Endocannabinoid Signaling in Autism

Neurotherapeutics

Volumn 12, Issue 4, 2015, Pages 837-847

  Chakrabarti, Bhismadev ^a   Persico, Antonio ^b,c   Battista, Natalia ^d   Maccarrone, Mauro ^b,e  

^a UNIVERSITY OF READING   (United Kingdom)

^b UNIVERSITY CAMPUS BIO MEDICO   (Italy)

^c Mafalda Luce Center for Pervasive Developmental Disorders   (Italy)

^d UNIVERSITY OF TERAMO   (Italy)

^e IRCCS FONDAZIONE SANTA LUCIA   (Italy)

Author keywords

Autism spectrum disorder; endocannabinoid system; fragile X syndrome; metabolic regulation; reward system

Indexed keywords

ENDOCANNABINOID;

AUTISM; CENTRAL NERVOUS SYSTEM; DEGENERATIVE DISEASE; DISEASE COURSE; FUNCTIONAL DISSOCIATION; HUMAN; INFORMATION PROCESSING; MEDICAL PROCEDURES; MENTAL DISEASE; NERVOUS SYSTEM INFLAMMATION; NEUROANATOMY; NONHUMAN; PRIORITY JOURNAL; REVIEW; REWARD; SIGNAL TRANSDUCTION; ANIMAL; AUTISTIC DISORDER; BRAIN; DRUG EFFECTS; METABOLISM; PATHOLOGY;

ANIMALS; AUTISTIC DISORDER; BRAIN; ENDOCANNABINOIDS; HUMANS; REWARD; SIGNAL TRANSDUCTION;

EID: 84973926590     PISSN: 19337213     EISSN: 18787479     Source Type: Journal    
DOI: 10.1007/s13311-015-0371-9     Document Type: Review

References (141)

1. Matsuda LA, Lolait SJ, Brownstein MJ, Young AC, Bonner TI. Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature 1990;346:561-564.
2. Pacher P, Kunos G. Modulating the endocannabinoid system in human health and disease-successes and failures. FEBS J 2013;280:1918-1943.
3. Maccarrone M, Guzman M, Mackie K, Doherty P, Harkany T. Programming and reprogramming neural cells by (endo-)cannabinoids: from physiological rules to emerging therapies. Nature Rev Neurosci 2014;15:786-801.
4. Maccarrone M, Bab I, Bíró T, et al. Endocannabinoid signaling at the periphery: 50 years after THC. Trends Pharmacol Sci 2015;36:277-296.
5. Maccarrone M, Dainese E, Oddi S. Intracellular trafficking of anandamide: new concepts for signaling. Trends Biochem Sci 2010;35:601-608.
6. Ueda N, Tsuboi K, Uyama T. Metabolism of endocannabinoids and related N-acylethanolamines: canonical and alternative pathways. FEBS J 2013;280:1874-1894.
7. Fezza F, Bari M, Florio R, Talamonti E, Feole M, Maccarrone M. Endocannabinoids, related compounds and their metabolic routes. Molecules 2014;19:17078-17106.
8. Okamoto Y, Morishita J, Tsuboi K, Tonai T, Ueda N. Molecular characterization of a phospholipase D generating anandamide and its congeners. J Biol Chem 2004;279:5298-5305.
9. Cravatt BF, Giang DK, Mayfield SP, Boger DL, Lerner RA, Gilula NB. Molecular characterization of an enzyme that degrades neuromodulatory fatty-acid amides. Nature 1996;384:83-87.
10. Wei BQ, Mikkelsen TS, McKinney MK, Lander ES, Cravatt BF. A second fatty acid amide hydrolase with variable distribution among placental mammals. J Biol Chem 2006;281:36569-36578.
11. Tsuboi K, Sun YX, Okamoto Y, Araki N, Tonai T, Ueda N. Molecular characterization of N-acylethanolamine-hydrolyzing acid amidase, a novel member of the choloylglycine hydrolase family with structural and functional similarity to acid ceramidase. J Biol Chem 2005;280:11082-11092.
12. Ueda N, Tsuboi K, Uyama T. N-acylethanolamine metabolism with special reference to N-acylethanolamine-hydrolyzing acid amidase (NAAA). Prog Lipid Res 2010;49:299-315.
13. Bisogno T, Howell F, Williams G, et al. Cloning of the first sn1-DAG lipases points to the spatial and temporal regulation of endocannabinoid signaling in the brain. J Cell Biol 2003;163:463-468.
14. Dinh TP, Freund TF, Piomelli D. A role for monoglyceride lipase in 2-arachidonoylglycerol inactivation. Chem Phys Lipids 2002;121:149-158.
15. Kozak KR, Crews BC, Morrow JD, et al. Metabolism of the endocannabinoids, 2-arachidonylglycerol and anandamide, into prostaglandin, thromboxane, and prostacyclin glycerol esters and ethanolamides. J Biol Chem 2002;277:44877-44885.
16. Kozak KR, Crews BC, Ray JL, Tai HH, Morrow JD, Marnett LJ. Metabolism of prostaglandin glycerol esters and prostaglandin ethanolamides in vitro and in vivo. J Biol Chem 2001;276:36993-36998.
17. Van der Stelt M, van Kuik JA, Bari M, et al. Oxygenated metabolites of anandamide and 2-arachidonoylglycerol: conformational analysis and interaction with cannabinoid receptors, membrane transporter, and fatty acid amide hydrolase. J Med Chem 2002;45:3709-3720.
18. Chen JK, Chen J, Imig JD, et al. Identification of novel endogenous cytochrome p450 arachidonate metabolites with high affinity for cannabinoid receptors. J Biol Chem 2008;283:24514-24524.
19. Fowler CJ. Anandamide uptake explained? Trends Pharmacol Sci 2012;33:181-185.
20. Fowler CJ. Transport of endocannabinoids across the plasma membrane and within the cell. FEBS J 2013;280:1895-1904.
21. Ehehalt R, Füllekrug J, Pohl J, Ring A, Herrmann T, Stremmel W. Translocation of long chain fatty acids across the plasma membrane – lipid rafts and fatty acid transport proteins. Mol Cell Biochem 2006;284:135-140.
22. Di Pasquale E, Chahinian H, Sanchez P, Fantini J. The insertion and transport of anandamide in synthetic lipid membranes are both cholesterol-dependent. PLoS One 2009;4:e4989.
23. Chicca A, Marazzi J, Nicolussi S, Gertsch J. Evidence for bidirectional endocannabinoid transport across cell membranes. J Biol Chem 2012;287:34660-34682.
24. Dainese E, Oddi S, Bari M, Maccarrone M. Modulation of the endocannabinoid system by lipid rafts. Curr Med Chem 2007;14:2702-2715.
25. Oddi S, Fezza F, Pasquariello N, et al. Evidence for the intracellular accumulation of anandamide in adiposomes. Cell Mol Life Sci 2008;65:840-850.
26. Maccarrone M, Bernardi G, Finazzi Agrò A, Centonze D. Cannabinoid receptor signalling in neurodegenerative diseases: a potential role for membrane fluidity disturbance. Br J Pharmacol 2011;163:1379-1390.
27. Di Marzo V, De Petrocellis L. Endocannabinoids as regulators of transient receptor potential (TRP) channels: a further opportunity to develop new endocannabinoid-based therapeutic drugs. Curr Med Chem 2010;17:1430-1449.
28. Zygmunt PM, Ermund A, Movahed P, et al. Monoacylglycerols activate TRPV1—a link between phospholipase C and TRPV1. PLoS One 2013;8:e81618.
29. Pistis M, Melis M. From surface to nuclear receptors: the endocannabinoid family extends its assets. Curr Med Chem 2010;17:1450-1467.
30. Moriconi A, Cerbara I, Maccarrone M, Topai A. GPR55: current knowledge and future perspectives of a purported “type-3” cannabinoid receptor. Curr Med Chem 2010;17:1411-1429.
31. Ross RA. L-α-lysophosphatidylinositol meets GPR55: a deadly relationship. Trends Pharmacol Sci 2011;32:265-269.
32. Di Marzo V, Stella N, Zimmer A. Endocannabinoid signalling and the deteriorating brain. Nat Rev Neurosci 2015;16:30-42.
33. Ben-Shabat S, Fride E, Sheskin T, et al. An entourage effect: inactive endogenous fatty acid glycerol esters enhance 2-arachidonoyl-glycerol cannabinoid activity. Eur J Pharmacol 1998;353:23-31.
34. Costa B, Comelli F, Bettoni I, Colleoni M, Giagnoni G. The endogenous fatty acid amide, palmitoylethanolamide, has anti-allodynic and anti-hyperalgesic effects in a murine model of neuropathic pain: involvement of CB(1), TRPV1 and PPARgamma receptors and neurotrophic factors. Pain 2008;139:541-550.
35. Ho WS, Barrett DA, Randall MD. “Entourage” effects of N-palmitoylethanolamine and N-oleoylethanolamine on vasorelaxation to anandamide occur through TRPV1 receptors. Br J Pharmacol 2008;155:837-846.
36. American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 5th ed. American Psychiatric Association, Arlington, VA, 2013.
37. Lord C, Rutter M, DiLavore PC, Risi S. ADOS, Autism Diagnostic Observation Schedule. Western Psychological Services, Los Angeles, CA, 2002.
38. Gotham K, Risi S, Pickles A, Lord C. The Autism Diagnostic Observation Schedule: revised algorithms for improved diagnostic validity. J Autism Dev Disord 2007;37:613-627.
39. Rutter M, Le Couter A, Lord C. ADI-R, Autism Diagnostic Interview-Revised. Western Psychological Services, Los Angeles, CA, 2003.
40. Persico AM. Autisms. In: Neural circuit development and function in the healthy and diseased brain: comprehensive developmental neuroscience, vol. 3 (Rakic P. and Rubenstein J, eds). Elsevier, New York, 2013, pp. 651-694.
41. Piven J, Palmer P, Jacobi D, Childress D, Arndt S. Broader autism phenotype: evidence from a family history study of multiple-incidence autism families. Am J Psychiatry 1997;154:185-190.
42. Baron-Cohen S, Wheelwright S, Skinner R, Martin J, Clubley E. The autism-spectrum quotient (AQ): evidence from Asperger syndrome/high-functioning autism, males and females, scientists and mathematicians. J Autism Dev Disord 2001;31:5-17.
43. Developmental Disabilities Monitoring Network Surveillance Year 2010 Principal Investigators; Centers for Disease Control and Prevention (CDC). Prevalence of autism spectrum disorder among children aged 8 years – autism and developmental disabilities monitoring network, 11 sites, United States, 2010. MMWR Surveill Summ 2014;63:1-21.
44. Ozonoff S, Young GS, Carter A, et al. Recurrence risk for autism spectrum disorders: a Baby Siblings Research Consortium study. Pediatrics 2011;128:e488-e495.
45. Elsabbagh M, Fernandes J, Jane Webb S, et al. Disengagement of visual attention in infancy is associated with emerging autism in toddlerhood. Biol Psychiatry 2013;74:189-194.
46. Chawarska K, Shic F, Macari S, et al. 18-month predictors of later outcomes in younger siblings of children with autism spectrum disorder: a baby siblings research consortium study. J Am Acad Child Adolesc Psychiatry 2014;53:1317-1327.
47. Gangi DN, Ibañez LV, Messinger DS. Joint attention initiation with and without positive affect: risk group differences and associations with ASD symptoms. J Autism Dev Disord 2014;44:1414-1424.
48. Gliga T, Jones EJ, Bedford R, Charman T, Johnson MH. From early markers to neuro-developmental mechanisms of autism. Dev Rev 2014;34:189-207.
49. Tuchman R, Rapin I. Epilepsy in autism. Lancet Neurol 2002;1:352-358.
50. Fombonne E. Epidemiology of autistic disorder and other pervasive developmental disorders. J Clin Psychiatry 2005;66:3-8.
51. Souders MC, Mason TB, Valladares O, et al. Sleep behaviors and sleep quality in children with autism spectrum disorders. Sleep 2009;32:1566-1578.
52. Tarazi F, Sahli Z, Pleskow J, Mousa S. Asperger’s syndrome: diagnosis, comorbidity and therapy. Expert Rev Neurother 2015;15:281-293.
53. Di Cicco-Bloom E, Lord C, Zwaigenbaum L, et al. The developmental neurobiology of autism spectrum disorder. J Neurosci 2006;26:6897-6906.
54. Amaral DG, Schumann CM, Nordahl CW. Neuroanatomy of autism. Trends Neurosci 2008; 31:137-145.
55. Blatt GJ. The neuropathology of autism. Scientifica 2012;2012:703675.
56. Bauman ML, Kemper TL. Neuroanatomic observations of the brain in autism: a review and future directions. Int J Dev Neurosci 2005;23:183-187.
57. Rice D, Barone S Jr. Critical periods of vulnerability for the developing nervous system: evidence from humans and animal models. Environ Health Perspect 2000;108(Suppl. 3):511-533.
58. Geschwind DH, Levitt P. Autism spectrum disorders: developmental disconnection syndromes. Curr Opin Neurobiol 2007;17:103-111.
59. Hahamy A, Behrmann M, Malach R. The idiosyncratic brain: distortion of spontaneous connectivity patterns in autism spectrum disorder. Nat Neurosci 2015;18:302-309.
60. Geschwind DH. Genetics of autism spectrum disorders. Trends Cogn Sci 2011;15:409-416.
61. Persico AM, Napolioni V. Autism genetics. Behav Brain Res 2013;251:95-112.
62. Persico AM, Merelli S. Environmental factors and autism spectrum disorder. Curr Dev Disord Rep 2014;1:8-19.
63. Tordjman S, Somogyi E, Coulon N, et al. Gene × environment interactions in autism spectrum disorders: role of epigenetic mechanisms. Front Psychiatry 2014;5:53.
64. Vargas DL, Nascimbene C, Krishnan C, Zimmerman AW, Pardo CA. Neuroglial activation and neuroinflammation in the brain of patients with autism. Ann Neurol 2005;57:67-81.
65. Garbett KA, Ebert PJ, Mitchell A, et al. Immune transcriptome alterations in the temporal cortex of subjects with autism. Neurobiol Dis 2008;30:303-311.
66. Lintas C, Sacco R, Persico AM. Genome-wide expression studies in Autism spectrum disorder, Rett syndrome, and Down syndrome. Neurobiol Dis 2012;45:57-68.
67. Sacco R, Curatolo P, Manzi B, et al. Principal pathogenetic components and biological endophenotypes in autism spectrum disorders. Autism Res 2010;3:237-252.
68. Fox E, Amaral D, Van de Water J. Maternal and fetal antibrain antibodies in development and disease. Dev Neurobiol 2012;72:1327-1334.
69. Onore C, Careaga M, Ashwood P. The role of immune dysfunction in the pathophysiology of autism. Brain Behav Immun 2012;26:383-392.
70. McElhanon BO, McCracken C, Karpen S, Sharp WG. Gastrointestinal symptoms in autism spectrum disorder: a meta-analysis. Pediatrics 2014;133:872-883.
71. Piras I, Haapanen L, Napolioni V, Sacco R, Van de Water J, Persico A. Anti-brain antibodies are associated with more severe cognitive and behavioural profiles in Italian children with Autism Spectrum Disorder. Brain Behav Immun 2014;38:91-99.
72. Chakrabarti B, Baron-Cohen S. Empathizing: neurocognitive developmental mechanisms and individual differences. Prog Brain Res 2006;156:403-417.
73. Chevallier C, Kohls G, Troiani V, Brodkin ES, Schultz RT. The social motivation theory of autism. Trends Cogn Sci 2012;16:231-239.
74. Sims TB, Van Reekum CM, Johnstone T, Chakrabarti B. How reward modulates mimicry: EMG evidence of greater facial mimicry of more rewarding happy faces. Psychophysiology 2012;49:998-1004.
75. Sims TB, Neufeld J, Johnstone T, Chakrabarti B. Autistic traits modulate frontostriatal connectivity during processing of rewarding faces. Soc Cogn Affect Neurosci 2014;9:2010201-2010206.
76. Dawson G, Carver L, Meltzoff AN, Panagiotides H, McPartland J, Webb SJ.Neural correlates of face and object recognition in young children with autism spectrum disorder, developmental delay, and typical development. Child Dev 2002;73:700-717.
77. Pierce K, Conant D, Hazin R, Stoner R, Desmond J. Preference for geometric patterns early in life as a risk factor for autism. Arch Gen Psychiatry 2011;68:101-109.
78. Schmitz N, Rubia K, van Amelsvoort T, Daly E, Smith A, Murphy DG. Neural correlates of reward in autism. Br J Psychiatry 2008;192:19-24.
79. Dichter GS, Richey JA, Rittenberg AM, Sabatino A, Bodfish JW. Reward circuitry function in autism during face anticipation and outcomes. J Autism Dev Disord 2012;42:147-160.
80. Kohls G, Schulte-Rüther M, Nehrkorn B, Reward system dysfunction in autism spectrum disorders. Soc Cogn Affect Neurosci 2013;8:565-572.
81. Demurie E, Roeyers H, Baeyens D, Sonuga-Barke E. Common alterations in sensitivity to type but not amount of reward in ADHD and autism spectrum disorders. J Child Psychol Psychiatry 2011;52:1164-1173.
82. Dawson G, Bernier R, Ring RH. Social attention: a possible early indicator of efficacy in autism clinical trials. J Neurodev Disord 2012;4:11.
83. Fletcher-Watson S, Leekam SR, Benson V, Frank MC, Findlay JM. Eye-movements reveal attention to social information in autism spectrum disorder. Neuropsychologia 2009;47:248-257.
84. Klin A, Jones W, Schultz R, Volkmar F, Cohen D. Visual fixation patterns during viewing of naturalistic social situations as predictors of social competence in individuals with autism. Arch Gen Psychiatry 2002;59:809-816.
85. Sasson NJ, Dichter GS, Bodfish JW. Affective responses by adults with autism are reduced to social images but elevated to images related to circumscribed interests. PLoS One 2012;7:e42457.
86. Krajbich I, Armel C, Rangel A. Visual fixations and the computation and comparison of value in simple choice. Nat Neurosci 2010;13:1292-1298.
87. Stavropoulos KK, Carver LJ. Effect of familiarity on reward anticipation in children with and without autism spectrum disorders. PLoS One 2014;9:e106667.
88. Richey JA, Rittenberg A, Hughes L, et al. Common and distinct neural features of social and non-social reward processing in autism and social anxiety disorder. Soc Cogn Affect Neurosci 2014;9:367-377.
89. Chakrabarti B, Bullmore E, Baron-Cohen S. Empathizing with basic emotions: common and discrete neural substrates. Soc Neurosci 2006;1:364-384.
90. Ruggeri B, Sarkans U, Schumann G, Persico AM. Biomarkers in autism spectrum disorder: the old and the new. Psychopharmacology 2014;231:1201-1216.
91. Vorstman JA, Spooren W, Persico AM, et al. Using genetic findings in autism for the development of new pharmaceutical compounds. Psychopharmacology 2014;231:1063-1078.
92. Battista N, Bari M, Tarditi A, et al. Severe deficiency of the fatty acid amide hydrolase (FAAH) activity segregates with the Huntington's disease mutation in peripheral lymphocytes. Neurobiol Dis 2007;27:108-116.
93. Centonze D, Battistini L, Maccarrone M. The endocannabinoid system in peripheral lymphocytes as a mirror of neuroinflammatory diseases. Curr Pharm Des 2008;14:2370-2382.
94. Marco EM, Scattoni ML, Rapino C, et al. Emotional, endocrine and brain anandamide response to social challenge in infant male rats. Psychoneuroendocrinology 2013;38:2152-2162.
95. Sciolino NR, Bortolato M, Eisenstein SA, et al. Social isolation and chronic handling alter endocannabinoid signaling and behavioral reactivity to context in adult rats. Neuroscience 2010;168:371-386.
96. Marco EM, Rapino C, Caprioli A, Borsini F, Maccarrone M, Laviola G. Social encounter with a novel partner in adolescent rats: activation of the central endocannabinoid system. Behav Brain Res 2011;220:140-145.
97. Bagni C, Tassone F, Neri G, Hagerman R. Fragile X syndrome: causes, diagnosis, mechanisms, and therapeutics. J Clin Invest 2012;122:4314-4322.
98. Ludwig AL, Espinal GM, Pretto DI, et al. CNS expression of murine fragile X protein (FMRP) as a function of CGG-repeat size. Hum Mol Genet 2014;23:3228-3238.
99. Gürkan CK, Hagerman RJ. Targeted treatments in autism and Fragile X syndrome. Res Autism Spectr Disord 2012;6:1311-1320.
100. Maccarrone M, Rossi S, Bari M, et al. Abnormal mGlu 5 receptor/endocannabinoid coupling in mice lacking FMRP and BC1 RNA. Neuropsychopharmacology. 2010;35:1500-1509.
101. Jung KM, Sepers M, Henstridge CM, et al. Uncoupling of the endocannabinoid signalling complex in a mouse model of fragile X syndrome. Nat Commun 2012;3:1080.
102. Busquets-Garcia A, Gomis-González M, Guegan T, et al. Targeting the endocannabinoid system in the treatment of fragile X syndrome. Nat Med 2013;19:603-607.
103. Schultz ST. Can autism be triggered by acetaminophen activation of the endocannabinoid system? Acta Neurobiol Exp (Wars) 2010;70:227-231.
104. Kerr DM, Downey L, Conboy M, Finn DP, Roche M. Alterations in the endocannabinoid system in the rat valproic acid model of autism. Behav Brain Res 2013;249:124-132.
105. Liu QR, Pan CH, Hishimoto A, et al. Species differences in cannabinoid receptor 2 (CNR2 gene): identification of novel human and rodent CB2 isoforms, differential tissue expression and regulation by cannabinoid receptor ligands. Genes Brain Behav 2009;8:519-530.
106. Onaivi ES, Benno R, Halpern T, et al. Consequences of cannabinoid and monoaminergic system disruption in a mouse model of autism spectrum disorders. Curr Neuropharmacol 2011;9:209-214.
107. Siniscalco D, Sapone A, Giordano C, et al. Cannabinoid receptor type 2, but not type 1, is up-regulated in peripheral blood mononuclear cells of children affected by autistic disorders. J Autism Dev Disord 2013;43:2686-2695.
108. Depino AM. Peripheral and central inflammation in autism spectrum disorders. Mol Cell Neurosci 2013;53:69-76.
109. 2 receptors in immune-related diseases. Curr Mol Pharmacol 2013;6:183-203.
110. Rom S, Persidsky Y. Cannabinoid receptor 2: potential role in immunomodulation and neuroinflammation. J Neuroimmune Pharmacol 2013;8:608-620.
111. Chiurchiù V, Battistini L, Maccarrone M. Endocannabinoid signaling in innate and adaptive immunity. Immunol 2015;144:352-364.
112. Cencioni MT, Chiurchiù V, Catanzaro G, et al. Anandamide suppresses proliferation and cytokine release from primary human T-lymphocytes mainly via CB2 receptors. PLoS One 2010;5:e8688.
113. Brown I, Cascio MG, Rotondo D, Pertwee RG, Heys SD, Wahle KW. Cannabinoids and omega-3/6 endocannabinoids as cell death and anticancer modulators. Prog Lipid Res 2013;52:80-109.
114. Das U. Autism as a disorder of deficiency of brain-derived neurotrophic factor and altered metabolism of polyunsaturated fatty acids. Nutrition 2013;29:1175-1185.
115. Van der Stelt M, Di Marzo V. The endocannabinoid system in the basal ganglia and in the mesolimbic reward system: implications for neurological and psychiatric disorders. Eur J Pharmacol 2003;480:133-150.
116. Chakrabarti B, Kent L, Suckling J, Bullmore E, Baron-Cohen S. Variations in the human cannabinoid receptor (CNR1) gene modulate striatal responses to happy faces. Eur J Neurosci 2006;23:1944-1948.
117. Domschke K, Dannlowski U, Ohrmann P, et al. Cannabinoid receptor 1 (CNR1) gene: impact on antidepressant treatment response and emotion processing in major depression. Eur Neuropsychopharmacol 2008;18:751-759.
118. Chakrabarti B, Baron-Cohen S. Variation in the human cannabinoid receptor CNR1 gene modulates gaze duration for happy faces. Mol Autism 2011;2:10.
119. Chakrabarti B, Dudbridge F, Kent L, et al. Genes related to sex steroids, neural growth, and social–emotional behavior are associated with autistic traits, empathy, and Asperger syndrome. Autism Res 2009;2:157-177.
120. Baron-Cohen S, Wheelwright S. The empathy quotient: an investigation of adults with Asperger syndrome or high functioning autism, and normal sex differences. J Autism Dev Disord 2004;34:163-175.
121. Purcell AE, Jeon OH, Zimmerman AW, Blue ME, Pevsner J. Postmortem brain abnormalities of the glutamate neurotransmitter system in autism. Neurol 2001;57:1618-1628.
122. Trezza V, Vanderschuren LJ. Bidirectional cannabinoid modulation of social behavior in adolescent rats. Psychopharmacol 2008;197:217-227.
123. Trezza V, Baarendse PJ, Vanderschuren LJ. The pleasures of play: pharmacological insights into social reward mechanisms. Trends Pharmacol Sci 2010;31:463-469.
124. Maccarrone M, Guzmán M, Mackie K, Doherty P, Harkany T. Programming of neural cells by (endo)cannabinoids: from physiological rules to emerging therapies. Nat Rev Neurosci 2014;15:786-801.
125. Belmonte MK, Allen G, Beckel-Mitchener A, Boulanger LM, Carper RA, Webb SJ. Autism and abnormal development of brain connectivity. J Neurosci 2004;24:9228-9231.
126. Persico AM, Bourgeron T. Searching for ways out of the autism maze: genetic, epigenetic and environmental clues. Trends Neurosci 2006;29:349-358.
127. Spooren W, Lindemann L, Ghosh A, Santarelli L. Synapse dysfunction in autism: a molecular medicine approach to drug discovery in neurodevelopmental disorders. Trends Pharmacol Sci 2012;33:669-684.
128. Tsai NP, Wilkerson JR, Guo W, et al. Multiple autism-linked genes mediate synapse elimination via proteasomal degradation of a synaptic scaffold PSD-95. Cell 2012;151:1581-1594.
129. Bourgeron T. A synaptic trek to autism. Current Opin Neurobiol 2009;19:231-234.
130. Jaramillo TC, Liu S, Pettersen A, Birnbaum SG, Powell CM. Autism-related neuroligin-3 mutation alters social behavior and spatial learning. Autism Res 2014;7:264-272.
131. Földy C, Malenka RC, Südhof TC. Autism-associated neuroligin-3 mutations commonly disrupt tonic endocannabinoid signaling. Neuron 2013;78:498-509.
132. Cota D, Steiner MA, Marsicano G, et al. Requirement of cannabinoid receptor type 1 for the basal modulation of hypothalamic-pituitary-adrenal axis function. Endocrinol 2007;148:1574-1581.
133. Atkinson HC, Leggett JD, Wood SA, Castrique ES, Kershaw YM, Lightman SL. Regulation of the hypothalamic-pituitary-adrenal axis circadian rhythm by endocannabinoids is sexually diergic. Endocrinol 2010;15:3720-3727.
134. Vaughn LK, Denning G, Stuhr KL, de Wit H, Hill MN, Hillard CJ. Endocannabinoid signalling: has it got rhythm? Br J Pharmacol 2010;160:530-543.
135. Glickman G. Circadian rhythms and sleep in children with autism. Neurosci Biobehav Rev 2010;34:755-768.
136. Melke J, Goubran Botros H, Chaste P. Abnormal melatonin synthesis in autism spectrum disorders. Mol Psychiat 2008;13:90-98.
137. Campos AC, Guimarães FS.Involvement of 5HT1A receptors in the anxiolytic-like effects of cannabidiol injected into the dorsolateral periaqueductal gray of rats. Psychopharmacology 2008;199:223-230.
138. Rubino T, Guidali C, Vigano D, et al. CB1 receptor stimulation in specific brain areas differently modulate anxiety-related behaviour. Neuropharmacol 2008;54:151-160.
139. Katona I, Freund TF. Endocannabinoid signaling as a synaptic circuit breaker in neurological disease. Nat Med 2008;14:923-930.
140. Sasso O, Migliore M, Habrant D, et al. Multitarget fatty acid amide hydrolase/cyclooxygenase blockade suppresses intestinal inflammation and protects against nonsteroidal anti-inflammatory drug dependent gastrointestinal damage. FASEB J 2015;29:2616-2627.
141. Arosio B, D’Addario C, Gussago C, et al. Peripheral blood mononuclear cells (PBMCs) as a laboratory to study dementia in the elderly. BioMed Res Int 2014;2014:169203.