Table Info

Table 1.

Major findings supporting the involvement of CB₂R in anxiety disorders

Animal studies
Genetic studies	Genetic manipulation	Animal specie		Experimental test	Behavioral changes		References
	CB₂xP	Mouse, ICR		LDB	↓ vulnerability (↓ time in the lighted box and open arms)		[39]
	CB₂xP	Mouse, ICR		EPM	↓ vulnerability (↓ time in the lighted box and open arms)		[39]
	CB₂^–/–	Mouse, ICR		LDB	↑ vulnerability (↑ time in the lighted box and open arms)		[44]
	CB₂^–/–	Mouse, ICR		EPM	↑ vulnerability (↑ time in the lighted box and open arms)		[44]
	Cnr2 KO	Mouse, C57BL/6J		SD	↑ aggressive behavior		[49]
Pharmacological studies	Acute treatment	Drug	Animal specie	Experimental test	Dosis	Behavioral changes	References
		CB₂R messenger RNA antisense probe	Mouse, DBA/2, C57BL/6J, BALB/c	EPM	4 µg/µL per 12 h (3 days)	↓ anxiogenic response	[45]
		JWH015 (CB₂R agonist)	Mouse, DBA/2, C57BL/6J, BALB/c	EPM	1–20 mg/kg	↑ anxiogenic response	[38]
		JWH133 (CB₂R agonist)	Mouse, ICR	LDB, EPM	0.5, 1, 2 mg/kg	No effect	[47]
		JWH133 (CB₂R agonist)	Mouse, C57BL/6J	SD	1, 2 mg/kg	↓ aggressive behavior	[49]
		GW405833 (CB₂R agonist)	Mouse, C57BL/6J	MB	10, 30, 100 mg/kg	↓ anxiogenic response	[46]
		GW405833 (CB₂R agonist)	Rat, Sprague-Dawley	Rotarod	100 mg/kg	↓ anxiogenic response	[46]
		AM630 (CB₂R antagonist)	Mouse, ICR	LDB	1, 2, 3 mg/kg	↑ anxiogenic response	[47]
	Chronic treatment	Drug	Animal specie	Experimental test	Dosis	Behavioral changes	References
		AM630 (CB₂R antagonist)	Mouse, ICR	LDB EPM	1, 2, 3 mg/kg per 12 h (7 days)	↓ anxiogenic response	[47]
		JWH133 (CB₂R agonist)	Mouse, ICR	LDB EPM	0.5, 1, 2 mg/kg per 12 h (7 days)	↑ anxiogenic response	[47]

Human studies
Variable	Population	Results	References
rs2070956 polymorphism	Caucasian (infant)	↓ response to the treatment	[50]

Cnr2 KO: mouse lacking CB₂R gene in the CNS with C57BL/6J background; LDB: light-dark box test; EPM: elevated plus-maze test; SD: experimental paradigm of social defeat; MB: marble-burying behavioral test. ↑: increases; ↓: decreases

Declarations

Acknowledgments

We thank all participants in this study. We greatly appreciated Biorender for helping to create figure 1.

Author contributions

MSGG and JM conceived the presented idea. MSGG took the lead in writing the manuscript. FN and AG wrote the manuscript in consultation with MSGG. All authors provided critical feedback and helped shape the research, analysis, and manuscript.

Conflicts of interest

The authors declare no conflict of interest.

Ethical approval

Not applicable.

Consent to participate

Not applicable.

Consent to publication

Not applicable.

Availability of data and materials

Not applicable.

Funding

Not applicable.

Copyright

References

Devane WA, Hanus L, Breuer A, Pertwee RG, Stevenson LA, Griffin G, et al. Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science. 1992;258:1946–9. [DOI] [PubMed]

Mechoulam R, Ben-Shabat S, Hanus L, Ligumsky M, Kaminski NE, Schatz AR, et al. Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors. Biochem Pharmacol. 1995;50:83–90. [DOI] [PubMed]

Sugiura T, Kondo S, Sukagawa A, Nakane S, Shinoda A, Itoh K, et al. 2-Arachidonoylglycerol: a possible endogenous cannabinoid receptor ligand in brain. Biochem Biophys Res Commun. 1995;215:89–97. [DOI] [PubMed]

Bracey MH, Hanson MA, Masuda KR, Stevens RC, Cravatt BF. Structural adaptations in a membrane enzyme that terminates endocannabinoid signaling. Science. 2002;298:1793–6. [DOI] [PubMed]

Cravatt BF, Giang DK, Mayfield SP, Boger DL, Lerner RA, Gilula NB, et al. Molecular characterization of an enzyme that degrades neuromodulatory fatty-acid amides. Nature. 1996;384:83–7. [DOI] [PubMed]

Dinh TP, Carpenter D, Leslie FM, Freund TF, Katona I, Sensi SL, et al. Brain monoglyceride lipase participating in endocannabinoid inactivation. Proc Natl Acad Sci U S A. 2002;99:10819–24. [DOI] [PubMed] [PMC]

Dinh TP, Kathuria S, Piomelli D. RNA interference suggests a primary role for monoacylglycerol lipase in the degradation of the endocannabinoid 2-arachidonoylglycerol. Mol Pharmacol. 2004;66:1260–4. [DOI] [PubMed]

Gulyas AI, Cravatt BF, Bracey MH, Dinh TP, Piomelli D, Boscia F, et al. Segregation of two endocannabinoid-hydrolyzing enzymes into pre- and postsynaptic compartments in the rat hippocampus, cerebellum and amygdala. Eur J Neurosci. 2004;20:441–58. [DOI] [PubMed]

Saario SM, Salo OM, Nevalainen T, Poso A, Laitinen JT, Järvinen T, et al. Characterization of the sulfhydryl-sensitive site in the enzyme responsible for hydrolysis of 2-arachidonoyl-glycerol in rat cerebellar membranes. Chem Biol. 2005;12:649–56. [DOI] [PubMed]

10.

Herkenham M, Lynn AB, Johnson MR, Melvin LS, de Costa BR, Rice KC. Characterization and localization of cannabinoid receptors in rat brain: a quantitative in vitro autoradiographic study. J Neurosci. 1991;11:563–83. [DOI] [PubMed] [PMC]

11.

Munro S, Thomas KL, Abu-Shaar M. Molecular characterization of a peripheral receptor for cannabinoids. Nature. 1993;365:61–5. [DOI] [PubMed]

12.

Johns DG, Behm DJ, Walker DJ, Ao Z, Shapland EM, Daniels DA, et al. The novel endocannabinoid receptor GPR55 is activated by atypical cannabinoids but does not mediate their vasodilator effects. Br J Pharmacol. 2007;152:825–31. [DOI] [PubMed] [PMC]

13.

Ryberg E, Larsson N, Sjögren S, Hjorth S, Hermansson NO, Leonova J, et al. The orphan receptor GPR55 is a novel cannabinoid receptor. Br J Pharmacol. 2007;152:1092–101. [DOI] [PubMed] [PMC]

14.

Zygmunt PM, Petersson J, Andersson DA, Chuang H, Sørgård M, Di Marzo V, et al. Vanilloid receptors on sensory nerves mediate the vasodilator action of anandamide. Nature. 1999;400:452–7. [DOI] [PubMed]

15.

Muller C, Morales P, Reggio PH. Cannabinoid ligands targeting TRP channels. Front Mol Neurosci. 2019;11:487. [DOI] [PubMed] [PMC]

16.

Bisogno T, Ligresti A, Di Marzo V. The endocannabinoid signalling system: biochemical aspects. Pharmacol Biochem Behav. 2005;81:224–38. [DOI] [PubMed]

17.

Freund TF, Katona I, Piomelli D. Role of endogenous cannabinoids in synaptic signaling. Physiol Rev. 2003;83:1017–66. [DOI] [PubMed]

18.

Piomelli D. The molecular logic of endocannabinoid signalling. Nat Rev Neurosci. 2003;4:873–84. [DOI] [PubMed]

19.

Mailleux P, Vanderhaeghen JJ. Distribution of neuronal cannabinoid receptor in the adult rat brain: a comparative receptor binding radioautography and in situ hybridization histochemistry. Neuroscience. 1992;48:655–68. [DOI] [PubMed]

20.

Glass M, Dragunow M, Faull RL. Cannabinoid receptors in the human brain: a detailed anatomical and quantitative autoradiographic study in the fetal, neonatal and adult human brain. Neuroscience. 1997;77:299–318. [DOI] [PubMed]

21.

Heim ME, Queisser W, Altenburg HP. Randomized crossover study of the antiemetic activity of levonantradol and metoclopramide in cancer patients receiving chemotherapy. Cancer Chemother Pharmacol. 1984;13:123–5. [DOI] [PubMed]

22.

Walsh D, Nelson KA, Mahmoud FA. Established and potential therapeutic applications of cannabinoids in oncology. Support Care Cancer. 2003;11:137–43. [DOI] [PubMed]

23.

Timpone JG, Wright DJ, Li N, Egorin MJ, Enama ME, Mayers J, et al. The safety and pharmacokinetics of single-agent and combination therapy with megestrol acetate and dronabinol for the treatment of HIV wasting syndrome. The DATRI 004 study group. Division of AIDS treatment research initiative. AIDS Res Hum Retroviruses. 1997;13:305–15. [DOI] [PubMed]

24.

Abrams DI, Hilton JF, Leiser RJ, Shade SB, Elbeik TA, Aweeka FT, et al. Short-term effects of cannabinoids in patients with HIV-1 infection: a randomized, placebo-controlled clinical trial. Ann Intern Med. 2003;139:258–66. [DOI] [PubMed]

25.

Wallace MS, Marcotte TD, Umlauf A, Gouaux B, Atkinson JH. Efficacy of inhaled cannabis on painful diabetic neuropathy. J Pain. 2015;16:616–27. [DOI] [PubMed] [PMC]

26.

Langford RM, Mares J, Novotna A, Vachova M, Novakova I, Notcutt W, et al. A double-blind, randomized, placebo-controlled, parallel-group study of THC/CBD oromucosal spray in combination with the existing treatment regimen, in the relief of central neuropathic pain in patients with multiple sclerosis. J Neurol. 2013;260:984–97. [DOI] [PubMed]

27.

Borgan F, Kokkinou M, Howes O. The cannabinoid CB₁ receptor in schizophrenia. Biol Psychiatry Cogn Neurosci Neuroimaging. 2020;[Epub ahead of print]. [DOI]

28.

Shearman LP, Rosko KM, Fleischer R, Wang J, Xu S, Tong XS, et al. Antidepressant-like and anorectic effects of the cannabinoid CB₁ receptor inverse agonist AM251 in mice. Behav Pharmacol. 2003;14:573–82. [DOI] [PubMed]

29.

Steiner MA, Marsicano G, Nestler EJ, Holsboer F, Lutz B, Wotjak CT. Antidepressant-like behavioral effects of impaired cannabinoid receptor type 1 signaling coincide with exaggerated corticosterone secretion in mice. Psychoneuroendocrinology. 2008;33:54–67. [DOI] [PubMed] [PMC]

30.

Steiner MA, Marsicano G, Wotjak CT, Lutz B. Conditional cannabinoid receptor type 1 mutants reveal neuron subpopulation-specific effects on behavioral and neuroendocrine stress responses. Psychoneuroendocrinology. 2008;33:1165–70. [DOI] [PubMed]

31.

Chakrabarti A, Onaivi ES, Chaudhuri G. Cloning and sequencing of a cDNA encoding the mouse brain-type cannabinoid receptor protein. DNA Seq. 1995;5:385–8. [DOI] [PubMed]

32.

Derocq JM, Ségui M, Marchand J, Le Fur G, Casellas P. Cannabinoids enhance human B-cell growth at low nanomolar concentrations. FEBS Lett. 1995;369:177–82. [DOI] [PubMed]

33.

Schatz AR, Lee M, Condie RB, Pulaski JT, Kaminski NE. Cannabinoid receptors CB₁ and CB₂: a characterization of expression and adenylate cyclase modulation within the immune system. Toxicol Appl Pharmacol. 1997;142:278–87. [DOI] [PubMed]

34.

Griffin G, Wray EJ, Tao Q, McAllister SD, Rorrer WK, Aung MM, et al. Evaluation of the cannabinoid CB₂ receptor-selective antagonist, SR144528: further evidence for cannabinoid CB₂ receptor absence in the rat central nervous system. Eur J Pharmacol. 1999;377:117–25. [DOI] [PubMed]

35.

Carlisle SJ, Marciano-Cabral F, Staab A, Ludwick C, Cabral GA. Differential expression of the CB₂ cannabinoid receptor by rodent macrophages and macrophage-like cells in relation to cell activation. Int Immunopharmacol. 2002;2:69–82. [DOI] [PubMed]

36.

Van Sickle MD, Duncan M, Kingsley PJ, Mouihate A, Urbani P, Mackie K, et al. Identification and functional characterization of brainstem cannabinoid CB₂ receptors. Science. 2005;310:329–32. [DOI] [PubMed]

37.

Gong JP, Onaivi ES, Ishiguro H, Liu QR, Tagliaferro PA, Brusco A, et al. Cannabinoid CB₂ receptors: immunohistochemical localization in rat brain. Brain Res. 2006;1071:10–23. [DOI] [PubMed]

38.

Onaivi ES. Neuropsychobiological evidence for the functional presence and expression of cannabinoid CB₂ receptors in the brain. Neuropsychobiology. 2006;54:231–46. [DOI] [PubMed]

39.

García-Gutiérrez MS, Pérez-Ortiz JM, Gutiérrez-Adán A, Manzanares J. Depression-resistant endophenotype in mice overexpressing cannabinoid CB₂ receptors. Br J Pharmacol. 2010;160:1773–84. [DOI] [PubMed] [PMC]

40.

Ishiguro H, Iwasaki S, Teasenfitz L, Higuchi S, Horiuchi Y, Saito T, et al. Involvement of cannabinoid CB₂ receptor in alcohol preference in mice and alcoholism in humans. Pharmacogenomics J. 2007;7:380–5. [DOI] [PubMed]

41.

Onaivi ES, Ishiguro H, Gong JP, Patel S, Meozzi PA, Myers L, et al. Brain neuronal CB₂ cannabinoid receptors in drug abuse and depression: from mice to human subjects. PLoS ONE. 2008;3:e1640. [DOI] [PubMed] [PMC]

42.

Ishiguro H, Horiuchi Y, Ishikawa M, Koga M, Imai K, Suzuki Y, et al. Brain cannabinoid CB₂ receptor in schizophrenia. Biol Psychiatry. 2010;67:974–82. [DOI] [PubMed]

43.

García-Gutiérrez MS, Manzanares J. Overexpression of CB₂ cannabinoid receptors decreased vulnerability to anxiety and impaired anxiolytic action of alprazolam in mice. J Psychopharmacol. 2011;25:111–20. [DOI] [PubMed]

44.

Ortega-Alvaro A, Aracil-Fernández A, García-Gutiérrez MS, Navarrete F, Manzanares J. Deletion of CB₂ cannabinoid receptor induces schizophrenia-related behaviors in mice. Neuropsychopharmacology. 2011;36:1489–504. [DOI] [PubMed] [PMC]

45.

Onaivi ES, Ishiguro H, Gong JP, Patel S, Meozzi PA, Myers L, et al. Functional expression of brain neuronal CB₂ cannabinoid receptors are involved in the effects of drugs of abuse and in depression. Ann N Y Acad Sci. 2008;1139:434–49. [DOI] [PubMed] [PMC]

46.

Valenzano KJ, Tafesse L, Lee G, Harrison JE, Boulet JM, Gottshall SL, et al. Pharmacological and pharmacokinetic characterization of the cannabinoid receptor 2 agonist, GW405833, utilizing rodent models of acute and chronic pain, anxiety, ataxia and catalepsy. Neuropharmacology. 2005;48:658–72. [DOI] [PubMed]

47.

García-Gutiérrez MS, García-Bueno B, Zoppi S, Leza JC, Manzanares J. Chronic blockade of cannabinoid CB₂ receptors induces anxiolytic-like actions associated with alterations in GABA_A receptors. Br J Pharmacol. 2012;165:951–64. [DOI] [PubMed] [PMC]

48.

Robertson JM, Achua JK, Smith JP, Prince MA, Staton CD, Ronan PJ, et al. Anxious behavior induces elevated hippocampal CB₂ receptor gene expression. Neuroscience. 2017;352:273–84. [DOI] [PubMed] [PMC]

49.

Rodríguez-Arias M, Navarrete F, Blanco-Gandia MC, Arenas MC, Aguilar MA, Bartoll-Andrés A, et al. Role of CB₂ receptors in social and aggressive behavior in male mice. Psychopharmacology (Berl). 2015;232:3019–31. [DOI] [PubMed]

50.

Lester KJ, Coleman JR, Roberts S, Keers R, Breen G, Bögels S, et al. Genetic variation in the endocannabinoid system and response to cognitive behavior therapy for child anxiety disorders. Am J Med Genet B Neuropsychiatr Genet. 2017;174:144–55. [DOI] [PubMed] [PMC]

51.

Liu QR, Canseco-Alba A, Zhang HY, Tagliaferro P, Chung M, Dennis E, et al. Cannabinoid type 2 receptors in dopamine neurons inhibits psychomotor behaviors, alters anxiety, depression and alcohol preference. Sci Rep. 2017;7:17410. [DOI] [PubMed] [PMC]

52.

Papp M, Nalepa I, Antkiewicz-Michaluk L, Sánchez C. Behavioural and biochemical studies of citalopram and WAY 100635 in rat chronic mild stress model. Pharmacol Biochem Behav. 2002;72:465–74. [DOI] [PubMed]

53.

Papp M, Moryl E, Willner P. Pharmacological validation of the chronic mild stress model of depression. Eur J Pharmacol. 1996;296:129–36. [DOI] [PubMed]

54.

Neisewander JL, Rowlett JK, Nonneman AJ, Bardo MT. Up-regulation of opiate receptors following chronic naltrexone treatment in mature and aged male and female rats. Prog Clin Biol Res. 1989;292:471–6. [PubMed]

55.

Patel M, Gomes B, Patel C, Yoburn BC. Antagonist-induced micro-opioid receptor up-regulation decreases G-protein receptor kinase-2 and dynamin-2 abundance in mouse spinal cord. Eur J Pharmacol. 2002;446:37–42. [DOI] [PubMed]

56.

García-Gutiérrez MS, Navarrete F, Navarro G, Reyes-Resina I, Franco R, Lanciego JL, et al. Alterations in gene and protein expression of cannabinoid CB₂ and GPR55 receptors in the dorsolateral prefrontal cortex of suicide victims. Neurotherapeutics. 2018;15:796–806. [DOI] [PubMed] [PMC]

57.

Bioque M, García-Bueno B, Macdowell KS, Meseguer A, Saiz PA, Parellada M, et al. Peripheral endocannabinoid system dysregulation in first-episode psychosis. Neuropsychopharmacology. 2013;38:2568–77. [DOI] [PubMed] [PMC]

58.

Tong D, He S, Wang L, Jin L, Si P, Cheng X. Association of single-nucleotide polymorphisms in the cannabinoid receptor 2 gene with schizophrenia in the Han Chinese population. J Mol Neurosci. 2013;51:454–60. [DOI] [PubMed]

59.

Bae JS, Kim JY, Park BL, Kim JH, Kim B, Park CS, et al. Genetic association analysis of Cnr1 and Cnr2 polymorphisms with schizophrenia in a Korean population. Psychiatr Genet. 2014;24:225–9. [DOI] [PubMed]

60.

Ellenbroek BA, de Bruin NM, van Den Kroonenburg PT, van Luijtelaar EL, Cools AR. The effects of early maternal deprivation on auditory information processing in adult wistar rats. Biol Psychiatry. 2004;55:701–7. [DOI] [PubMed]

61.

Garner B, Wood SJ, Pantelis C, van den Buuse M. Early maternal deprivation reduces prepulse inhibition and impairs spatial learning ability in adulthood: no further effect of post-pubertal chronic corticosterone treatment. Behav Brain Res. 2007;176:323–32. [DOI] [PubMed]

62.

López-Gallardo M, Llorente R, Llorente-Berzal A, Marco EM, Prada C, Di Marzo V, et al. Neuronal and glial alterations in the cerebellar cortex of maternally deprived rats: gender differences and modulatory effects of two inhibitors of endocannabinoid inactivation. Dev Neurobiol. 2008;68:1429–40. [DOI] [PubMed]

63.

Llorente R, Llorente-Berzal A, Petrosino S, Marco EM, Guaza C, Prada C, et al. Gender-dependent cellular and biochemical effects of maternal deprivation on the hippocampus of neonatal rats: a possible role for the endocannabinoid system. Dev Neurobiol. 2008;68:1334–47. [DOI] [PubMed]

64.

Suárez J, Llorente R, Romero-Zerbo SY, Mateos B, Bermúdez-Silva FJ, de Fonseca FR, et al. Early maternal deprivation induces gender-dependent changes on the expression of hippocampal CB₁ and CB₂ cannabinoid receptors of neonatal rats. Hippocampus. 2009;19:623–32. [DOI] [PubMed]

65.

Errico F, Rossi S, Napolitano F, Catuogno V, Topo E, Fisone G, et al. D-aspartate prevents corticostriatal long-term depression and attenuates schizophrenia-like symptoms induced by amphetamine and MK-801. J Neurosci. 2008;28:10404–14. [DOI] [PubMed] [PMC]

66.

Gray L, McOmish CE, Scarr E, Dean B, Hannan AJ. Sensitivity to MK-801 in phospholipase C-beta1 knockout mice reveals a specific NMDA receptor deficit. Int J Neuropsychopharmacol. 2009;12:917–28. [DOI] [PubMed]

67.

Khella R, Short JL, Malone DT. CB₂ receptor agonism reverses MK-801-induced disruptions of prepulse inhibition in mice. Psychopharmacology (Berl). 2014;231:3071–87. [DOI] [PubMed]

68.

Gobira PH, Oliveira AC, Gomes JS, da Silveira VT, Asth L, Bastos JR, et al. Opposing roles of CB₁ and CB₂ cannabinoid receptors in the stimulant and rewarding effects of cocaine. Br J Pharmacol. 2019;176:1541–51. [DOI] [PubMed] [PMC]

69.

Xi ZX, Peng XQ, Li X, Song R, Zhang HY, Liu QR, et al. Brain cannabinoid CB₂ receptors modulate cocaine’s actions in mice. Nat Neurosci. 2011;14:1160–6. [DOI] [PubMed] [PMC]

70.

Kruk-Slomka M, Banaszkiewicz I, Biala G. The impact of CB₂ receptor ligands on the MK-801-induced hyperactivity in mice. Neurotox Res. 2017;31:410–20. [DOI] [PubMed] [PMC]

71.

García-Gutiérrez MS, Ortega-Álvaro A, Busquets-García A, Pérez-Ortiz JM, Caltana L, Ricatti MJ, et al. Synaptic plasticity alterations associated with memory impairment induced by deletion of CB₂ cannabinoid receptors. Neuropharmacology. 2013;73:388–96. [DOI] [PubMed]

72.

Foster DJ, Wilson JM, Remke DH, Mahmood MS, Uddin MJ, Wess J, et al. Antipsychotic-like effects of M4 positive allosteric modulators are mediated by CB₂ receptor-dependent inhibition of dopamine release. Neuron. 2016;91:1244–52. [DOI] [PubMed] [PMC]

73.

Minocci D, Massei J, Martino A, Milianti M, Piz L, Di Bello D, et al. Genetic association between bipolar disorder and 524A>C (Leu133Ile) polymorphism of Cnr2 gene, encoding for CB₂ cannabinoid receptor. J Affect Disord. 2011;134:427–30. [DOI] [PubMed]

74.

Atwood BK, Mackie K. CB₂: a cannabinoid receptor with an identity crisis. Br J Pharmacol. 2010;160:467–79. [DOI] [PubMed] [PMC]

75.

Thomas WG. Immunoprecipitation and phosphorylation of G protein-coupled receptors. Methods Mol Biol. 2009;552:359–71. [DOI] [PubMed]

76.

Stempel AV, Stumpf A, Zhang HY, Özdoğan T, Pannasch U, Theis AK, et al. Cannabinoid type 2 receptors mediate a cell type-specific plasticity in the hippocampus. Neuron. 2016;90:795–809. [DOI] [PubMed] [PMC]

77.

Li Y, Kim J. Distinct roles of neuronal and microglial CB₂ cannabinoid receptors in the mouse hippocampus. Neuroscience. 2017;363:11–25. [DOI] [PubMed]

78.

Navarrete F, Rodríguez-Arias M, Martín-García E, Navarro D, García-Gutiérrez MS, Aguilar MA, et al. Role of CB₂ cannabinoid receptors in the rewarding, reinforcing, and physical effects of nicotine. Neuropsychopharmacology. 2013;38:2515–24. [DOI] [PubMed] [PMC]

79.

Aracil-Fernández A, Trigo JM, García-Gutiérrez MS, Ortega-Álvaro A, Ternianov A, Navarro D, et al. Decreased cocaine motor sensitization and self-administration in mice overexpressing cannabinoid CB₂ receptors. Neuropsychopharmacology. 2012;37:1749–63. [DOI] [PubMed] [PMC]

80.

García MC, Cinquina V, Palomo-Garo C, Rábano A, Fernández-Ruiz J. Identification of CB₂ receptors in human nigral neurons that degenerate in Parkinson’s disease. Neurosci Lett. 2015;587:1–4. [DOI] [PubMed]

81.

Zhang HY, Gao M, Liu QR, Bi GH, Li X, Yang HJ, et al. Cannabinoid CB₂ receptors modulate midbrain dopamine neuronal activity and dopamine-related behavior in mice. Proc Natl Acad Sci U S A. 2014;111:E5007–15. [DOI] [PubMed] [PMC]

82.

Zhang HY, Gao M, Shen H, Bi GH, Yang HJ, Liu QR, et al. Expression of functional cannabinoid CB₂ receptor in VTA dopamine neurons in rats. Addict Biol. 2017;22:752–65. [DOI] [PubMed] [PMC]

83.

Núñez E, Benito C, Pazos MR, Barbachano A, Fajardo O, González S, et al. Cannabinoid CB₂ receptors are expressed by perivascular microglial cells in the human brain: an immunohistochemical study. Synapse. 2004;53:208–13. [DOI] [PubMed]

84.

Stella N. Cannabinoid and cannabinoid-like receptors in microglia, astrocytes, and astrocytomas. Glia. 2010;58:1017–30. [DOI] [PubMed] [PMC]

85.

Di Marzo V, Stella N, Zimmer A. Endocannabinoid signalling and the deteriorating brain. Nat Rev Neurosci. 2015;16:30–42. [DOI] [PubMed] [PMC]

86.

Fernández-Ruiz J, Moro MA, Martínez-Orgado J. Cannabinoids in neurodegenerative disorders and stroke/brain trauma: from preclinical models to clinical applications. Neurotherapeutics. 2015;12:793–806. [DOI] [PubMed] [PMC]

87.

Komorowska-Müller JA, Schmöle AC. CB₂ receptor in microglia: the guardian of self-control. Int J Mol Sci. 2020;22:19. [DOI]

88.

Tanaka M, Sackett S, Zhang Y. Endocannabinoid modulation of microglial phenotypes in neuropathology. Front Neurol. 2020;11:87. [DOI] [PubMed] [PMC]

89.

Aubry JM. CRF system and mood disorders. J Chem Neuroanat. 2013;54:20–4. [DOI] [PubMed]

90.

Timmermans W, Xiong H, Hoogenraad CC, Krugers HJ. Stress and excitatory synapses: from health to disease. Neuroscience. 2013;248:626–36. [DOI] [PubMed]

91.

Ziegler CG, Mohn C, Lamounier-Zepter V, Rettori V, Bornstein SR, Krug AW, et al. Expression and function of endocannabinoid receptors in the human adrenal cortex. Horm Metab Res. 2010;42:88–92. [DOI] [PubMed]

92.

Bhandari A, Voineskos D, Daskalakis ZJ, Rajji TK, Blumberger DM. A review of impaired neuroplasticity in schizophrenia investigated with non-invasive brain stimulation. Front Psychiatry. 2016;7:45. [DOI] [PubMed] [PMC]

93.

Vyas S, Rodrigues AJ, Silva JM, Tronche F, Almeida OF, Sousa N, et al. Chronic stress and glucocorticoids: from neuronal plasticity to neurodegeneration. Neural Plast. 2016;2016:6391686. [DOI] [PubMed] [PMC]

94.

Gerhard DM, Wohleb ES, Duman RS. Emerging treatment mechanisms for depression: focus on glutamate and synaptic plasticity. Drug Discov Today. 2016;21:454–64. [DOI] [PubMed] [PMC]

95.

Levy MJF, Boulle F, Steinbusch HW, van den Hove DLA, Kenis G, Lanfumey L. Neurotrophic factors and neuroplasticity pathways in the pathophysiology and treatment of depression. Psychopharmacology (Berl). 2018;235:2195–220. [DOI] [PubMed] [PMC]

96.

Toda T, Gage FH. Review: adult neurogenesis contributes to hippocampal plasticity. Cell Tissue Res. 2018;373:693–709. [DOI] [PubMed]

97.

Howlett AC. Cannabinoid receptor signaling. Handb Exp Pharmacol. 2005:53–79. [DOI] [PubMed]

98.

Cabral GA, Griffin-Thomas L. Emerging role of the cannabinoid receptor CB₂ in immune regulation: therapeutic prospects for neuroinflammation. Expert Rev Mol Med. 2009;11:e3. [DOI] [PubMed] [PMC]

99.

Köfalvi A, Lemos C, Martín-Moreno AM, Pinheiro BS, García-García L, Pozo MA, et al. Stimulation of brain glucose uptake by cannabinoid CB₂ receptors and its therapeutic potential in Alzheimer’s disease. Neuropharmacology. 2016;110:519–29. [DOI] [PubMed]

100.

Jayant S, Sharma BM, Bansal R, Sharma B. Pharmacological benefits ofselective modulation ofcannabinoid receptor type 2 (CB₂) in experimental Alzheimer’s disease. Pharmacol Biochem Behav. 2016;140:39–50. [DOI] [PubMed]

101.

Morgan NH, Stanford IM, Woodhall GL. Functional CB₂ type cannabinoid receptors at CNS synapses. Neuropharmacology. 2009;57:356–68. [DOI] [PubMed]

102.

Williams T, Hattingh CJ, Kariuki CM, Tromp SA, van Balkom AJ, Ipser JC, et al. Pharmacotherapy for social anxiety disorder (SAnD). Cochrane Database Syst Rev. 2017;10:CD001206. [DOI] [PubMed] [PMC]

103.

de Jonge JC, Vinkers CH, Hulshoff Pol HE, Marsman A. GABAergic mechanisms in schizophrenia: linking postmortem and in vivo studies. Front Psychiatry. 2017;8:118. [DOI] [PubMed] [PMC]

104.

Egerton A, Modinos G, Ferrera D, McGuire P. Neuroimaging studies of GABA in schizophrenia: a systematic review with meta-analysis. Transl Psychiatry. 2017;7:e1147. [DOI] [PubMed] [PMC]

105.

Sudol K, Mann JJ. Biomarkers of suicide attempt behavior: towards a biological model of risk. Curr Psychiatry Rep. 2017;19:31. [DOI] [PubMed]

106.

Lener MS, Niciu MJ, Ballard ED, Park M, Park LT, Nugent AC, et al. Glutamate and gamma-aminobutyric acid systems in the pathophysiology of major depression and antidepressant response to ketamine. Biol Psychiatry. 2017;81:886–97. [DOI] [PubMed] [PMC]

107.

Franklin JM, Carrasco GA. Cannabinoid receptor agonists upregulate and enhance serotonin 2A (5-HT_2A) receptor activity via ERK1/2 signaling. Synapse. 2013;67:145–59. [DOI] [PubMed] [PMC]

108.

Franklin JM, Vasiljevik T, Prisinzano TE, Carrasco GA. Cannabinoid agonists increase the interaction between beta-arrestin 2 and ERK1/2 and upregulate beta-arrestin 2 and 5-HT_2A receptors. Pharmacol Res. 2013;68:46–58. [DOI] [PubMed] [PMC]

109.

Spiera R, Hummers L, Chung L, Frech TM, Domsic R, Hsu V, et al. Safety and efficacy of lenabasum in a phase II, randomized, placebo-controlled trial in adults with systemic sclerosis. Arthritis Rheumatol. 2020;72:1350–60. [DOI] [PubMed] [PMC]

110.

Ostenfeld T, Price J, Albanese M, Bullman J, Guillard F, Meyer I, et al. A randomized, controlled study to investigate the analgesic efficacy of single doses of the cannabinoid receptor-2 agonist GW842166, ibuprofen or placebo in patients with acute pain following third molar tooth extraction. Clin J Pain. 2011;27:668–76. [DOI] [PubMed]