Hostname: page-component-76fb5796d-x4r87 Total loading time: 0 Render date: 2024-04-26T05:02:25.130Z Has data issue: false hasContentIssue false

Modulation of Fear and Anxiety by the Endogenous Cannabinoid System

Published online by Cambridge University Press:  07 November 2014

Abstract

The last decade has witnessed remarkable progress in the understanding of the mammalian cannabinoid system, from the cloning of the endogenous cannabinoid receptor to the discovery of new pharmacologic compounds acting on this receptor. Current and planned studies in humans include compounds with effects ranging from direct antagonists to inhibitors of reuptake and breakdown. This progress has been accompanied by a much greater understanding of the role of the cannabinoid system in modulating the neural circuitry that mediates anxiety and fear responses. This review focuses on the neural circuitry and pharmacology of the cannabinoid system as it relates to the acquisition, expression, and extinction of conditioned fear as a model of human anxiety. Preclinical studies suggest that these may provide important emerging targets for new treatments of anxiety disorders.

Type
Review Article
Copyright
Copyright © Cambridge University Press 2007

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

REFERENCES

1.Stein, DJ, Ipser, JC, Seedat, S. Pharmacotherapy for post traumatic stress disorder (PTSD). Cochrane Database Syst Rev. 2006(1):CD002795.Google Scholar
2.Davidson, JR. Pharmacologic treatment of acute and chronic stress following trauma: 2006. J Clin Psychiatry. 2006;67(suppl 2):3439.Google ScholarPubMed
3.Holmes, A, Heilig, M, Rupniak, NM, Steckler, T, Griebel, G. Neuropeptide systems as novel therapeutic targets for depression and anxiety disorders. Trends Pharmacol Sci. 2003;24:580588.CrossRefGoogle ScholarPubMed
4.Roy-Byrne, PP. The GABA-benzodiazepine receptor complex: structure, function, and role in anxiety. J Clin Psychiatry. 2005;66(suppl 2):1420.Google ScholarPubMed
5.Otto, MW, Bruce, SE, Deckersbach, T. Benzodiazepine use, cognitive impairment, and cognitive-behavioral therapy for anxiety disorders: issues in the treatment of a patient in need. J Clin Psychiatry. 2005;66(suppl 2):3438.Google ScholarPubMed
6.Myers, KM, Davis, M. Mechanisms of fear extinction. Mol Psychiatry. 2007;12:120150.CrossRefGoogle ScholarPubMed
7.Davis, M, Myers, KM, Chhatwal, J, Ressler, KJ. Pharmacological treatments that facilitate extinction of fear: relevance to psychotherapy. NeuroRx. 2006;3:8296.CrossRefGoogle ScholarPubMed
8.Pacher, P, Batkai, S, Kunos, G. The endocannabinoid system as an emerging target of pharmacotherapy. Pharmacol Rev. 2006;58:389462.CrossRefGoogle ScholarPubMed
9.Porter, AC, Felder, CC. The endocannabinoid nervous system: unique opportunities for therapeutic intervention. Pharmacol Ther. 2001;90:4560.CrossRefGoogle ScholarPubMed
10.Haller, J, Varga, B, Ledent, C, Freund, TF. CB1 cannabinoid receptors mediate anxiolytic effects: convergent genetic and pharmacological evidence with CB1-specific agents. Behav Pharmacol. 2004;15:299304.CrossRefGoogle ScholarPubMed
11.Witkin, JM, Tzavara, ET, Davis, RJ, Li, X, Nomikos, GG. A therapeutic role for cannabinoid CB1 receptor antagonists in major depressive disorders. Trends Pharmacol Sci. 2005;26:609617.CrossRefGoogle ScholarPubMed
12.La Rana, G, Russo, R, Campolongo, P, et al.Modulation of neuropathic and inflammatory pain by the endocannabinoid transport inhibitor AM404 [N-(4-hydroxyphenyl)-eicosa-5,8,11,14-tetraenamide]. J Pharmacol Exp Ther. 2006;317:13651371.CrossRefGoogle ScholarPubMed
13.Bortolato, M, Campolongo, P, Mangieri, RA, et al.Anxiolytic-like properties of the anandamide transport inhibitor AM404. Neuropsychopharmacology. 2006;31:26522659.CrossRefGoogle ScholarPubMed
14.Kathuria, S, Gaetani, S, Fegley, D, et al.Modulation of anxiety through blockade of anandamide hydrolysis. Nat Med. 2003;9:7681.CrossRefGoogle ScholarPubMed
15.Scheen, AJ, Finer, N, Hollander, P, Jensen, MD, Van Gaal, LF. Efficacy and tolerability of rimonabant in overweight or obese patients with type 2 diabetes: a randomised controlled study. Lancet. 2006;368:16601672.CrossRefGoogle ScholarPubMed
16.LeDoux, JE. Emotion circuits in the brain. Annu Rev Neurosci. 2000;23:155184.CrossRefGoogle ScholarPubMed
17.Davis, M. The role of the amygdala in fear and anxiety. Annu Rev Neurosci. 1992;15:353375.CrossRefGoogle ScholarPubMed
18.Maren, S. The amygdala, synaptic plasticity, and fear memory. Ann N Y Acad Sci. 2003;985:106113.CrossRefGoogle ScholarPubMed
19.Quirk, GJ, Gehlert, DR. Inhibition of the amygdala: key to pathological states? Ann N Y Acad Sci. 2003;985:263272.CrossRefGoogle ScholarPubMed
20.Rescorla, R. Experimental Extinction. In: Mowrer, R, Klein, S, eds. Handbook of Contemporary Learning Theories. Mahwah, NJ: Lawrence Erlbaum Associates; 2001:119154.Google Scholar
21.Myers, KM, Davis, M. Behavioral and neural analysis of extinction. Neuron. 2002;36:567584.CrossRefGoogle ScholarPubMed
22.Walker, DL, Davis, M. The role of amygdala glutamate receptors in fear learning, fear-potentiated startle, and extinction. Pharmacol Biochem Behav. 2002;71:379392.CrossRefGoogle ScholarPubMed
23.Baker, D, Pryce, G, Davies, WL, Hiley, CR. In silico patent searching reveals a new cannabinoid receptor. Trends Pharmacol Sci. 2006;27:14.CrossRefGoogle ScholarPubMed
24.Begg, M, Pacher, P, Batkai, S, et al.Evidence for novel cannabinoid receptors. Pharmacol Ther. 2005;106:133145.CrossRefGoogle ScholarPubMed
25.Sawzdargo, M, Nguyen, T, Lee, DK, et al.Identification and cloning of three novel human G protein-coupled receptor genes GPR52, PsiGPR53 and GPR55: GPR55 is extensively expressed in human brain. Brain Res Mol Brain Res. 1999;64:193198.CrossRefGoogle Scholar
26.Isokawa, M, Alger, BE. Ryanodine receptor regulates endogenous cannabinoid mobilization in the hippocampus. J Neurophysiol. 2006;95:30013011.CrossRefGoogle ScholarPubMed
27.Rancz, EA, Hausser, M. Dendritic calcium spikes are tunable triggers of cannabinoid release and short-term synaptic plasticity in cerebellar Purkinje neurons. J Neurosci. 2006;26:54285437.CrossRefGoogle ScholarPubMed
28.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. 1996;16:39343942.CrossRefGoogle ScholarPubMed
29.Cadas, H, di Tomaso, E, Piomelli, D. Occurrence and biosynthesis of endogenous cannabinoid precursor, N-arachidonoyl phosphatidylethanolamine, in rat brain. J Neurosci. 1997;17:12261242.CrossRefGoogle ScholarPubMed
30.Hashimotodani, Y, Ohno-Shosaku, T, Tsubokawa, H, et al.Phospholipase Cbeta serves as a coincidence detector through its Ca2+ dependency for triggering retrograde endocannabinoid signal. Neuron. 2005;45:257268.CrossRefGoogle ScholarPubMed
31.Ohno-Shosaku, T, Hashimotodani, Y, Maejima, T, Kano, M. Calcium signaling and synaptic modulation: regulation of endocannabinoid-mediated synaptic modulation by calcium. Cell Calcium. 2005;38:369374.CrossRefGoogle ScholarPubMed
32.Ohno-Shosaku, T, Maejima, T, Kano, M. Endogenous cannabinoids mediate retrograde signals from depolarized postsynaptic neurons to presynaptic terminals. Neuron. 2001;29:729738.CrossRefGoogle ScholarPubMed
33.Mackie, K. Mechanisms of CB1 receptor signaling: endocannabinoid modulation of synaptic strength. Int J Obes (Lond). 2006;30(suppl 1):S19S23.CrossRefGoogle ScholarPubMed
34.Iversen, L. Pharmacology. Endogenous cannabinoids. Nature. 1994;372:619.CrossRefGoogle ScholarPubMed
35.Iversen, L. Cannabis and the brain. Brain. 2003;126(pt 6):12521270.CrossRefGoogle ScholarPubMed
36.Gulyas, Al, Cravatt, BF, Bracey, MH, et al.Segregation of two endocannabinoid-hydrolyzing enzymes into pre- and postsynaptic compartments in the rat hippocampus, cerebellum and amygdala. Eur J Neurosci. 2004;20:441458.CrossRefGoogle ScholarPubMed
37.Schlicker, E, Kathmann, M. Modulation of transmitter release via presynaptic cannabinoid receptors. Trends Pharmacol Sci. 2001;22:565572.CrossRefGoogle ScholarPubMed
38.Pertwee, RG. Pharmacology of cannabinoid CB1 and CB2 receptors. Pharmacol Ther. 1997;74:129180.CrossRefGoogle ScholarPubMed
39.Mechoulam, R, Gaoni, Y. A Total Synthesis of DI-Delta-1-Tetrahydrocannabinol, the active constituent of hashish. J Am Chem Soc. 1965;87:32733275.CrossRefGoogle ScholarPubMed
40.D'Souza, DC, Kosten, TR. Cannabinoid antagonists: a treatment in search of an illness. Arch Gen Psychiatry. 2001;58:330331.CrossRefGoogle ScholarPubMed
41.Reeve, VC, Grant, JD, Robertson, W, Gillespie, HK, Hollister, LE. Plasma concentrations of delta-9-tetrahydrocannabinol and impaired motor function. Drug Alcohol Depend. 1983;11:167175.CrossRefGoogle ScholarPubMed
42.McDonald, J, Schleifer, L, Richards, JB, de Wit, H. Effects of THC on behavioral measures of impulsivity in humans. Neuropsychopharmacology. 2003;28:13561365.CrossRefGoogle ScholarPubMed
43.Yesavage, JA, Leirer, VO, Denari, M, Hollister, LE. Carry-over effects of marijuana intoxication on aircraft pilot performance: a preliminary report. Am J Psychiatry. 1985;142:13251329.Google ScholarPubMed
44.Dannon, PN, Lowengrub, K, Amiaz, R, Grunhaus, L, Kotler, M. Comorbid cannabis use and panic disorder: short term and long term follow-up study. Hum Psychopharmacol. 2004;19:97101.CrossRefGoogle ScholarPubMed
45.Fride, E. Endocannabinoids in the central nervous system: from neuronal networks to behavior. Curr Drug Targets CNS Neurol Disord. 2005;4:633642.CrossRefGoogle ScholarPubMed
46.Heishman, SJ, Arasteh, K, Stitzer, ML. Comparative effects of alcohol and marijuana on mood, memory, and performance. Pharmacol Biochem Behav. 1997;58:93101.CrossRefGoogle ScholarPubMed
47.Mallet, PE, Beninger, RJ. The cannabinoid CB1 receptor antagonist SR141716A attenuates the memory impairment produced by delta9-tetrahydrocannabinol or anandamide. Psychopharmacology (Berl). 1998:140:1119.CrossRefGoogle ScholarPubMed
48.Hampson, RE, Deadwyler, SA. Cannabinoids reveal the necessity of hippocampal neural encoding for short-term memory in rats. J Neurosci. 2000;20:89328942.CrossRefGoogle ScholarPubMed
49.Hampson, RE, Hedberg, T, Deadwyler, SA. Differential information processing by hippocampal and subicular neurons. Ann N Y Acad Sci. 2000;911:151165.CrossRefGoogle ScholarPubMed
50.Braida, D, Sala, M. Cannabinoid-induced working memory impairment is reversed by a second generation cholinesterase inhibitor in rats. Neuroreport. 2000;11:20252029.CrossRefGoogle ScholarPubMed
51.Varvel, SA, Lichtman, AH. Evaluation of CB1 receptor knockout mice in the Morris water maze. J Pharmacol Exp Ther. 2002;301:915924.CrossRefGoogle ScholarPubMed
52.Da, S, Takahashi, RN. SR 141716A prevents delta 9-tetrahydrocannabinol-induced spatial learning deficit in a Morris-type water maze in mice. Prog Neuropsychopharmacol Biol Psychiatry. 2002;26:321325.Google Scholar
53.Pamplona, FA, Takahashi, RN. WIN 55212-2 impairs contextual fear conditioning through the activation of CB1 cannabinoid receptors. Neurosci Lett. 2006;397:8892.CrossRefGoogle ScholarPubMed
54.Hollister, LE. Health aspects of cannabis. Pharmacol Rev. 1986;38:120.Google ScholarPubMed
55.Viveros, MP, Llorente, R, Moreno, E, Marco, EM. Behavioral and neuroendocrine effects of cannabinoids in critical developmental periods. Behav Pharmacol. 2005;16:353362.CrossRefGoogle ScholarPubMed
56.Vinod, KY, Hungund, BL. Role of the endocannabinoid system in depression and suicide. Trends Pharmacol Sci. 2006;27:539545.CrossRefGoogle ScholarPubMed
57.Kamprath, K, Wotjak, CT. Nonassociative learning processes determine expression and extinction of conditioned fear in mice. Learn Mem. 2004;11:770786.CrossRefGoogle ScholarPubMed
58.Patel, S, Cravatt, BF, Hillard, CJ. Synergistic interactions between cannabinoids and environmental stress in the activation of the central amygdala. Neuropsychopharmacology. 2005;30:497507.CrossRefGoogle ScholarPubMed
59.Genn, RF, Tucci, S, Marco, EM, Viveros, MP, File, SE. Unconditioned and conditioned anxiogenic effects of the cannabinoid receptor agonist CP 55,940 in the social interaction test. Pharmacol Biochem Behav. 2004;77:567573.CrossRefGoogle ScholarPubMed
60.Uriguen, L, Perez-Rial, S, Ledent, C, Palomo, T, Manzanares, J. Impaired action of anxiolytic drugs in mice deficient in cannabinoid CB1 receptors. Neuropharmacology. 2004;46:966973.CrossRefGoogle ScholarPubMed
61.Haller, J, Bakos, N, Szirmay, M, Ledent, C, Freund, TF. The effects of genetic and pharmacological blockade of the CB1 cannabinoid receptor on anxiety. Eur J Neurosci. 2002;16:13951398.CrossRefGoogle ScholarPubMed
62.Rodriguez de Fonseca, F, Rubio, P, Menzaghi, F, et al.Corticotropin-releasing factor (CRF) antagonist [D-Phe12,Nle21,38,C alpha MeLeu37]CRF attenuates the acute actions of the highly potent cannabinoid receptor agonist HU-210 on defensive-withdrawal behavior in rats. J Pharmacol Exp Ther. 1996;276:5664.Google ScholarPubMed
63.Reich, CG, Alger, BE. Endocannabinoids modulate acquisition and extinction in trace fear conditioning. Paper presented at: Annual Meeting of the Society for Neuroscience. November 12-16, 2005; Washington, D.C.Google Scholar
64.Marsicano, G, Moosmann, B, Hermann, H, Lutz, B, Behl, C. Neuroprotective properties of cannabinoids against oxidative stress: role of the cannabinoid receptor CB1. J Neurochem. 2002;80:448456.CrossRefGoogle ScholarPubMed
65.Martin, M, Ledent, C, Parmentier, M, Maldonado, R, Valverde, O. Involvement of CB1 cannabinoid receptors in emotional behaviour. Psychopharmacology (Berl). 2002;159:379387.CrossRefGoogle ScholarPubMed
66.Chhatwal, JP, Davis, M, Maguschak, KA, Ressler, KJ. Enhancing cannabinoid neurotransmission augments the extinction of conditioned fear. Neuropsychopharmacology. 2005;30:516524.CrossRefGoogle ScholarPubMed
67.Mikics, E, Dombi, T, Barsvari, B, et al.The effects of cannabinoids on contextual conditioned fear in CB1 knockout and CD1 mice. Behav Pharmacol. 2006;17:223230.CrossRefGoogle ScholarPubMed
68.Arenos, JD, Musty, RE, Bucci, DJ. Blockade of cannabinoid CB(1) receptors alters contextual learning and memory. Eur J Pharmacol. 2006;539:177183.CrossRefGoogle ScholarPubMed
69.Marsicano, G, Wotjak, CT, Azad, SC, et al.The endogenous cannabinoid system controls extinction of aversive memories. Nature. 2002;418:530534.CrossRefGoogle ScholarPubMed
70.Izquierdo, A, Wellman, CL, Holmes, A. Brief uncontrollable stress causes dendritic retraction in infralimbic cortex and resistance to fear extinction in mice. J Neurosci. 2006;26:57335738.CrossRefGoogle ScholarPubMed
71.Walker, DL, Ressler, KJ, Lu, KT, Davis, M. Facilitation of conditioned fear extinction by systemic administration or intra-amygdala infusions of D-cycloserine as assessed with fear-potentiated startle in rats. J Neurosci. 2002;22:23432351.CrossRefGoogle ScholarPubMed
72.Ressler, KJ, Rothbaum, BO, Tannenbaum, L, et al.Cognitive enhancers as adjuncts to psychotherapy: use of D-cycloserine in phobic individuals to facilitate extinction of fear. Arch Gen Psychiatry. 2004;61:11361144.CrossRefGoogle ScholarPubMed
73.Hofmann, SG, Meuret, AE, Smits, JA, et al.Augmentation of exposure therapy with D-cycloserine for social anxiety disorder. Arch Gen Psychiatry. 2006;63:298304.CrossRefGoogle ScholarPubMed
74.Hofmann, SG, Pollack, MH, Otto, MW. Augmentation treatment of psychotherapy for anxiety disorders with D-cycloserine. CNS Drug Rev. 2006;12:208217.CrossRefGoogle ScholarPubMed
75.Chhatwal, JP, Gutman, AR, Maguschak, K, Davis, M, Ressler, KJ. Endocannabinoid modulation of CCK2 receptor activation may be a key event in the extinction of conditioned fear. Paper presented at: Annual Meeting of the Society for Neuroscience. October 14-18, 2006; Atlanta, Ga.Google Scholar
76.Suzuki, A, Josselyn, SA, Frankland, PW, Masushige, S, Silva, AJ, Kida, S. Memory reconsolidation and extinction have distinct temporal and biochemical signatures. J Neurosci. 2004;24:47874795.CrossRefGoogle ScholarPubMed
77.Rescorla, RA. Extinction can be enhanced by a concurrent excitor. J Exp Psychol Anim Behav Process. 2000;26:251260.CrossRefGoogle ScholarPubMed
78.Cain, CK, Blouin, AM, Barad, M. Adrenergic transmission facilitates extinction of conditional fear in mice. Learn Mem. 2004;11:179187.CrossRefGoogle ScholarPubMed