The molecular logic of endocannabinoid signalling

Key Points

  • 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.

Abstract

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.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Chemical structures of plant-derived and synthetic compounds that bind to cannabinoid receptors.
Figure 2
Figure 3: Mechanism of anandamide formation in neurons.
Figure 4: Pathways of 2-arachidonoylglycerol (2-AG) formation in neurons.
Figure 5: Mechanisms of endocannabinoid deactivation in neurons.
Figure 6: Chemical structures of endocannabinoid deactivation inhibitors.
Figure 7: Regulation of presynaptic ion channel activities by CB1 cannabinoid receptors.
Figure 8: Endocannabinoid-mediated synaptic signalling.
Figure 9: Roles of the endocannabinoids in long-term synaptic plasticity.

References

  1. 1

    Rouyer, M. Sur les medicaments usuels des Egyptiens. Bull. Pharmacie 2, 25 (1810).

    Google Scholar 

  2. 2

    O'Shaugnessy, W. B. On the Cannabis indica or Indian hemp. Pharmacol. J. Trans. 2, 594 (1843).

    Google Scholar 

  3. 3

    Moreau, J. J. Du Hachisch et de l'Aliénation Mentale (Fortin, Masson & Co., Paris, 1845).

    Google Scholar 

  4. 4

    Christison, R. in A Dispensatory, or Commentary on the Pharmacopoeias of Great Britain (and the United States) 971–974 (Lea and Blanchard, Philadelphia, 1848).

    Google Scholar 

  5. 5

    Adams, R. Marihuana. Harvey Lect. 37, 168 (1941).

    Google Scholar 

  6. 6

    Gaoni, Y. & Mechoulam, R. Isolation, structure and partial synthesis of an active constituent of hashish. J. Am. Chem. Soc. 86, 1646–1647 (1964).

    Article  CAS  Google Scholar 

  7. 7

    Melvin, L. S. & Johnson, M. R. Structure–activity relationships of tricyclic and nonclassical bicyclic cannabinoids. NIDA Res. Monogr. 79, 31–47 (1987).

    CAS  PubMed  Google Scholar 

  8. 8

    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.

    CAS  PubMed  Google Scholar 

  9. 9

    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).

    Article  CAS  Google Scholar 

  10. 10

    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.

    Article  CAS  Google Scholar 

  11. 11

    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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. 12

    Piomelli, D. & Greengard, P. Lipoxygenase metabolites of arachidonic acid in neuronal transmembrane signalling. Trends Pharmacol. Sci. 11, 367–373 (1990).

    Article  CAS  PubMed  Google Scholar 

  13. 13

    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).

    Article  CAS  PubMed  Google Scholar 

  14. 14

    Di Marzo, V. et al. Formation and inactivation of endogenous cannabinoid anandamide in central neurons. Nature 372, 686–691 (1994).

    Article  CAS  PubMed  Google Scholar 

  15. 15

    Giuffrida, A. et al. Dopamine activation of endogenous cannabinoid signaling in dorsal striatum. Nature Neurosci. 2, 358–363 (1999).

    Article  CAS  PubMed  Google Scholar 

  16. 16

    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.

    Article  CAS  PubMed  Google Scholar 

  17. 17

    Sugiura, T. et al. 2-Arachidonoylglycerol: a possible endogenous cannabinoid receptor ligand in brain. Biochem. Biophys. Res. Commun. 215, 89–97 (1995).

    Article  CAS  PubMed  Google Scholar 

  18. 18

    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).

    Article  CAS  PubMed  Google Scholar 

  19. 19

    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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. 20

    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).

    Article  CAS  PubMed  Google Scholar 

  21. 21

    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).

    Article  CAS  PubMed  Google Scholar 

  22. 22

    Chapman, K. D. Emerging physiological roles for N-acylphosphatidylethanolamine metabolism in plants: signal transduction and membrane protection. Chem. Phys. Lipids 108, 221–229 (2000).

    Article  CAS  PubMed  Google Scholar 

  23. 23

    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).

    Article  CAS  PubMed  Google Scholar 

  24. 24

    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).

    Article  CAS  PubMed  Google Scholar 

  25. 25

    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).

    Article  CAS  PubMed  Google Scholar 

  26. 26

    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).

    Article  CAS  PubMed  Google Scholar 

  27. 27

    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).

    Article  PubMed  Google Scholar 

  28. 28

    Varma, N., Carlson, G. C., Ledent, C. & Alger, B. E. Metabotropic glutamate receptors drive the endocannabinoid system in hippocampus. J. Neurosci. 21, RC188 (2001).

  29. 29

    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).

    Article  CAS  PubMed  Google Scholar 

  30. 30

    Senogles, S. E. The D2s dopamine receptor stimulates phospholipase D activity: a novel signaling pathway for dopamine. Mol. Pharmacol. 58, 455–462 (2000).

    Article  CAS  PubMed  Google Scholar 

  31. 31

    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).

    Article  PubMed  Google Scholar 

  32. 32

    Stella, N., Schweitzer, P. & Piomelli, D. A second endogenous cannabinoid that modulates long-term potentiation. Nature 388, 773–778 (1997).

    Article  CAS  PubMed  Google Scholar 

  33. 33

    Kanoh, H., Yamada, K. & Sakane, F. Diacylglycerol kinases: emerging downstream regulators in cell signaling systems. J. Biochem. 131, 629–633 (2002).

    Article  CAS  PubMed  Google Scholar 

  34. 34

    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).

    Article  CAS  PubMed  Google Scholar 

  35. 35

    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).

    Article  CAS  PubMed  Google Scholar 

  36. 36

    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).

    CAS  PubMed  Google Scholar 

  37. 37

    Stella, N. & Piomelli, D. Receptor-dependent formation of endogenous cannabinoids in cortical neurons. Eur. J. Pharmacol. 425, 189–196 (2001).

    Article  CAS  PubMed  Google Scholar 

  38. 38

    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).

    Article  CAS  PubMed  Google Scholar 

  39. 39

    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).

    CAS  PubMed  Google Scholar 

  40. 40

    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).

    Article  CAS  PubMed  Google Scholar 

  41. 41

    Wilson, R. I. & Nicoll, R. A. Endogenous cannabinoids mediate retrograde signalling at hippocampal synapses. Nature 410, 588–592 (2001).

    Article  CAS  PubMed  Google Scholar 

  42. 42

    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).

    Article  CAS  PubMed  Google Scholar 

  43. 43

    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.

    Article  CAS  PubMed  Google Scholar 

  44. 44

    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).

    Article  CAS  PubMed  Google Scholar 

  45. 45

    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).

    Article  CAS  PubMed  Google Scholar 

  46. 46

    Chevaleyre, V. & Castillo, P. E. Heterosynaptic LTD of hippocampal GABAergic synapses. A novel role of endocannabinoids in regulating excitability. Neuron 38, 461–472 (2003).

    Article  CAS  PubMed  Google Scholar 

  47. 47

    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).

    Article  CAS  PubMed  Google Scholar 

  48. 48

    Bojensen, I. N. & Hansen, H. S. Binding of anandamide to bovine serum albumin. J. Lipid Res. 44, 1790–1794 (2003).

    Article  CAS  Google Scholar 

  49. 49

    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.

    Article  CAS  PubMed  Google Scholar 

  50. 50

    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).

    Article  CAS  PubMed  Google Scholar 

  51. 51

    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).

    Article  CAS  PubMed  Google Scholar 

  52. 52

    Piomelli, D. et al. Structural determinants for recognition and translocation by the anandamide transporter. Proc. Natl Acad. Sci. USA 96, 5802–5807 (1999).

    Article  CAS  PubMed  Google Scholar 

  53. 53

    Beltramo, M. et al. Reversal of dopamine D2 receptor responses by an anandamide transport inhibitor. J. Neurosci. 20, 3401–3407 (2000).

    Article  CAS  PubMed  Google Scholar 

  54. 54

    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).

    Article  CAS  PubMed  Google Scholar 

  55. 55

    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).

    Article  CAS  PubMed  Google Scholar 

  56. 56

    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.

    CAS  PubMed  Google Scholar 

  57. 57

    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).

    Article  PubMed  Google Scholar 

  58. 58

    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).

    Article  CAS  PubMed  Google Scholar 

  59. 59

    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.

    Article  CAS  PubMed  Google Scholar 

  60. 60

    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).

    Article  CAS  PubMed  Google Scholar 

  61. 61

    Fu, J. et al. Oleylethanolamide regulates feeding and body weight through activation of the nuclear receptor PPAR-α. Nature 425, 90–93 (2003).

    Article  CAS  PubMed  Google Scholar 

  62. 62

    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).

    Article  CAS  PubMed  Google Scholar 

  63. 63

    Calignano, A., La Rana, G., Giuffrida, A. & Piomelli, D. Control of pain initiation by endogenous cannabinoids. Nature 394, 277–281 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. 64

    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).

    Article  CAS  PubMed  Google Scholar 

  65. 65

    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.

    Article  CAS  Google Scholar 

  66. 66

    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).

    Article  CAS  PubMed  Google Scholar 

  67. 67

    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).

    Article  CAS  PubMed  Google Scholar 

  68. 68

    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).

    Article  CAS  PubMed  Google Scholar 

  69. 69

    Dinh, T. P. et al. Brain monoglyceride lipase participating in endocannabinoid inactivation. Proc. Natl Acad. Sci. USA 99, 10819–10824 (2002).

    Article  CAS  PubMed  Google Scholar 

  70. 70

    Herkenham, M. et al. Cannabinoid receptor localization in brain. Proc. Natl Acad. Sci. USA 87, 1932–1936 (1990).

    Article  CAS  PubMed  Google Scholar 

  71. 71

    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.

    Article  CAS  PubMed  Google Scholar 

  72. 72

    Ledent, C. et al. Unresponsiveness to cannabinoids and reduced addictive effects of opiates in CB1 receptor knockout mice. Science 283, 401–404 (1999).

    Article  CAS  PubMed  Google Scholar 

  73. 73

    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).

    Article  CAS  PubMed  Google Scholar 

  74. 74

    Mackie, K. & Hille, B. Cannabinoids inhibit N-type calcium channels in neuroblastoma-glioma cells. Proc. Natl Acad. Sci. USA 89, 3825–3829 (1992).

    Article  CAS  PubMed  Google Scholar 

  75. 75

    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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. 76

    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).

    Article  CAS  PubMed  Google Scholar 

  77. 77

    Wilson, R. I. & Nicoll, R. A. Endocannabinoid signaling in the brain. Science 296, 678–682 (2002).

    Article  CAS  PubMed  Google Scholar 

  78. 78

    Hoffman, A. F. & Lupica, C. R. Mechanisms of cannabinoid inhibition of GABAA synaptic transmission in the hippocampus. J. Neurosci. 20, 2470–2479 (2000).

    Article  CAS  PubMed  Google Scholar 

  79. 79

    Gerdeman, G. & Lovinger, D. M. CB1 cannabinoid receptor inhibits synaptic release of glutamate in rat dorsolateral striatum. J. Neurophysiol. 85, 468–471 (2001).

    Article  CAS  PubMed  Google Scholar 

  80. 80

    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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. 81

    Wilson, R. I., Kunos, G. & Nicoll, R. A. Presynaptic specificity of endocannabinoid signaling in the hippocampus. Neuron 31, 1–20 (2001).

    Article  Google Scholar 

  82. 82

    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).

    CAS  PubMed  Google Scholar 

  83. 83

    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).

    Article  CAS  PubMed  Google Scholar 

  84. 84

    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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. 85

    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).

    Article  CAS  PubMed  Google Scholar 

  86. 86

    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).

    Article  PubMed  PubMed Central  Google Scholar 

  87. 87

    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).

    Article  CAS  PubMed  Google Scholar 

  88. 88

    Derkinderen, P. et al. Regulation of a neuronal form of focal adhesion kinase by anandamide. Science 273, 1719–1722 (1996).

    Article  CAS  PubMed  Google Scholar 

  89. 89

    Derkinderen, P. et al. Regulation of extracellular signal-regulated kinase by cannabinoids in hippocampus. J. Neurosci. 23, 2371–2382 (2003).

    Article  CAS  PubMed  Google Scholar 

  90. 90

    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).

    Article  CAS  PubMed  Google Scholar 

  91. 91

    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).

    Article  CAS  PubMed  Google Scholar 

  92. 92

    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).

    Article  CAS  PubMed  Google Scholar 

  93. 93

    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).

    Article  CAS  PubMed  Google Scholar 

  94. 94

    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).

    Article  CAS  PubMed  Google Scholar 

  95. 95

    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).

    Article  CAS  PubMed  Google Scholar 

  96. 96

    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).

    Article  CAS  PubMed  Google Scholar 

  97. 97

    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).

    Article  CAS  PubMed  Google Scholar 

  98. 98

    Hohmann, A. G. & Herkenham, M. Cannabinoid receptors undergo axonal flow in sensory nerves. Neuroscience 92, 1171–1175 (1999).

    Article  CAS  PubMed  Google Scholar 

  99. 99

    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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. 100

    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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. 101

    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.

    Article  PubMed  Google Scholar 

  102. 102

    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).

    Article  PubMed  Google Scholar 

  103. 103

    Hájos, N. & Freund, T. F. Pharmacological separation of cannabinoid sensitive receptors on hippocampal excitatory and inhibitory fibers. Neuropharmacology 43, 503–510 (2002).

    Article  PubMed  Google Scholar 

  104. 104

    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).

    Article  CAS  PubMed  Google Scholar 

  105. 105

    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).

    Article  CAS  PubMed  Google Scholar 

  106. 106

    Wagner, J. A., Varga, K., Jarai, Z. & Kunos, G. Mesenteric vasodilation mediated by endothelial anandamide receptors. Hypertension 33, 429–434 (1999).

    Article  CAS  PubMed  Google Scholar 

  107. 107

    Bátkai, S. et al. Endocannabinoids acting at vascular CB1 receptors mediate the vasodilated state in advanced liver cirrhosis. Nature Med. 7, 827–832 (2001).

    Article  PubMed  Google Scholar 

  108. 108

    Alger, B. E. Retrograde signaling in the regulation of synaptic transmission: focus on endocannabinoids. Prog. Neurobiol. 68, 247–286 (2002).

    Article  CAS  PubMed  Google Scholar 

  109. 109

    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).

    Article  CAS  PubMed  Google Scholar 

  110. 110

    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).

    Article  CAS  PubMed  Google Scholar 

  111. 111

    Hájos, N. et al. Cannabinoids inhibit hippocampal GABAergic transmission and network oscillations. Eur. J. Neurosci. 12, 3239–3249 (2000).

    Article  PubMed  Google Scholar 

  112. 112

    Harris, K. D., Csicsvari, J., Hirase, H., Dragoi, G. & Buzsaki, G. Organization of cell assemblies in the hippocampus. Nature 424, 552–556 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. 113

    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).

    Article  CAS  PubMed  Google Scholar 

  114. 114

    Hampson, R. E. & Deadwyler, S. A. Cannabinoids, hippocampal function and memory. Life Sci. 65, 715–723 (1999).

    Article  CAS  PubMed  Google Scholar 

  115. 115

    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).

    Article  CAS  PubMed  Google Scholar 

  116. 116

    Kreitzer, A. C. & Regehr, W. G. Cerebellar depolarization-induced suppression of inhibition is mediated by endogenous cannabinoids. J. Neurosci. 21, RC174 (2001).

  117. 117

    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).

    Article  CAS  PubMed  Google Scholar 

  118. 118

    Martin, W. J. et al. Anatomical basis for cannabinoid-induced antinociception as revealed by intracerebral microinjections. Brain Res. 822, 237–242 (1999).

    Article  CAS  PubMed  Google Scholar 

  119. 119

    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).

    Article  CAS  PubMed  Google Scholar 

  120. 120

    Martin, M., Ledent, C., Parmentier, M., Maldonado, R. & Valverde, O. Involvement of CB1 cannabinoid receptors in emotional behaviour. Psychopharmacology (Berl.) 159, 379–387 (2002).

    Article  CAS  Google Scholar 

  121. 121

    Marsicano, G. et al. The endogenous cannabinoid system controls extinction of aversive memories. Nature 418, 530–534 (2002).

    Article  CAS  PubMed  Google Scholar 

  122. 122

    Romero, J. et al. The endogenous cannabinoid system and the basal ganglia: biochemical, pharmacological, and therapeutic aspects. Pharmacol. Ther. 95, 137–152 (2002).

    Article  CAS  PubMed  Google Scholar 

  123. 123

    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).

    Article  CAS  PubMed  Google Scholar 

  124. 124

    Koos, T. & Tepper, J. M. Inhibitory control of neostriatal projection neurons by GABAergic interneurons. Nature Neurosci. 2, 467–472 (1999).

    Article  CAS  PubMed  Google Scholar 

  125. 125

    Sieradzan, K. A. et al. Cannabinoids reduce levodopa-induced dyskinesia in Parkinson's disease: a pilot study. Neurology 57, 2108–2111 (2001).

    Article  CAS  PubMed  Google Scholar 

  126. 126

    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).

    Article  PubMed  Google Scholar 

  127. 127

    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).

    CAS  PubMed  Google Scholar 

  128. 128

    Meng, I. D., Manning, B. H., Martin, W. J. & Fields, H. L. An analgesia circuit activated by cannabinoids. Nature 395, 381–383 (1998).

    Article  CAS  PubMed  Google Scholar 

  129. 129

    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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. 130

    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).

    CAS  PubMed  Google Scholar 

  131. 131

    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).

    Article  CAS  PubMed  Google Scholar 

  132. 132

    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).

    Article  CAS  PubMed  Google Scholar 

  133. 133

    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.

    Article  CAS  PubMed  Google Scholar 

  134. 134

    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).

    Article  CAS  PubMed  Google Scholar 

  135. 135

    Szabo, B., Wallmichrath, I., Mathonia, P. & Pfreundtner, C. Cannabinoids inhibit excitatory neurotransmission in the substantia nigra pars reticulata. Neuroscience 97, 89–97 (2000).

    Article  CAS  PubMed  Google Scholar 

  136. 136

    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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. 137

    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).

    CAS  PubMed  Google Scholar 

  138. 138

    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).

    Article  CAS  PubMed  Google Scholar 

  139. 139

    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).

    Article  CAS  PubMed  Google Scholar 

  140. 140

    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).

    Article  CAS  PubMed  Google Scholar 

  141. 141

    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).

    Article  CAS  PubMed  Google Scholar 

  142. 142

    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).

    Article  CAS  PubMed  Google Scholar 

  143. 143

    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.

    Article  CAS  PubMed  Google Scholar 

  144. 144

    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).

    Article  CAS  PubMed  Google Scholar 

  145. 145

    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).

    CAS  PubMed  Google Scholar 

  146. 146

    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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. 147

    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).

    Article  CAS  PubMed  Google Scholar 

  148. 148

    Masson, J., Sagne, C., Hamon, M. & Mestikawy, S. E. Neurotransmitter transporters in the central nervous system. Pharmacol. Rev. 51, 439–464 (1999).

    CAS  PubMed  Google Scholar 

  149. 149

    Glaser, S. T. et al. Evidence against the presence of an anandamide transporter. Proc. Natl Acad. Sci. USA 100, 4269–4274 (2003).

    Article  CAS  PubMed  Google Scholar 

  150. 150

    Berry, E. M. & Mechoulam, R. Tetrahydrocannabinol and endocannabinoids in feeding and appetite. Pharmacol. Ther. 95, 185–190 (2002).

    Article  CAS  PubMed  Google Scholar 

  151. 151

    Di Marzo, V. et al. Leptin-regulated endocannabinoids are involved in maintaining food intake. Nature 410, 822–825 (2001).

    Article  CAS  Google Scholar 

  152. 152

    Gomez, R. et al. A peripheral mechanism for CB1 cannabinoid receptor-dependent modulation of feeding. J. Neurosci. 22, 9612–9617 (2002).

    Article  CAS  PubMed  Google Scholar 

  153. 153

    Koob, G. F. & Le Moal, M. Drug addiction, dysregulation of reward, and allostasis. Neuropsychopharmacology 24, 97–129 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

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.

Author information

Affiliations

Authors

Related links

Related links

DATABASES

LocusLink

CB1

CB2

D2 receptor

FAAH

MGL

FURTHER INFORMATION

International Cannabinoid Research Society

International Association for Cannabis as Medicine

National Institute on Drug Abuse

Glossary

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.

EICOSANOIDS

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).

PHOSPHATIDYLETHANOLAMINE

An important class of membrane phospholipids comprising a glycerol skeleton linked to two fatty acid residues, phosphoric acid and ethanolamine.

PHOSPHOLIPASE

(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.

PHOSPHATIDYLCHOLINE

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.

MICRODIALYSIS

A technique that allows the sampling of neurochemicals in the brain of live animals.

MONOACYLGLYCEROL

A glycerol derivative in which one of the hydroxyl groups is linked to a fatty acid residue by an ester bond.

LYSOPHOSPHOLIPID

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.

CAPSAZEPINE

A synthetic drug that acts as a competitive antagonist of capsaicin at vanilloid receptors.

PARACRINE

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.

HYPERALGESIA

A state of enhanced sensitivity to painful stimuli.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Piomelli, D. The molecular logic of endocannabinoid signalling. Nat Rev Neurosci 4, 873–884 (2003). https://doi.org/10.1038/nrn1247

Download citation

Further reading

Search

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing