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Endocannabinoids and Mental Disorders

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Endocannabinoids

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 231))

Abstract

Preclinical and clinical data fully support the involvement of the endocannabinoid system in the etiopathogenesis of several mental diseases. In this review we will briefly summarize the most common alterations in the endocannabinoid system, in terms of cannabinoid receptors and endocannabinoid levels, present in mood disorders (anxiety, posttraumatic stress disorder, depression, bipolar disorder, and suicidality) as well as psychosis (schizophrenia) and autism. The arising picture for each pathology is not always straightforward; however, both animal and human studies seem to suggest that pharmacological modulation of this system might represent a novel approach for treatment.

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Abbreviations

2-AG:

2-Arachidonoylglycerol

AEA:

Anandamide

CB1r:

Cannabinoid type 1 receptor(s)

CB2r:

Cannabinoid type 2 receptor(s)

CBD:

Cannabidiol

CNS:

Central nervous system

CSF:

Cerebrospinal fluid

DAGL:

Diacylglycerol lipase

dlPAG:

Dorsolateral periaqueductal gray

EC:

Endocannabinoid

ECS:

Endocannabinoid system

EPM:

Elevated plus-maze

FAAH:

Fatty acid amide hydrolase

HPA:

Hypothalamus–pituitary–adrenal

MAGL:

Monoacylglycerol lipase

NAc:

Nucleus accumbens

OEA:

Oleoylethanolamide

PCP:

Phencyclidine

PEA:

Palmitoylethanolamide

PET:

Positron emission tomography

PFC:

Prefrontal cortex

PPI:

Prepulse inhibition

PTSD:

Posttraumatic stress disorder

THC:

Delta-9-tetrahydrocannabinol

VPA:

Valproic acid

VTA:

Ventral tegmental area

References

  • Agrawal A, Nelson EC, Littlefield AK et al (2012) Cannabinoid receptor genotype moderation of the effects of childhood physical abuse on anhedonia and depression. Arch Gen Psychiatry 69:732–740

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Aguiar DC, Terzian AL, Guimarães FS et al (2009) Anxiolytic-like effects induced by blockade of transient receptor potential vanilloid type 1 (TRPV1) channels in the medial prefrontal cortex of rats. Psychopharmacology (Berl) 205:217–225

    Article  CAS  Google Scholar 

  • Akinshola BE, Chakrabarti A, Onaivi ES (1999) In-vitro and in-vivo action of cannabinoids. Neurochem Res 24:1233–1240

    Article  CAS  PubMed  Google Scholar 

  • Aliczki M, Balogh Z, Tulogdi A et al (2012) The temporal dynamics of the effects of monoacylglycerol lipase blockade on locomotion, anxiety, and body temperature. Behav Pharmacol 23:348–357

    Article  CAS  PubMed  Google Scholar 

  • Almeida V, Peres FF, Levin R et al (2014) Effects of cannabinoid and vanilloid drugs on positive and negative-like symptoms on an animal model of schizophrenia: the SHR strain. Schizophr Res 153:150–159

    Article  PubMed  Google Scholar 

  • Almeida-Santos AF, Gobira PH, Rosa LC et al (2013) Modulation of anxiety-like behavior by the endocannabinoid 2-arachidonoylglycerol (2-AG) in the dorsolateral periaqueductal gray. Behav Brain Res 252:10–17

    Article  CAS  PubMed  Google Scholar 

  • Arevalo C, De Miguel R, Hernandez-Tristan R (2001) Cannabinoid effects on anxiety-related behaviours and hypothalamic neurotransmitters. Pharmacol Biochem Behav 70:123–131

    Article  CAS  PubMed  Google Scholar 

  • Aso E, Ozaita A, Valdizán EM et al (2008) BDNF impairment in the hippocampus is related to enhanced despair behavior in CB1 knockout mice. J Neurochem 105:565–572

    Article  CAS  PubMed  Google Scholar 

  • Azad SC, Eder M, Marsicano G et al (2003) 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

    Article  PubMed Central  PubMed  Google Scholar 

  • Bagdy G, Juhasz G, Gonda X (2012) A new clinical evidence-based gene-environment interaction model of depression. Neuropsychopharmacol Hung 14:213–220

    PubMed  Google Scholar 

  • Beltramo M, de Fonseca FR, Navarro M et al (2000) Reversal of dopamine D(2) receptor responses by an anandamide transport inhibitor. J Neurosci 20:3401–3407

    CAS  PubMed  Google Scholar 

  • Beyer CE, Dwyer JM, Piesla MJ et al (2010) Depression-like phenotype following chronic CB1 receptor antagonism. Neurobiol Dis 39:148–155

    Article  CAS  PubMed  Google Scholar 

  • Bhattacharyya S, Morrison PD, Fusar-Poli P et al (2010) Opposite effects of delta-9-tetrahydrocannabinol and cannabidiol on human brain function and psychopathology. Neuropsychopharmacology 35:764–774

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Bilkei-Gorzo A, Racz I, Valverde O et al (2005) Early age-related cognitive impairment in mice lacking cannabinoid CB1 receptors. Proc Natl Acad Sci USA 102:15670–15675

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Black MD, Stevens RJ, Rogacki N et al (2011) AVE1625, a cannabinoid CB1 receptor antagonist, as a co-treatment with antipsychotics for schizophrenia: improvement in cognitive function and reduction of antipsychotic-side effects in rodents. Psychopharmacology (Berl) 215:149–163

    Article  CAS  Google Scholar 

  • Bluett RJ, Gamble-George JC, Hermanson DJ et al (2014) Central anandamide deficiency predicts stress-induced anxiety: behavioral reversal through endocannabinoid augmentation. Transl Psychiatry 4, e408

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Bortolato M, Campolongo P, Mangieri RA et al (2006) Anxiolytic-like properties of the anandamide transport inhibitor AM404. Neuropsychopharmacology 31:2652–2659

    Article  CAS  PubMed  Google Scholar 

  • Bortolato M, Mangieri RA, Fu J et al (2007) Antidepressant-like activity of the fatty acid amide hydrolase inhibitor URB597 in a rat model of chronic mild stress. Biol Psychiatry 62:1103–1110

    Article  CAS  PubMed  Google Scholar 

  • Bosi DC, Hallak JE, Dursun SM et al (2003) Effects of cannabidiol on (s)-ketamine-induced psychopathology in healthy volunteers. J Psychopharmacology 17:55

    Google Scholar 

  • Braida D, Limonta V, Malabarba L et al (2007) 5-HT1A receptors are involved in the anxiolytic effect of Delta9-tetrahydrocannabinol and AM 404, the anandamide transport inhibitor, in Sprague–Dawley rats. Eur J Pharmacol 555:156–163

    Article  CAS  PubMed  Google Scholar 

  • Burns HD, Van Laere K, Sanabria-Bohórquez S et al (2007) [18F]MK-9470, a positron emission tomography (PET) tracer for in vivo human PET brain imaging of the cannabinoid-1 receptor. Proc Natl Acad Sci USA 104:9800–9805

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Busquets-Garcia A, Puighermanal E, Pastor A et al (2011) Differential role of anandamide and 2-arachidonoylglycerol in memory and anxiety-like responses. Biol Psychiatry 70:479–486

    Article  CAS  PubMed  Google Scholar 

  • Cameron C, Watson D, Robinson J (2014) Use of a synthetic cannabinoid in a correctional population for posttraumatic stress disorder-related insomnia and nightmares, chronic pain, harm reduction, and other indications: a retrospective evaluation. J Clin Psychopharmacol 34:559–564

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Campos AC, Ferreira FR, Guimarães FS et al (2010) Facilitation of endocannabinoid effects in the ventral hippocampus modulates anxiety-like behaviors depending on previous stress experience. Neuroscience 167:238–246

    Article  CAS  PubMed  Google Scholar 

  • Ceccarini J, De Hert M, Van Winkel R et al (2013) Increased ventral striatal CB1 receptor binding is related to negative symptoms in drug-free patients with schizophrenia. Neuroimage 79:304–312

    Article  CAS  PubMed  Google Scholar 

  • Chavarría-Siles I, Contreras-Rojas J, Hare E et al (2008) Cannabinoid receptor 1 gene (CNR1) and susceptibility to a quantitative phenotype for hebephrenic schizophrenia. Am J Med Genet B Neuropsychiatr Genet 147:279–284

    Article  PubMed  CAS  Google Scholar 

  • Choi K, Le T, McGuire J et al (2012) Expression pattern of the cannabinoid receptor genes in the frontal cortex of mood disorder patients and mice selectively bred for high and low fear. J Psychiatr Res 46:882–889

    Article  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • Cornelius JR, Kirisci L, Reynolds M et al (2010) PTSD contributes to teen and young adult cannabis use disorders. Addict Behav 35:91–94

    Article  PubMed Central  PubMed  Google Scholar 

  • Dalton VS, Long LE, Weickert CS et al (2011) Paranoid schizophrenia is characterized by increased CB1 receptor binding in the dorsolateral prefrontal cortex. Neuropsychopharmacology 36:1620–1630

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • De Marchi N, De Petrocellis L, Orlando P et al (2003) Endocannabinoid signalling in the blood of patients with schizophrenia. Lipids Health Dis 19:2–5

    Google Scholar 

  • Dean B, Sundram S, Bradbury R et al (2001) Studies on [3H]CP-55940 binding in the human central nervous system: regional specific changes in density of cannabinoid-1 receptors associated with schizophrenia and cannabis use. Neuroscience 103:9–15

    Article  CAS  PubMed  Google Scholar 

  • Degroot A, Nomikos GG (2004) Genetic deletion and pharmacological blockade of CB1 receptors modulates anxiety in the shock-probe burying test. Eur J Neurosci 20:1059–1064

    Article  PubMed  Google Scholar 

  • Di Forti M, Morgan C, Dazzan P et al (2009) High-potency cannabis and the risk of psychosis. Br J Psychiatry 195:488–491

    Article  PubMed Central  PubMed  Google Scholar 

  • Dlugos A, Childs E, Stuhr KL et al (2012) Acute stress increases circulating anandamide and other N-acylethanolamines in healthy humans. Neuropsychopharmacology 37:2416–2427

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Domschke K, Dannlowski U, Ohrmann P et al (2008) Cannabinoid receptor 1 (CNR1) gene: impact on antidepressant treatment response and emotion processing in major depression. Eur Neuropsychopharmacol 18:751–759

    Article  CAS  PubMed  Google Scholar 

  • Dono LM, Currie PJ (2012) The cannabinoid receptor CB1 inverse agonist AM251 potentiates the anxiogenic activity of urocortin I in the basolateral amygdala. Neuropharmacology 62:192–199

    Article  CAS  PubMed  Google Scholar 

  • Dubreucq S, Matias I, Cardinal P et al (2012) Genetic dissection of the role of cannabinoid type-1 receptors in the emotional consequences of repeated social stress in mice. Neuropsychopharmacology 37:1885–1900

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Eggan SM, Hashimoto T, Lewis DA (2008) Reduced cortical cannabinoid 1 receptor messenger RNA and protein expression in schizophrenia. Arch Gen Psychiatry 65:772–784

    Article  PubMed Central  PubMed  Google Scholar 

  • Eggan SM, Stoyak SR, Verrico CD et al (2010) Cannabinoid CB1 receptor immunoreactivity in the prefrontal cortex: comparison of schizophrenia and major depressive disorder. Neuropsychopharmacology 35:2060–2071

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Englund A, Morrison PD, Nottage J et al (2013) Cannabidiol inhibits THC-elicited paranoid symptoms and hippocampal-dependent memory impairment. J Psychopharmacol 27:19–27

    Article  CAS  PubMed  Google Scholar 

  • Ferretjans R, de Campos SM, Ribeiro-Santos R et al (2014) Cognitive performance and peripheral endocannabinoid system receptor expression in schizophrenia. Schizophr Res 156:254–260

    Article  PubMed  Google Scholar 

  • Fraser GA (2009) The use of a synthetic cannabinoid in the management of treatment-resistant nightmares in posttraumatic stress disorder (PTSD). CNS Neurosci Ther 15:84–88

    Article  PubMed  Google Scholar 

  • Gamble-George JC, Conger JR, Hartley ND et al (2013) Dissociable effects of CB1 receptor blockade on anxiety-like and consummatory behaviors in the novelty-induced hypophagia test in mice. Psychopharmacology (Berl) 228:401–409

    Article  CAS  Google Scholar 

  • García-Gutiérrez MS, García-Bueno B, Zoppi S et al (2012) Chronic blockade of cannabinoid CB2 receptors induces anxiolytic-like actions associated with alterations in GABA(A) receptors. Br J Pharmacol 165:951–964

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Giuffrida A, Leweke FM, Gerth CW et al (2004) Cerebrospinal anandamide levels are elevated in acute schizophrenia and are inversely correlated with psychotic symptoms. Neuropsychopharmacology 29:2108–2114

    Article  CAS  PubMed  Google Scholar 

  • Gomes FV, Casarotto PC, Resstel LB et al (2011) Facilitation of CB1 receptor-mediated neurotransmission decreases marble burying behavior in mice. Prog Neuropsychopharmacol Biol Psychiatry 35:434–438

    Article  CAS  PubMed  Google Scholar 

  • Gorzalka BB, Hill MN (2011) Putative role of endocannabinoid signaling in the etiology of depression and actions of antidepressants. Prog Neuropsychopharmacol Biol Psychiatry 35:1575–1585

    Article  CAS  PubMed  Google Scholar 

  • Griebel G, Stemmelin J, Scatton B (2005) Effects of the cannabinoid CB1 receptor antagonist rimonabant in models of emotional reactivity in rodents. Biol Psychiatry 57:261–267

    Article  CAS  PubMed  Google Scholar 

  • Guidali C, Viganò D, Petrosino S et al (2011) Cannabinoid CB1 receptor antagonism prevents neurochemical and behavioural deficits induced by chronic phencyclidine. Int J Neuropsychopharmacol 14:17–28

    Article  CAS  PubMed  Google Scholar 

  • Gunduz-Cinar O, Hill MN, McEwen BS et al (2013a) FAAH and anandamide: mediating protection and recovery from stress. Trends Pharmacol Sci 34:637–644

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Gunduz-Cinar O, MacPherson KP, Cinar R et al (2013b) Convergent translational evidence of a role for anandamide in amygdala-mediated fear extinction, threat processing and stress-reactivity. Mol Psychiatry 18:813–823

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Haller J, Bakos N, Szirmay M et al (2002) The effects of genetic and pharmacological blockade of the CB1 cannabinoid receptor on anxiety. Eur J Neurosci 16:1395–1398

    Article  CAS  PubMed  Google Scholar 

  • Haller J, Varga B, Ledent C et al (2004) Context-dependent effects of CB1 cannabinoid gene disruption on anxiety-like and social behavior in mice. Eur J Neurosci 19:1906–1912

    Article  CAS  PubMed  Google Scholar 

  • Haller J, Szirmai M, Varga B et al (2005) Cannabinoid CB1 receptor dependent effects of the NMDA antagonist phencyclidine in the social withdrawal model of schizophrenia. Behav Pharmacol 16:415–422

    Article  CAS  PubMed  Google Scholar 

  • Haller J, Barna I, Barsvari B et al (2009) Interactions between environmental aversiveness and the anxiolytic effects of enhanced cannabinoid signaling by FAAH inhibition in rats. Psychopharmacology (Berl) 204:607–616

    Article  CAS  Google Scholar 

  • Hauer D, Schelling G, Gola H et al (2013) Plasma concentrations of endocannabinoids and related primary fatty acid amides in patients with post-traumatic stress disorder. PLoS One 8, e62741

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Hill MN, Gorzalka BB (2005) Is there a role for the endocannabinoid system in the etiology and treatment of melancholic depression? Behav Pharmacol 16:333–352

    Article  CAS  PubMed  Google Scholar 

  • Hill MN, Tasker JG (2012) Endocannabinoid signaling, glucocorticoid-mediated negative feedback, and regulation of the hypothalamic-pituitary-adrenal axis. Neuroscience 204:5–16

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Hill MN, Patel S, Carrier EJ et al (2005) Downregulation of endocannabinoid signaling in the hippocampus following chronic unpredictable stress. Neuropsychopharmacology 30:508–515

    Article  CAS  PubMed  Google Scholar 

  • Hill MN, Carrier EJ, McLaughlin RJ et al (2008) Regional alterations in the endocannabinoid system in an animal model of depression: effects of concurrent antidepressant treatment. J Neurochem 106:2322–2336

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Hill MN, Miller GE, Carrier EJ et al (2009) Circulating endocannabinoids and N-acyl ethanolamines are differentially regulated in major depression and following exposure to social stress. Psychoneuroendocrinology 34:1257–1262

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Hill MN, McLaughlin RJ, Pan B et al (2011) Recruitment of prefrontal cortical endocannabinoid signaling by glucocorticoids contributes to termination of the stress response. J Neurosci 31:10506–10515

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Hill MN, Bierer LM, Makotkine I et al (2013a) Reductions in circulating endocannabinoid levels in individuals with post-traumatic stress disorder following exposure to the World Trade Center attacks. Psychoneuroendocrinology 38:2952–2961

    Article  CAS  PubMed  Google Scholar 

  • Hill MN, Kumar SA, Filipski SB et al (2013b) Disruption of fatty acid amide hydrolase activity prevents the effects of chronic stress on anxiety and amygdalar microstructure. Mol Psychiatry 18:1125–1135

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Horder J, Harmer CJ, Cowen PJ et al (2010) Reduced neural response to reward following 7 days treatment with the cannabinoid CB1 antagonist rimonabant in healthy volunteers. Int J Neuropsychopharmacol 13:1103–1113

    Article  CAS  PubMed  Google Scholar 

  • Horti AG, Fan H, Kuwabara H et al (2006) 11C-JHU75528: a radiotracer for PET imaging of CB1 cannabinoid receptors. J Nucl Med 47:1689–1696

    CAS  PubMed  Google Scholar 

  • Huang YC, Wang SJ, Chiou LC et al (2003) Mediation of amphetamine-induced long-term depression of synaptic transmission by CB1 cannabinoid receptors in the rat amygdala. J Neurosci 23:10311–10320

    CAS  PubMed  Google Scholar 

  • Hungund BL, Vinod KY, Kassir SA et al (2004) Upregulation of CB1 receptors and agonist-stimulated [35S]GTPgammaS binding in the prefrontal cortex of depressed suicide victims. Mol Psychiatry 9:184–190

    Article  CAS  PubMed  Google Scholar 

  • Ishiguro H, Horiuchi Y, Ishikawa M et al (2010) Brain cannabinoid CB2 receptor in schizophrenia. Biol Psychiatry 67:974–982

    Article  CAS  PubMed  Google Scholar 

  • Jacob W, Yassouridis A, Marsicano G et al (2009) Endocannabinoids render exploratory behaviour largely independent of the test aversiveness: role of glutamatergic transmission. Genes Brain Behav 8:685–698

    Article  CAS  PubMed  Google Scholar 

  • John CS, Currie PJ (2012) N-arachidonoyl-serotonin in the basolateral amygdala increases anxiolytic behavior in the elevated plus maze. Behav Brain Res 233:382–388

    Article  CAS  PubMed  Google Scholar 

  • Juhasz G, Chase D, Pegg E et al (2009) CNR1 gene is associated with high neuroticism and low agreeableness and interacts with recent negative life events to predict current depressive symptoms. Neuropsychopharmacology 34:2019–2027

    Article  CAS  PubMed  Google Scholar 

  • Kamprath K, Marsicano G, Tang J et al (2006) Cannabinoid CB1 receptor mediates fear extinction via habituation-like processes. J Neurosci 26:6677–6686

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • Kasckow JW, Mulchahey JJ, Geracioti TD Jr (2004) Effects of the vanilloid agonist olvanil and antagonist capsazepine on rat behaviors. Prog Neuropsychopharmacol Biol Psychiatry 28:291–295

    Article  CAS  PubMed  Google Scholar 

  • Kathuria S, Gaetani S, Fegley D et al (2003) Modulation of anxiety through blockade of anandamide hydrolysis. Nat Med 9:76–81

    Article  CAS  PubMed  Google Scholar 

  • Kelly DL, Gorelick DA, Conley RR et al (2011) Effects of the cannabinoid-1 receptor antagonist rimonabant on psychiatric symptoms in overweight people with schizophrenia: a randomized, double-blind, pilot study. J Clin Psychopharmacol 31:86–91

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Kerr DM, Downey L, Conboy M et al (2013) Alterations in the endocannabinoid system in the rat valproic acid model of autism. Behav Brain Res 249:124–132

    Article  CAS  PubMed  Google Scholar 

  • Kinsey SG, O'Neal ST, Long JZ et al (2011) Inhibition of endocannabinoid catabolic enzymes elicits anxiolytic-like effects in the marble burying assay. Pharmacol Biochem Behav 98:21–27

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Kiritoshi T, Sun H, Ren W et al (2013) Modulation of pyramidal cell output in the medial prefrontal cortex by mGluR5 interacting with CB1. Neuropharmacology 66:170–178

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Koethe D, Llenos IC, Dulay JR et al (2007) Expression of CB1 cannabinoid receptor in the anterior cingulate cortex in schizophrenia, bipolar disorder, and major depression. J Neural Transm 114:1055–1063

    Article  CAS  PubMed  Google Scholar 

  • Koethe D, Giuffrida A, Schreiber D et al (2009) Anandamide elevation in cerebrospinal fluid in initial prodromal states of psychosis. Br J Psychiatry 194:371–372

    Article  PubMed  Google Scholar 

  • Levin R, Peres FF, Almeida V et al (2014) Effects of cannabinoid drugs on the deficit of prepulse inhibition of startle in an animal model of schizophrenia: the SHR strain. Front Pharmacol 5:10

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Leweke FM, Giuffrida A, Wurster U et al (1999) Elevated endogenous cannabinoids in schizophrenia. Neuroreport 10:1665–1669

    Article  CAS  PubMed  Google Scholar 

  • Leweke FM, Piomelli D, Pahlisch F et al (2012) Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia. Transl Psychiatry 2, e94

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Lin QS, Yang Q, Liu DD et al (2011) Hippocampal endocannabinoids play an important role in induction of long-term potentiation and regulation of contextual fear memory formation. Brain Res Bull 86:139–145

    Article  CAS  PubMed  Google Scholar 

  • Lisboa SF, Resstel LB, Aguiar DC et al (2008) Activation of cannabinoid CB1 receptors in the dorsolateral periaqueductal gray induces anxiolytic effects in rats submitted to the Vogel conflict test. Eur J Pharmacol 593:73–78

    Article  CAS  PubMed  Google Scholar 

  • Litvin Y, Phan A, Hill MN et al (2013) CB1 receptor signaling regulates social anxiety and memory. Genes Brain Behav 12:479–489

    Article  CAS  PubMed  Google Scholar 

  • Maccarrone M, Valverde O, Barbaccia ML et al (2002) Age-related changes of anandamide metabolism in CB1 cannabinoid receptor knockout mice: correlation with behaviour. Eur J Neurosci 15:1178–1186

    Article  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • Marsicano G, Wotjak CT, Azad SC et al (2002) The endogenous cannabinoid system controls extinction of aversive memories. Nature 418:530–534

    Article  CAS  PubMed  Google Scholar 

  • Martin M, Ledent C, Parmentier M et al (2002) Involvement of CB1 cannabinoid receptors in emotional behaviour. Psychopharmacology (Berl) 159:379–387

    Article  CAS  Google Scholar 

  • McLaughlin RJ, Hill MN, Dang SS et al (2013) Upregulation of CB1 receptor binding in the ventromedial prefrontal cortex promotes proactive stress-coping strategies following chronic stress exposure. Behav Brain Res 237:333–337

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Melis M, Perra S, Muntoni AL et al (2004) Prefrontal cortex stimulation induces 2-arachidonoyl-glycerol-mediated suppression of excitation in dopamine neurons. J Neurosci 24:10707–10715

    Article  CAS  PubMed  Google Scholar 

  • Meltzer HY, Arvanitis L, Bauer D et al (2004) Placebo-controlled evaluation of four novel compounds for the treatment of schizophrenia and schizoaffective disorder. Am J Psychiatry 161:975–984

    Article  PubMed  Google Scholar 

  • Meye FJ, Trezza V, Vanderschuren LJ et al (2013) Neutral antagonism at the cannabinoid 1 receptor: a safer treatment for obesity. Mol Psychiatry 18:1294–1301

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • Mikics E, Vas J, Aliczki M et al (2009) Interactions between the anxiogenic effects of CB1 gene disruption and 5-HT3 neurotransmission. Behav Pharmacol 20:265–272

    Article  CAS  PubMed  Google Scholar 

  • Minocci D, Massei J, Martino A et al (2011) Genetic association between bipolar disorder and 524A>C (Leu133Ile) polymorphism of CNR2 gene, encoding for CB2 cannabinoid receptor. J Affect Disord 134:427–430

    Article  CAS  PubMed  Google Scholar 

  • Mitchell PB, Morris MJ (2007) Depression and anxiety with rimonabant. Lancet 370(9600):1671–1672

    Article  PubMed  Google Scholar 

  • Mitjans M, Serretti A, Fabbri C et al (2013) Screening genetic variability at the CNR1 gene in both major depression etiology and clinical response to citalopram treatment. Psychopharmacology (Berl) 227:509–519

    Article  CAS  Google Scholar 

  • Moise AM, Eisenstein SA, Astarita G et al (2008) An endocannabinoid signaling system modulates anxiety-like behavior in male Syrian hamsters. Psychopharmacology (Berl) 200:333–346

    Article  CAS  Google Scholar 

  • Monteleone P, Bifulco M, Maina G et al (2010) Investigation of CNR1 and FAAH endocannabinoid gene polymorphisms in bipolar disorder and major depression. Pharmacol Res 61:400–404

    Article  CAS  PubMed  Google Scholar 

  • Moreira FA, Aguiar DC, Guimarães FS (2007) Anxiolytic-like effect of cannabinoids injected into the rat dorsolateral periaqueductal gray. Neuropharmacology 52:958–965

    Article  CAS  PubMed  Google Scholar 

  • Moreira FA, Kaiser N, Monory K et al (2008) Reduced anxiety-like behaviour induced by genetic and pharmacological inhibition of the endocannabinoid-degrading enzyme fatty acid amide hydrolase (FAAH) is mediated by CB1 receptors. Neuropharmacology 54:141–150

    Article  CAS  PubMed  Google Scholar 

  • Muguruza C, Lehtonen M, Aaltonen N et al (2013) Quantification of endocannabinoids in postmortem brain of schizophrenic subjects. Schizophr Res 148:145–150

    Article  PubMed  Google Scholar 

  • Naderi N, Haghparast A, Saber-Tehrani A et al (2008) Interaction between cannabinoid compounds and diazepam on anxiety-like behaviour of mice. Pharmacol Biochem Behav 89:64–75

    Article  CAS  PubMed  Google Scholar 

  • Naidu PS, Varvel SA, Ahn K et al (2007) Evaluation of fatty acid amide hydrolase inhibition in murine models of emotionality. Psychopharmacology (Berl) 192:61–70

    Article  CAS  Google Scholar 

  • Navarro M, Hernandez E, Munoz RM et al (1997) Acute administration of the CB1 cannabinoid receptor antagonist SR 141716A induces anxiety-like responses in the rat. Neuroreport 8:491–496

    Article  CAS  PubMed  Google Scholar 

  • Neumeister A, Normandin MD, Pietrzak RH et al (2013) Elevated brain cannabinoid CB1 receptor availability in post-traumatic stress disorder: a positron emission tomography study. Mol Psychiatry 18:1034–1040

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Newell KA, Deng C, Huang XF (2006) Increased cannabinoid receptor density in the posterior cingulate cortex in schizophrenia. Exp Brain Res 172:556–560

    Article  CAS  PubMed  Google Scholar 

  • O’Brien LD, Wills KL, Segsworth B et al (2013) Effect of chronic exposure to rimonabant and phytocannabinoids on anxiety-like behavior and saccharin palatability. Pharmacol Biochem Behav 103:597–602

    Article  PubMed  CAS  Google Scholar 

  • Onaivi ES, Ishiguro H, Gong JP et al (2008) Brain neuronal CB2 cannabinoid receptors in drug abuse and depression: from mice to human subjects. PLoS One 3, e1640

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Ortega-Alvaro A, Aracil-Fernández A, García-Gutiérrez MS et al (2011) Deletion of CB2 cannabinoid receptor induces schizophrenia-related behaviors in mice. Neuropsychopharmacology 36:1489–1504

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Parolaro D, Zamberletti E, Rubino T (2014) Cannabidiol/Phytocannabinoids: a new opportunity for schizophrenia treatment. In: Pertwee R (ed) Handbook of Cannabis. Oxford University Press edn, Oxford, pp 526–537

    Chapter  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • Perra S, Pillolla G, Luchicchi A et al (2008) Alcohol inhibits spontaneous activity of basolateral amygdala projection neurons in the rat: involvement of the endocannabinoid system. Alcohol Clin Exp Res 32:443–449

    Article  CAS  PubMed  Google Scholar 

  • Plendl W, Wotjak CT (2010) Dissociation of within- and between-session extinction of conditioned fear. J Neurosci 30:4990–4998

    Article  CAS  PubMed  Google Scholar 

  • Potvin S, Joyal CC, Pelletier J et al (2008) Contradictory cognitive capacities among substance-abusing patients with schizophrenia: a meta-analysis. Schizophr Res 100:242–251

    Article  PubMed  Google Scholar 

  • Realini N, Vigano’ D, Guidali C et al (2011) Chronic URB597 treatment at adulthood reverted most depressive-like symptoms induced by adolescent exposure to THC in female rats. Neuropharmacology 60:235–243

    Article  CAS  PubMed  Google Scholar 

  • Reich CG, Taylor ME, McCarthy MM (2009) Differential effects of chronic unpredictable stress on hippocampal CB1 receptors in male and female rats. Behav Brain Res 203:264–269

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Rey AA, Purrio M, Viveros MP et al (2012) Biphasic effects of cannabinoids in anxiety responses: CB1 and GABAB receptors in the balance of GABAergic and glutamatergic neurotransmission. Neuropsychopharmacology 37:2624–2634

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Robinson SA, Loiacono RE, Christopoulos A et al (2010) The effect of social isolation on rat brain expression of genes associated with endocannabinoid signaling. Brain Res 1343:153–167

    Article  CAS  PubMed  Google Scholar 

  • Rodgers RJ, Haller J, Halasz J et al (2003) ‘One-trial sensitization’ to the anxiolytic-like effects of cannabinoid receptor antagonist SR141716A in the mouse elevated plus-maze. Eur J Neurosci 17:1279–1286

    Article  CAS  PubMed  Google Scholar 

  • Rodgers RJ, Evans PM, Murphy A (2005) Anxiogenic profile of AM-251, a selective cannabinoid CB1 receptor antagonist, in plus-maze-naive and plus-maze-experienced mice. Behav Pharmacol 16:405–413

    Article  CAS  PubMed  Google Scholar 

  • Roohbakhsh A, Keshavarz S, Hasanein P et al (2009) Role of endocannabinoid system in the ventral hippocampus of rats in the modulation of anxiety-like behaviours. Basic Clin Pharmacol Toxicol 105:333–338

    Article  CAS  PubMed  Google Scholar 

  • Rubino T, Realini N, Castiglioni C et al (2008a) Role in anxiety behavior of the endocannabinoid system in the prefrontal cortex. Cereb Cortex 18:1292–1301

    Article  CAS  PubMed  Google Scholar 

  • Rubino T, Guidali C, Vigano D, Realini N, Valenti M, Massi P, Parolaro D. (2008b). CB1 receptor stimulation in specific brain areas differently modulate anxiety-related behaviour. Neuropharmacology 54, 151-160.

    Google Scholar 

  • Rubino T, Realini N, Braida D et al (2009) The depressive phenotype induced in adult female rats by adolescent exposure to THC is associated with cognitive impairment and altered neuroplasticity in the prefrontal cortex. Neurotox Res 15:291–302

    Article  CAS  PubMed  Google Scholar 

  • Rubio M, Fernandez-Ruiz J, De Miguel R et al (2008) CB1 receptor blockade reduces the anxiogenic-like response and ameliorates the neurochemical imbalances associated with alcohol withdrawal in rats. Neuropharmacology 54:976–988

    Article  CAS  PubMed  Google Scholar 

  • Ruehle S, Rey AA, Remmers F et al (2012) The endocannabinoid system in anxiety, fear memory and habituation. J Psychopharmacol 26:23–39

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Sanchis-Segura C, Cline BH, Marsicano G et al (2004) Reduced sensitivity to reward in CB1 knockout mice. Psychopharmacology (Berl) 176:223–232

    Article  CAS  Google Scholar 

  • Santos CJ, Stern CA, Bertoglio LJ (2008) Attenuation of anxiety-related behavior after the antagonism of transient receptor potential vanilloid type 1 channels in the rat ventral hippocampus. Behav Pharmacol 19:357–360

    Article  CAS  PubMed  Google Scholar 

  • Scherma M, Medalie J, Fratta W et al (2008) The endogenous cannabinoid anandamide has effects on motivation and anxiety that are revealed by fatty acid amide hydrolase (FAAH) inhibition. Neuropharmacology 54:129–140

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Schubart CD, Sommer IE, van Gastel WA et al (2011) Cannabis with high cannabidiol content is associated with fewer psychotic experiences. Schizophr Res 130:216–221

    Article  PubMed  Google Scholar 

  • Sciolino NR, Zhou W, Hohmann AG (2011) Enhancement of endocannabinoid signaling with JZL184, an inhibitor of the 2-arachidonoylglycerol hydrolyzing enzyme monoacylglycerol lipase, produces anxiolytic effects under conditions of high environmental aversiveness in rats. Pharmacol Res 64:226–234

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Seifert J, Ossege S, Emrich HM et al (2007) No association of CNR1 gene variations with susceptibility to schizophrenia. Neurosci Lett 426:29–33

    Article  CAS  PubMed  Google Scholar 

  • Seillier A, Advani T, Cassano T et al (2010) Inhibition of fatty-acid amide hydrolase and CB1 receptor antagonism differentially affect behavioural responses in normal and PCP-treated rats. Int J Neuropsychopharmacol 13:373–386

    Article  CAS  PubMed  Google Scholar 

  • Seillier A, Martinez AA, Giuffrida A (2013) Phencyclidine-induced social withdrawal results from deficient stimulation of cannabinoid CB1 receptors: implications for schizophrenia. Neuropsychopharmacology 38:1816–1824

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Shin LM, Liberzon I (2010) The neurocircuitry of fear, stress, and anxiety disorders. Neuropsychopharmacology 35:169–191

    Article  PubMed Central  PubMed  Google Scholar 

  • Sink KS, McLaughlin PJ, Wood JA et al (2008) The novel cannabinoid CB1 receptor neutral antagonist AM4113 suppresses food intake and food-reinforced behavior but does not induce signs of nausea in rats. Neuropsychopharmacology 33:946–955

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Sink KS, Segovia KN, Collins LE et al (2010a) The CB1 inverse agonist AM251, but not the CB1 antagonist AM4113, enhances retention of contextual fear conditioning in rats. Pharmacol Biochem Behav 95:479–484

    Article  CAS  PubMed  Google Scholar 

  • Sink KS, Segovia KN, Sink J et al (2010b) Potential anxiogenic effects of cannabinoid CB1 receptor antagonists/inverse agonists in rats: comparisons between AM4113, AM251, and the benzodiazepine inverse agonist FG-7142. Eur Neuropsychopharmacol 20:112–122

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Spano MS, Fadda P, Frau R et al (2010) Cannabinoid self-administration attenuates PCP-induced schizophrenia-like symptoms in adult rats. Eur Neuropsychopharmacol 20:25–36

    Article  CAS  PubMed  Google Scholar 

  • Steiner MA, Wanisch K, Monory K et al (2008) Impaired cannabinoid receptor type 1 signaling interferes with stress-coping behavior in mice. Pharmacogenomics J 8:196–208

    Article  CAS  PubMed  Google Scholar 

  • Terzian AL, Aguiar DC, Guimarães FS et al (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

    Article  CAS  PubMed  Google Scholar 

  • Thiemann G, Watt CA, Ledent C et al (2009) Modulation of anxiety by acute blockade and genetic deletion of the CB(1) cannabinoid receptor in mice together with biogenic amine changes in the forebrain. Behav Brain Res 200:60–67

    Article  CAS  PubMed  Google Scholar 

  • Trezza V, Campolongo P (2013) The endocannabinoid system as a possible target to treat both the cognitive and emotional features of post-traumatic stress disorder (PTSD). Front Behav Neurosci 7:100

    Article  PubMed Central  PubMed  Google Scholar 

  • Tsai SJ, Wang YC, Hong CJ (2000) Association study of a cannabinoid receptor gene (CNR1) polymorphism and schizophrenia. Psychiatr Genet 10:149–151

    Article  CAS  PubMed  Google Scholar 

  • Ujike H, Takaki M, Nakata K et al (2002) CNR1, central cannabinoid receptor gene, associated with susceptibility to hebephrenic schizophrenia. Mol Psychiatry 7:515–518

    Article  CAS  PubMed  Google Scholar 

  • Uriguen L, Perez-Rial S, Ledent C et al (2004) Impaired action of anxiolytic drugs in mice deficient in cannabinoid CB1 receptors. Neuropharmacology 46:966–973

    Article  CAS  PubMed  Google Scholar 

  • Uriguen L, García-Fuster MJ, Callado LF et al (2009) Immunodensity and mRNA expression of A2A adenosine, D2 dopamine, and CB1 cannabinoid receptors in postmortem frontal cortex of subjects with schizophrenia: effect of antipsychotic treatment. Psychopharmacology (Berl) 206:313–324

    Article  CAS  Google Scholar 

  • Varga B, Kassai F, Gyertyan I (2012) Interactions of CB1 and mGLU5 receptor antagonists in food intake, anxiety and memory models in rats. Pharmacol Biochem Behav 103:425–430

    Article  CAS  PubMed  Google Scholar 

  • Varvel SA, Lichtman AH (2002) Evaluation of CB1 receptor knockout mice in the Morris water maze. J Pharmacol Exp Ther 301:915–924

    Article  CAS  PubMed  Google Scholar 

  • Vetter S, Rossegger A, Rossler W et al (2008) Exposure to the tsunami disaster, PTSD symptoms and increased substance use - an Internet based survey of male and female residents of Switzerland. BMC Public Health 8:92

    Article  PubMed Central  PubMed  Google Scholar 

  • Viganò D, Guidali C, Petrosino S et al (2009) Involvement of the endocannabinoid system in phencyclidine-induced cognitive deficits modelling schizophrenia. Int J Neuropsychopharmacol 12:599–614

    Article  PubMed  CAS  Google Scholar 

  • Vinod KY, Kassir SA, Hungund BL et al (2010) Selective alterations of the CB1 receptors and the fatty acid amide hydrolase in the ventral striatum of alcoholics and suicides. J Psychiatr Res 44:591–597

    Article  PubMed Central  PubMed  Google Scholar 

  • Vinod KY, Xie S, Psychoyos D et al (2012) Dysfunction in fatty acid amide hydrolase is associated with depressive-like behavior in Wistar Kyoto rats. PLoS One 7, e36743

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Viveros M, Marco EM, File SE (2005) Endocannabinoid system and stress and anxiety responses. Pharmacol Biochem Behav 81:331–342

    Article  CAS  PubMed  Google Scholar 

  • Volk DW, Eggan SM, Horti AG et al (2014) Reciprocal alterations in cortical cannabinoid receptor 1 binding relative to protein immunoreactivity and transcript levels in schizophrenia. Schizophr Res 159:124–129

    Article  PubMed  PubMed Central  Google Scholar 

  • Wong DF, Kuwabara H, Horti AG et al (2010) Quantification of cerebral cannabinoid receptors subtype 1 (CB1) in healthy subjects and schizophrenia by the novel PET radioligand [11C]OMAR. Neuroimage 52:1505–1513

    Article  CAS  PubMed  Google Scholar 

  • Zamberletti E, Viganò D, Guidali C et al (2010) Long-lasting recovery of psychotic-like symptoms in isolation-reared rats after chronic but not acute treatment with the cannabinoid antagonist AM251. Int J Neuropsychopharmacol 15:267–280

    Article  PubMed  CAS  Google Scholar 

  • Zamberletti E, Piscitelli F, Cadeddu F et al (2012a) Chronic blockade of CB(1) receptors reverses startle gating deficits and associated neurochemical alterations in rats reared in isolation. Br J Pharmacol 167:1652–1664

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Zamberletti E, Rubino T, Parolaro D (2012b) The endocannabinoid system and schizophrenia: integration of evidence. Curr Pharm Des 18:4980–4990

    Article  CAS  PubMed  Google Scholar 

  • Zammit S, Spurlock G, Williams H et al (2007) Genotype effects of CHRNA7, CNR1 and COMT in schizophrenia: interactions with tobacco and cannabis use. Br J Psychiatry 191:402–407

    Article  PubMed  Google Scholar 

  • Zavitsanou K, Garrick T, Huang XF (2004) Selective antagonist [3H]SR141716A binding to cannabinoid CB1 receptors is increased in the anterior cingulate cortex in schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 28:355–360

    Article  CAS  PubMed  Google Scholar 

  • Zhong P, Wang W, Pan B et al (2014) Monoacylglycerol lipase inhibition blocks chronic stress-induced depressive-like behaviors via activation of mTOR signaling. Neuropsychopharmacology 39:1763–1776

    Article  PubMed Central  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Theoretical and Applied Sciences and Neuroscience Centre, University of Insubria, Via Manara 7, 21052, Busto Arsizio, VA, Italy

    TIziana Rubino, Erica Zamberletti & Daniela Parolaro

  2. Fondazione Zardi Gori, Milan, Italy

    Erica Zamberletti & Daniela Parolaro

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  1. TIziana Rubino
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  2. Erica Zamberletti
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  3. Daniela Parolaro
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Correspondence to Daniela Parolaro .

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  1. Professor of Neuropharmacology, University of Aberdeen Institute of Medical Sciences, Aberdeen, United Kingdom

    Roger G. Pertwee

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Rubino, T., Zamberletti, E., Parolaro, D. (2015). Endocannabinoids and Mental Disorders. In: Pertwee, R. (eds) Endocannabinoids. Handbook of Experimental Pharmacology, vol 231. Springer, Cham. https://doi.org/10.1007/978-3-319-20825-1_9

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