Abstract
The term cannabinoids encompasses compounds produced by the plant Cannabis sativa, such as Δ 9-tetrahydrocannabinol, and synthetic counterparts. Their actions occur mainly through activation of cannabinoid type 1 (CB1) receptors. Arachidonoyl ethanolamide (anandamide) and 2-arachidonoyl glycerol (2-AG) serve as major endogenous ligands (endocannabinoids) of CB1 receptors. Hence, the cannabinoid receptors, the endocannabinoids, and their metabolizing enzymes comprise the endocannabinoid system. Cannabinoids induce diverse responses on anxiety- and fear-related behaviors. Generally, low doses tend to induce anxiolytic-like effects, whereas high doses often cause the opposite. Inhibition of endocannabinoid degradation seems to circumvent these biphasic effects by enhancing CB1 receptor signaling in a temporarily and spatially restricted manner, thus reducing anxiety-like behaviors. Pharmacological blockade or genetic deletion of CB1 receptors, in turn, primarily exerts anxiogenic-like effects and impairments in extinction of aversive memories. Interestingly, pharmacological blockade of Transient Receptor Potential Vanilloid Type-1 (TRPV1) channel, which can be activated by anandamide as well, has diametrically opposite consequences. This book chapter summarizes and conceptualizes our current knowledge about the role of (endo)cannabinoids in fear and anxiety and outlines implications for an exploitation of the endocannabinoid system as a target for new anxiolytic drugs.
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Abbreviations
- 2-AG:
-
2-Arachidonoyl glycerol (endocannabinoid; i.e., activates CB1 receptors)
- AA-5HT:
-
Arachidonoyl serotonin (synthetic inhibitor of FAAH-mediated endocannabinoid degradation and TRPV1 antagonist)
- AEA:
-
Anandamide or arachidonoyl ethanolamide (endocannabinoid and endovanilloid; i.e., activates CB1 receptors and TRPV1)
- AM251:
-
(Synthetic CB1 receptor antagonist)
- AM404:
-
(Synthetic inhibitor of endocannabinoid uptake and FAAH-mediated degradation)
- CB1:
-
Cannabinoid type 1 receptor
- CB2:
-
Cannabinoid type 2 receptor
- CBD:
-
Cannabidiol (phytocannabinoid)
- CP-55940:
-
(Synthetic CB1 receptor agonist)
- Cre/loxP:
-
(Recombinatory system used in conditional mouse mutagenesis)
- FAAH:
-
Fatty acid amide hydrolase (major degrading enzyme of AEA)
- GABA:
-
Gama-aminobutyric acid (major inhibitory transmitter of the brain)
- GPR55:
-
(G-protein-coupled cannabinoid receptor)
- HU210:
-
(Synthetic CB1 receptor agonist)
- JZL184:
-
(Synthetic inhibitor of MGL-mediated endocannabinoid degradation)
- MGL:
-
Monoacylglycerol lipase (major degrading enzyme of AEA)
- PAG:
-
Periaqueductal grey (matter brain structure orchestrating fear responses)
- PPARα:
-
(cannabinoid receptor)
- SB366971:
-
(Synthetic TRPV1 antagonist)
- SR141716A:
-
Rimonabant/acompliaTM (synthetic CB1 receptor antagonist)
- SR144528:
-
(Synthetic CB2 receptor antagonist)
- Δ 9-THC:
-
Δ 9-Tetrahydrocannabinol (phytocannabinoid; major psychoactive ingredient of Cannabis sativa)
- TRPV1:
-
Transient receptor potential vanilloid type-1 channel
- UCM707:
-
(Synthetic inhibitor of endocannabinoid uptake)
- URB597:
-
(Synthetic inhibitor of FAAH-mediated endocannabinoid degradation)
- VDM11:
-
(Synthetic inhibitor of endocannabinoid uptake)
- WIN-55212-2:
-
(Synthetic CB1 receptor agonist)
References
Blanchard DC, Blanchard RJ (1988) Ethoexperimental approaches to the biology of emotion. Annu Rev Psychol 39:43–68
Bortolato M, Campolongo P, Mangieri RA et al (2006) Anxiolytic-like properties of the anandamide transport inhibitor AM404. Neuropsychopharmacology 31:2652–2659
Brown AJ (2007) Novel cannabinoid receptors. Br J Pharmacol 152:567–575
Chevaleyre V, Takahashi KA, Castillo PE (2006) Endocannabinoid-mediated synaptic plasticity in the CNS. Annu Rev Neurosci 29:37–76
Chhatwal JP, Davis M, Maguschak KA, Ressler KJ et al (2005) Enhancing cannabinoid neurotransmission augments the extinction of conditioned fear. Neuropsychopharmacology 30:516–524
Christensen R, Kristensen PK, Bartels EM et al (2007) Efficacy and safety of the weight-loss drug rimonabant: a meta-analysis of randomised trials. Lancet 370:1706–1713
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
Deakin JFW, Graeff FG (1991) 5-HT and mechanisms of defence. J Psychopharmacol 5:305–315
Devane WA, Dysarz FA III, Johnson MR et al (1988) Determination and characterization of a cannabinoid receptor in rat brain. Mol Pharmacol 34:605–613
Devane WA, Hanus L, Breuer A et al (1992) Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science 258:1946–1949
Di Marzo V, Bifulco M, De Petrocellis L (2004) The endocannabinoid system and its therapeutic exploitation. Nat Rev Drug Discov 3:771–784
Di Marzo V, Gobbi G, Szallasi A (2008) Brain TRPV1: a depressing TR(i)P down memory lane? Trends Pharmacol Sci 29:594–600
Gaoni Y, Mechoulam R (1964) Isolation, structure and partial synthesis of an active constituent of hashish. J Am Chem Soc 86:1646
Gatley SJ, Gifford AN, Volkow ND et al (1996) 3I-labeled AM251: a radioiodinated ligand which binds in vivo to mouse brain cannabinoid CB1 receptors. Eur J Pharmacol 307:331–338
Gray JA (1982) The Neuropsychology of anxiety: an enquiry into the functions of the septo-hippocampal system, 1st edn. Oxford University Press, Oxford
Guimarães FS, Chiaretti TM, Graeff FG, Zuardi AW (1990) Antianxiety effect of cannabidiol in the elevated plus-maze. Psychopharmacology (Berl) 100:558–559
Hall W, Solowij N (1998) Adverse effects of cannabis. Lancet 352:1611–1616
Haller J, Varga B, Ledent C et al (2004) Context-dependent effects of CB1 cannabinoid gene disruption on anxiety-like and social behaviour in mice. Eur J Neurosci 19:1906–1912
Harkany T, Guzmán M, Galve-Roperh I et al (2007) The emerging functions of endocannabinoid signaling during CNS development. Trends Pharmacol Sci 28:83–92
Hölter SM, Kallnik M, Wurst W et al (2005) Cannabinoid CB1 receptor is dispensable for memory extinction in an appetitively-motivated learning task. Eur J Pharmacol 510:69–74
Howlett AC, Barth F, Bonner TI et al (2002) International Union of Pharmacology. XXVII. Classification of cannabinoid receptors. Pharmacol Rev 54:161–202
Kamprath K, Marsicano G, Tang J et al (2006) Cannabinoid CB1 receptor mediates fear extinction via habituation-like processes. J Neurosci 26:6677–6686
Kamprath K, Plendl W, Marsicano G et al (2009) Endocannabinoids mediate acute fear adaptation via glutamatergic neurons independently of corticotropin-releasing hormone signaling. Genes Brain Behav 8:203–211
Kathuria S, Gaetani S, Fegley D et al (2003) Modulation of anxiety through blockade of anandamide hydrolysis. Nature Med 9:76–81
Long JZ, Li W, Booker L et al (2009) Selective blockade of 2-arachidonoylglycerol hydrolysis produces cannabinoid behavioural effects. Nat Chem Biol 5:37–44
Marsch R, Foeller E, Rammes G et al (2007) Reduced anxiety, conditioned fear, and hippocampal long-term potentiation in transient receptor potential vanilloid type 1 receptor-deficient mice. J Neurosci 27:832–839
Marsicano G, Lutz B (2006) Neuromodulatory functions of the endocannabinoid system. J Endocrinol Invest 29(Suppl 3):27–46
Marsicano G, Wotjak CT, Azad SC et al (2002) The endogenous cannabinoid system controls extinction of aversive memories. Nature 418:530–534
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
McNaughton N, Corr PJ (2004) Two-dimensional neuropsychology of defense: fear/anxiety and defensive distance. Neurosci Biobehav Rev 28:285–305
Mechoulam R, Devane WA, Breuer A, Zahalka J (1991) A random walk through a cannabis field. Pharmacol Biochem Behav 40:461–464
Mechoulam R, Ben-Shabat S, Hanus L et al (1995) Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors. Biochem Pharmacol 50:83–90
Micale V, Cristino L, Tamburella A et al (2009) Anxiolytic effects in mice of a dual blocker of fatty acid amide hydrolase and transient receptor potential vanilloid type-1 channels. Neuropsychopharmacology 34:593–606
Monory K, Blaudzun H, Massa F et al (2007) Genetic dissection of behavioural and autonomic effects of Delta(9)-tetrahydrocannabinol in mice. PLoS Biol 5:e269
Moreira FA, Lutz B (2008) The endocannabinoid system: emotion, learning and addiction. Addict Biol 13:196–212
Moreira FA, Aguiar DC, Guimarães FS (2006) Anxiolytic-like effect of cannabidiol in the rat Vogel conflict test. Prog Neuropsychopharmacol Biol Psychiatry 30:1466–1471
Moreira FA, Aguiar DC, Guimarães FS (2007) Anxiolytic-like effect of cannabinoids injected into the rat dorsolateral periaqueductal gray. Neuropharmacology 52:958–65
Moreira FA, Aguiar DC, Campos AC et al (2009) Antiaversive effects of cannabinoids: is the periaqueductal gray involved? Neural Plast 2009:625469
Myers KM, Davis M (2007) Mechanisms of fear extinction. Mol Psychiatry 12:120–150
Nissen SE, Nicholls SJ, Wolski K et al (2008) Effect of rimonabant on progression of atherosclerosis in patients with abdominal obesity and coronary artery disease: the STRADIVARIUS randomized controlled trial. JAMA 299:1547–1560
O’Sullivan SE (2007) Cannabinoids go nuclear: evidence for activation of peroxisome proliferator-activated receptors. Br J Pharmacol 152:576–582
Patel S, Hillard CJ (2006) Pharmacological evaluation of cannabinoid receptor ligands in a mouse model of anxiety: further evidence for an anxiolytic role for endogenous cannabinoid signaling. J Pharmacol Exp Ther 318:304–311
Patel S, Hillard CJ (2008) Adaptations in endocannabinoid signaling in response to repeated homotypic stress: a novel mechanism for stress habituation. Eur J Neurosci 27:2821–2829
Pertwee RG (2008) Ligands that target cannabinoid receptors in the brain: from THC to anandamide and beyond. Addict Biol 13:147–159
Piomelli D (2003) The molecular logic of endocannabinoid signalling. Nature Rev Neurosci 4:873–884
Ranganathan M, D’Souza DC (2006) The acute effects of cannabinoids on memory in humans: a review. Psychopharmacology (Berl) 188:425–444
Rinaldi-Carmona M, Barth F, Héaulme M et al (1994) SR141716A, a potent and selective antagonist of the brain cannabinoid receptor. FEBS Lett 350:240–244
Ross RA (2003) Anandamide and vanilloid TRPV1 receptors. Br J Pharmacol 140:790–801
Ross RA (2007) Allosterism and cannabinoid CB(1) receptors: the shape of things to come. Trends Pharmacol Sci 28:567–572
Rubino T, Guidali C, Vigano D et al (2008) CB1 receptor stimulation in specific brain areas differently modulate anxiety-related behaviour. Neuropharmacology 54:151–160
Sousa N, Almeida OF, Wotjak CT (2006) A hitchhiker’s guide to behavioral analysis in laboratory rodents. Genes Brain Behav 5(Suppl 2):5–24
Starowicz K, Nigam S, Di Marzo V (2007) Biochemistry and pharmacology of endovanilloids. Pharmacol Ther 114:13–33
Steiner MA, Wotjak CT (2008) Role of the endocannabinoid system in regulation of the hypothalamic-pituitary-adrenocortical axis. Prog Brain Res 170:397–432
Sugiura T, Kondo S, Sukagawa A et al (1995) 2-Arachidonoylglycerol: a possible endogenous cannabinoid receptor ligand in brain. Biochem Biophys Res Commun 215:89–97
Terzian AL, Aguiar DC, Guimarães FS, Moreira FA (2009) Modulation of anxiety-like behaviour by Transient Receptor Potential Vanilloid Type 1 (TRPV1) channels located in the dorsolateral periaqueductal gray. Eur Neuropsychopharmacol 19:188–195
Viveros MP, Marco EM, File SE (2005) Endocannabinoid system and stress and anxiety responses. Pharmacol Biochem Behav 81:331–342
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Moreira, F.A., Wotjak, C.T. (2009). Cannabinoids and Anxiety. In: Stein, M., Steckler, T. (eds) Behavioral Neurobiology of Anxiety and Its Treatment. Current Topics in Behavioral Neurosciences, vol 2. Springer, Berlin, Heidelberg. https://doi.org/10.1007/7854_2009_16
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