ohno-Shosaku, T. et al. Presynaptic cannabinoid sensitivity is a major determinant of depolarization-induced retrograde suppression at hippocampal synapses. J. Neurosci. 22, 3864–3872 (2002).
Jarai, Z. et al. Cannabinoid-induced mesenteric vasodilation through an endothelial site distinct from CB1 or CB2 receptors. Proc. Natl Acad. Sci. USA 96, 14136–14141 (1999).
Wagner, J. A., Varga, K., Jarai, Z. & Kunos, G. Mesenteric vasodilation mediated by endothelial anandamide receptors. Hypertension 33, 429–434 (1999).
Bátkai, S. et al. Endocannabinoids acting at vascular CB1 receptors mediate the vasodilated state in advanced liver cirrhosis. Nature Med. 7, 827–832 (2001).
Alger, B. E. Retrograde signaling in the regulation of synaptic transmission: focus on endocannabinoids. Prog. Neurobiol. 68, 247–286 (2002).
Yoshida, T. et al. The cannabinoid CB1 receptor mediates retrograde signals for depolarization-induced suppression of inhibition in cerebellar Purkinje cells. J. Neurosci. 22, 1690–1697 (2002).
Hampson, R. E., Zhuang, S. Y., Weiner, J. L. & Deadwyler, S. A. Functional significance of cannabinoid-mediated, depolarization-induced suppression of inhibition (DSI) in the hippocampus. J. Neurophysiol. 90, 55–64 (2003).
Hájos, N. et al. Cannabinoids inhibit hippocampal GABAergic transmission and network oscillations. Eur. J. Neurosci. 12, 3239–3249 (2000).
Harris, K. D., Csicsvari, J., Hirase, H., Dragoi, G. & Buzsaki, G. Organization of cell assemblies in the hippocampus. Nature 424, 552–556 (2003).
Carlson, G., Wang, Y. & Alger, B. E. Endocannabinoids facilitate the induction of LTP in the hippocampus. Nature Neurosci. 5, 723–724 (2002). This paper reports that endocannabinoids can facilitate hippocampal long-term potentiation (LTP) at the single-cell level, although pharmacological administration of cannabinoid agonists inhibits LTP and impairs memory (reviewed in reference 114).
Hampson, R. E. & Deadwyler, S. A. Cannabinoids, hippocampal function and memory. Life Sci. 65, 715–723 (1999).
Llano, I., Leresche, N. & Marty, A. Calcium entry increases the sensitivity of cerebellar Purkinje cells to applied GABA and decreases inhibitory synaptic currents. Neuron 6, 565–574 (1991).
Kreitzer, A. C. & Regehr, W. G. Cerebellar depolarization-induced suppression of inhibition is mediated by endogenous cannabinoids. J. Neurosci. 21, RC174 (2001).
Trettel, J. & Levine, E. S. Endocannabinoids mediate rapid retrograde signaling at interneuron right-arrow pyramidal neuron synapses of the neocortex. J. Neurophysiol. 89, 2334–2338 (2003).
Martin, W. J. et al. Anatomical basis for cannabinoid-induced antinociception as revealed by intracerebral microinjections. Brain Res. 822, 237–242 (1999).
Navarro, M. et al. Acute administration of the CB1 cannabinoid receptor antagonist SR 141716A induces anxiety-like responses in the rat. Neuroreport 8, 491–496 (1997).
Martin, M., Ledent, C., Parmentier, M., Maldonado, R. & Valverde, O. Involvement of CB1 cannabinoid receptors in emotional behaviour. Psychopharmacology (Berl.) 159, 379–387 (2002).
Marsicano, G. et al. The endogenous cannabinoid system controls extinction of aversive memories. Nature 418, 530–534 (2002).
Romero, J. et al. The endogenous cannabinoid system and the basal ganglia: biochemical, pharmacological, and therapeutic aspects. Pharmacol. Ther. 95, 137–152 (2002).
Gorriti, M. A., Rodríguez de Fonseca, F., Navarro, M. & Palomo, T. Chronic (–)-Δ9-tetrahydrocannabinol treatment induces sensitization to the psychomotor effects of amphetamine in rats. Eur. J. Pharmacol. 365, 133–142 (1999).
Koos, T. & Tepper, J. M. Inhibitory control of neostriatal projection neurons by GABAergic interneurons. Nature Neurosci. 2, 467–472 (1999).
Sieradzan, K. A. et al. Cannabinoids reduce levodopa-induced dyskinesia in Parkinson's disease: a pilot study. Neurology 57, 2108–2111 (2001).
Muller-Vahl, K. R. et al. Δ9-Tetrahydrocannabinol (THC) is effective in the treatment of tics in Tourette syndrome: a 6-week randomized trial. J. Clin. Psychiatry 64, 459–465 (2003).
Lichtman, A. H., Cook, S. A. & Martin, B. R. Investigation of brain sites mediating cannabinoid-induced antinociception in rats: evidence supporting periaqueductal gray involvement. J. Pharmacol. Exp. Ther. 276, 585–593 (1996).
Meng, I. D., Manning, B. H., Martin, W. J. & Fields, H. L. An analgesia circuit activated by cannabinoids. Nature 395, 381–383 (1998).
Jennings, E. A., Vaughan, C. W. & Christie, M. J. Cannabinoid actions on rat superficial medullary dorsal horn neurons in vitro. J. Physiol. 534, 805–812 (2001).
Vaughan, C. W., Connor, M., Bagley, E. E. & Christie, M. J. Actions of cannabinoids on membrane properties and synaptic transmission in rat periaqueductal gray neurons in vitro. Mol. Pharmacol. 57, 288–295 (2000).
Richardson, J. D., Aanonsen, L. & Hargreaves, K. M. SR 141716A, a cannabinoid receptor antagonist, produces hyperalgesia in untreated mice. Eur. J. Pharmacol. 319, R3–R4 (1997).
Strangman, N. M., Patrick, S. L., Hohmann, A. G., Tsou, K. & Walker, J. M. Evidence for a role of endogenous cannabinoids in the modulation of acute and tonic pain sensitivity. Brain Res. 813, 323–328 (1998).
Iversen, L. & Chapman, V. Cannabinoids: a real prospect for pain relief. Curr. Opin. Pharmacol. 2, 50–55 (2002). A recent review of the therapeutic potential of cannabinoid drugs as analgesic agents.
Auclair, N., Otani, S., Soubrie, P. & Crepel, F. Cannabinoids modulate synaptic strength and plasticity at glutamatergic synapses of rat prefrontal cortex pyramidal neurons. J. Neurophysiol. 83, 3287–3293 (2000).
Szabo, B., Wallmichrath, I., Mathonia, P. & Pfreundtner, C. Cannabinoids inhibit excitatory neurotransmission in the substantia nigra pars reticulata. Neuroscience 97, 89–97 (2000).
Schlicker, E. & Kathmann, M. Modulation of transmitter release via presynaptic cannabinoid receptors. Trends Pharmacol. Sci. 22, 565–572 (2001). An exhaustive review of the effects of cannabinoids on the release of brain neurotransmitters.
Gifford, A. N. & Ashby, C. R. Jr. Electrically evoked acetylcholine release from hippocampal slices is inhibited by the cannabinoid receptor agonist, WIN 55212-2, and is potentiated by the cannabinoid antagonist, SR 141716A. J. Pharmacol. Exp. Ther. 277, 1431–1436 (1996).
Gessa, G. L., Casu, M. A., Carta, G. & Mascia, M. S. Cannabinoids decrease acetylcholine release in the medial-prefrontal cortex and hippocampus, reversal by SR 141716A. Eur. J. Pharmacol. 355, 119–124 (1998).
Beinfeld, M. C. & Connolly, K. Activation of CB1 cannabinoid receptors in rat hippocampal slices inhibits potassium-evoked cholecystokinin release, a possible mechanism contributing to the spatial memory defects produced by cannabinoids. Neurosci. Lett. 301, 69–71 (2001).
Calabresi, P., Maj, R., Pisani, A., Mercuri, N. B. & Bernardi, G. Long-term synaptic depression in the striatum: physiological and pharmacological characterization. J. Neurosci. 12, 4224–4233 (1992).
Choi, S. & Lovinger, D. M. Decreased probability of neurotransmitter release underlies striatal long-term depression and postnatal development of corticostriatal synapses. Proc. Natl Acad. Sci. USA 94, 2665–2670 (1997).
Gerdeman, G. L., Partridge, J. G., Lupica, C. R. & Lovinger, D. M. It could be habit forming: drugs of abuse and striatal synaptic plasticity. Trends Neurosci. 26, 184–192 (2003).
De Vries, T. J. et al. A cannabinoid mechanism in relapse to cocaine seeking. Nature Med. 7, 1151–1154 (2001). This article showed that the cannabinoid antagonist rimonabant prevents relapse to cocaine abuse in animals, revealing a key role for the endocannabinoid system in the regulation of reward.
Fattore, L., Spano, M. S., Cossu, G., Deiana, S. & Fratta, W. Cannabinoid mechanism in reinstatement of heroin-seeking after a long period of abstinence in rats. Eur. J. Neurosci. 17, 1723–1726 (2003).
Hillard, C. J. et al. Synthesis and characterization of potent and selective agonists of the neuronal cannabinoid receptor (CB1). J. Pharmacol. Exp. Ther. 289, 1427–1433 (1999).
Ibrahim, M. M. et al. Activation of CB2 cannabinoid receptors by AM1241 inhibits experimental neuropathic pain: pain inhibition by receptors not present in the CNS. Proc. Natl Acad. Sci. USA 100, 10529–10533 (2003).
Boger, D. L. et al. Exceptionally potent inhibitors of fatty acid amide hydrolase: the enzyme responsible for degradation of endogenous oleamide and anandamide. Proc. Natl Acad. Sci. USA 97, 5044–5049 (2000).
Masson, J., Sagne, C., Hamon, M. & Mestikawy, S. E. Neurotransmitter transporters in the central nervous system. Pharmacol. Rev. 51, 439–464 (1999).
Glaser, S. T. et al. Evidence against the presence of an anandamide transporter. Proc. Natl Acad. Sci. USA 100, 4269–4274 (2003).
Berry, E. M. & Mechoulam, R. Tetrahydrocannabinol and endocannabinoids in feeding and appetite. Pharmacol. Ther. 95, 185–190 (2002).
Di Marzo, V. et al. Leptin-regulated endocannabinoids are involved in maintaining food intake. Nature 410, 822–825 (2001).
Gomez, R. et al. A peripheral mechanism for CB1 cannabinoid receptor-dependent modulation of feeding. J. Neurosci. 22, 9612–9617 (2002).
Koob, G. F. & Le Moal, M. Drug addiction, dysregulation of reward, and allostasis. Neuropsychopharmacology 24, 97–129 (2001).
Work in the author's laboratory was supported by the National Institute on Drug Abuse, and by the National Alliance for Research on Schizophrenia and Depression.
- ARACHIDONIC ACID
Common name of 5,8,11,14-eicosatetraenoic acid, an essential (diet-derived) fatty acid that serves as precursor for eicosanoids and endocannabinoids.
A family of biologically active compounds produced through the enzymatic oxygenation of arachidonic acid. Examples are prostaglandins, leukotrienes and lipoxins.
- FATTY ACID
An organic acid characterized by a non-branched carbon chain and an even number of carbon atoms. Examples of saturated fatty acids (without double bonds) are palmitic (16 carbons) and stearic (18 carbons). Examples of unsaturated and polyunsaturated fatty acids include oleic (18 carbons, one double bond) and arachidonic (20 carbons, 4 double bonds).
An important class of membrane phospholipids comprising a glycerol skeleton linked to two fatty acid residues, phosphoric acid and ethanolamine.
(PL). A group of enzymes that catalyse the hydrolysis of phospholipids at their glycerol ester (PLA) or phosphodiester (PLC, PLD) bonds.
- FATTY ACID ETHANOLAMIDE
A lipid-derived signalling molecule characterized by an ethanolamine residue linked to a long-chain fatty acid through an amide bond. Examples are anandamide (arachidonoylethanolamide), oleoylethanolamide and palmitoylethanolamide.
- SN: STEREOSPECIFIC NUMBERING
Defines a convention on how to designate the stereochemistry of glycerol-based lipids. When the glycerol moiety is drawn with the secondary hydroxyl to the left, the carbons are numbered 1,2,3 from top to bottom.
A major class of membrane phospholipids comprised of a glycerol skeleton linked to two fatty acid residues, phosphoric acid and choline. In the mammalian brain, the sn-2 position of phosphatidylcholine most often contains an arachidonic acid residue, but a small pool of this fatty acid is also stored in the sn-1 position.
A technique that allows the sampling of neurochemicals in the brain of live animals.
A glycerol derivative in which one of the hydroxyl groups is linked to a fatty acid residue by an ester bond.
A phospholipid containing only one fatty acid chain. Examples include lysophosphatidic acid and lysophosphatidylethanolamine.
- SCHAFFER COLLATERALS
Axons of the CA3 pyramidal cells of the hippocampus that form synapses with the apical dendrites of CA1 neurons.
- FACILITATED DIFFUSION
A common mechanism of transmembrane transfer that involves a protein carrier, but does not require expenditure of cellular energy.
- VANILLOID RECEPTORS
Membrane receptor-channels permeable to monovalent cations. They are activated by noxious heat and capsaicin, the active constituent of hot chili peppers.
- RETROGRADE SIGNALLING
The backward movement of signalling molecules from postsynaptic to presynaptic structures, which underlies a variety of short- and long-term changes in synaptic efficacy.
- PARALLEL FIBRES
Axons of cerebellar granule cells. Parallel fibres emerge from the molecular layer of the cerebellar cortex towards the periphery, where they extend branches perpendicular to the main axis of the Purkinje neurons and form en passant synapses with this cell type.
- PERTUSSIS TOXIN
The causative agent of whooping cough, pertussis toxin causes the persistent activation of Gi proteins by catalysing the ADP-ribosylation of the α-subunit.
A synthetic drug that acts as a competitive antagonist of capsaicin at vanilloid receptors.
A bioactive substance formed in the body by the action of primary messengers (hormones, neurotransmitters) on their receptors, which produces its effects by acting on cells near its sites of synthesis.
- GAMMA OSCILLATIONS
Fast (20–80 Hz) synchronous oscillations of brain activity, which are thought to contribute to cognition and movement.
- LEVODOPA-INDUCED DYSKINESIAS
Unwanted movements that appear after prolonged use of the anti-Parkinsonian drug levodopa, β-(3,4-dihydroxyphenyl)-L-alanine.
- TOURETTE'S SYNDROME
A psychiatric disorder of unknown aetiology, characterized by the presence of compulsive vocal and motor tics.
A state of enhanced sensitivity to painful stimuli.
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