Skip to main content
SpringerLink
Log in

Fatty Acid Amide Hydrolase and Cannabinoid Receptor Type 1 Genes Regulation is Modulated by Social Isolation in Rats

  • Original Paper
  • Published:
Neurochemical Research Aims and scope Submit manuscript

Abstract

Social isolation is a state of lack of social connections, involving the modulation of different molecular signalling cascades and associated with high risk of mental health issues. To investigate if and how gene expression is modulated by social experience at the central level, we analyzed the effects of 5 weeks of social isolation in rats focusing on endocannabinoid system genes transcription in key brain regions involved in emotional control. We observed selective reduction in mRNA levels for fatty acid amide hydrolase (Faah) and cannabinoid receptor type 1 (Cnr1) genes in the amygdala complex and of Cnr1 in the prefrontal cortex of socially isolated rats when compared to controls, and these changes appear to be partially driven by trimethylation of Lysine 27 and acetylation of Lysine 9 at Histone 3. The alterations of Cnr1 transcriptional regulation result also directly correlated with those of oxytocin receptor gene. We here suggest that to counteract the effects of SI, it is of relevance to restore the endocannabinoid system homeostasis via the use of environmental triggers able to revert those epigenetic mechanisms accounting for the alterations observed.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Data Availability

Data can be provided from the corresponding author upon reasonable request.

References

  1. Umberson D, Montez JK (2010) Social relationships and health: a flashpoint for health policy. J Health Soc Behav 51(Suppl):S54-66. https://doi.org/10.1177/0022146510383501

    Article  PubMed  PubMed Central  Google Scholar 

  2. Shankar A, McMunn A, Banks J, Steptoe A (2011) Loneliness, social isolation, and behavioral and biological health indicators in older adults. Health Psychol 30:377–385. https://doi.org/10.1037/a0022826

    Article  PubMed  Google Scholar 

  3. Sterne JA, Hernán MA, Reeves BC et al (2016) ROBINS-I: a tool for assessing risk of bias in non-randomised studies of interventions. BMJ 355:i4919. https://doi.org/10.1136/bmj.i4919

    Article  PubMed  PubMed Central  Google Scholar 

  4. Yang YC, McClintock MK, Kozloski M, Li T (2013) Social isolation and adult mortality: the role of chronic inflammation and sex differences. J Health Soc Behav 54:183–203. https://doi.org/10.1177/0022146513485244

    Article  PubMed  PubMed Central  Google Scholar 

  5. National Academies of Sciences, Engineering, and Medicine (2020) Social isolation and loneliness in older adults. National Academies Press, Washington, DC

    Google Scholar 

  6. Robb CE, de Jager CA, Ahmadi-Abhari S et al (2020) Associations of social isolation with anxiety and depression during the early COVID-19 pandemic: a survey of older adults in London, UK. Front Psychiatry. https://doi.org/10.3389/fpsyt.2020.591120

    Article  PubMed  PubMed Central  Google Scholar 

  7. Santini ZI, Jose PE, York Cornwell E et al (2020) Social disconnectedness, perceived isolation, and symptoms of depression and anxiety among older Americans (NSHAP): a longitudinal mediation analysis. Lancet Public Health 5:e62–e70. https://doi.org/10.1016/S2468-2667(19)30230-0

    Article  PubMed  Google Scholar 

  8. Chen P, Hong W (2018) Neural circuit mechanisms of social behavior. Neuron 98:16–30. https://doi.org/10.1016/j.neuron.2018.02.026

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Cole SW, Hawkley LC, Arevalo JM et al (2007) Social regulation of gene expression in human leukocytes. Genome Biol 8:R189. https://doi.org/10.1186/gb-2007-8-9-r189

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Zayed A, Robinson GE (2012) Understanding the relationship between brain gene expression and social behavior: lessons from the honey bee. Annu Rev Genet 46:591–615. https://doi.org/10.1146/annurev-genet-110711-155517

    Article  CAS  PubMed  Google Scholar 

  11. Agrawal S, Dickinson ES, Sustar A et al (2020) Central processing of leg proprioception in Drosophila. Elife. https://doi.org/10.7554/eLife.60299

    Article  PubMed  PubMed Central  Google Scholar 

  12. Wallace DL, Han M-H, Graham DL et al (2009) CREB regulation of nucleus accumbens excitability mediates social isolation-induced behavioral deficits. Nat Neurosci 12:200–209. https://doi.org/10.1038/nn.2257

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Zelikowsky M, Hui M, Karigo T et al (2018) The neuropeptide Tac2 controls a distributed brain state induced by chronic social isolation stress. Cell 173:1265-1279.e19. https://doi.org/10.1016/j.cell.2018.03.037

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Arzate-Mejía RG, Lottenbach Z, Schindler V et al (2020) Long-term impact of social isolation and molecular underpinnings. Front Genet. https://doi.org/10.3389/fgene.2020.589621

    Article  PubMed  PubMed Central  Google Scholar 

  15. Bludau A, Royer M, Meister G et al (2019) Epigenetic regulation of the social brain. Trends Neurosci 42:471–484. https://doi.org/10.1016/j.tins.2019.04.001

    Article  CAS  PubMed  Google Scholar 

  16. Hwang J-Y, Aromolaran KA, Zukin RS (2017) The emerging field of epigenetics in neurodegeneration and neuroprotection. Nat Rev Neurosci 18:347–361. https://doi.org/10.1038/nrn.2017.46

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Nord AS, West AE (2020) Neurobiological functions of transcriptional enhancers. Nat Neurosci 23:5–14. https://doi.org/10.1038/s41593-019-0538-5

    Article  CAS  PubMed  Google Scholar 

  18. Seebacher F, Krause J (2019) Epigenetics of social behaviour. Trends Ecol Evol 34:818–830. https://doi.org/10.1016/j.tree.2019.04.017

    Article  PubMed  Google Scholar 

  19. Yao B, Christian KM, He C et al (2016) Epigenetic mechanisms in neurogenesis. Nat Rev Neurosci 17:537–549. https://doi.org/10.1038/nrn.2016.70

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Hilakivi LA, Ota M, Lister R (1989) Effect of isolation on brain monoamines and the behavior of mice in tests of exploration, locomotion, anxiety and behavioral ‘despair.’ Pharmacol Biochem Behav 33:371–374. https://doi.org/10.1016/0091-3057(89)90516-9

    Article  CAS  PubMed  Google Scholar 

  21. Weiss IC, Pryce CR, Jongen-Rêlo AL et al (2004) Effect of social isolation on stress-related behavioural and neuroendocrine state in the rat. Behav Brain Res 152:279–295. https://doi.org/10.1016/j.bbr.2003.10.015

    Article  CAS  PubMed  Google Scholar 

  22. Fone KCF, Porkess MV (2008) Behavioural and neurochemical effects of post-weaning social isolation in rodents—relevance to developmental neuropsychiatric disorders. Neurosci Biobehav Rev 32:1087–1102. https://doi.org/10.1016/j.neubiorev.2008.03.003

    Article  CAS  PubMed  Google Scholar 

  23. Haller J, Halász J (1999) Mild social stress abolishes the effects of isolation on anxiety and chlordiazepoxide reactivity. Psychopharmacology 144:311–315. https://doi.org/10.1007/s002130051012

    Article  CAS  PubMed  Google Scholar 

  24. Lukkes JL (2009) Consequences of post-weaning social isolation on anxiety behavior and related neural circuits in rodents. Front Behav Neurosci. https://doi.org/10.3389/neuro.08.018.2009

    Article  PubMed  PubMed Central  Google Scholar 

  25. Advani T, Hensler JG, Koek W (2007) Effect of early rearing conditions on alcohol drinking and 5-HT1A receptor function in C57BL/6J mice. Int J Neuropsychopharmacol. https://doi.org/10.1017/S1461145706007401

    Article  PubMed  Google Scholar 

  26. Hall F, Humby T, Wilkinson L, Robbins T (1997) The effects of isolation-rearing on sucrose consumption in rats. Physiol Behav 62:291–297. https://doi.org/10.1016/S0031-9384(97)00116-9

    Article  CAS  PubMed  Google Scholar 

  27. Howes SR, Dalley JW, Morrison CH et al (2000) Leftward shift in the acquisition of cocaine self-administration in isolation-reared rats: relationship to extracellular levels of dopamine, serotonin and glutamate in the nucleus accumbens and amygdala-striatal FOS expression. Psychopharmacology 151:55–63. https://doi.org/10.1007/s002130000451

    Article  CAS  PubMed  Google Scholar 

  28. Schubert MI, Porkess MV, Dashdorj N et al (2009) Effects of social isolation rearing on the limbic brain: a combined behavioral and magnetic resonance imaging volumetry study in rats. Neuroscience 159:21–30. https://doi.org/10.1016/j.neuroscience.2008.12.019

    Article  CAS  PubMed  Google Scholar 

  29. Varty GB, Braff DL, Geyer MA (1999) Is there a critical developmental ‘window’ for isolation rearing-induced changes in prepulse inhibition of the acoustic startle response? Behav Brain Res 100:177–183. https://doi.org/10.1016/S0166-4328(98)00129-6

    Article  CAS  PubMed  Google Scholar 

  30. Bowen MT, Neumann ID (2017) Rebalancing the addicted brain: oxytocin interference with the neural substrates of addiction. Trends Neurosci 40:691–708. https://doi.org/10.1016/j.tins.2017.10.003

    Article  CAS  PubMed  Google Scholar 

  31. Jurek B, Neumann ID (2018) The oxytocin receptor: from intracellular signaling to behavior. Physiol Rev 98:1805–1908. https://doi.org/10.1152/physrev.00031.2017

    Article  CAS  PubMed  Google Scholar 

  32. Leong K-C, Cox S, King C et al (2018) (2018) Oxytocin and rodent models of addiction. Int Rev Neurobiol 140:201–247

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Love TM (2014) Oxytocin, motivation and the role of dopamine. Pharmacol Biochem Behav 119:49–60. https://doi.org/10.1016/j.pbb.2013.06.011

    Article  CAS  PubMed  Google Scholar 

  34. Shamay-Tsoory SG, Abu-Akel A (2016) The social salience hypothesis of oxytocin. Biol Psychiatry 79:194–202. https://doi.org/10.1016/j.biopsych.2015.07.020

    Article  CAS  PubMed  Google Scholar 

  35. Vanderschuren LJMJ, Trezza V (2013) What the laboratory rat has taught us about social play behavior: role in behavioral development and neural mechanisms. Curr Top Behav Neurosci 16:189–212. https://doi.org/10.1007/7854_2013_268

    Article  Google Scholar 

  36. D’Addario C, Pucci M, Bellia F et al (2022) Regulation of oxytocin receptor gene expression in obsessive–compulsive disorder: a possible role for the microbiota-host epigenetic axis. Clin Epigenetics. https://doi.org/10.1186/s13148-022-01264-0

    Article  PubMed  PubMed Central  Google Scholar 

  37. Wei D, Lee DY, Cox CD et al (2015) Endocannabinoid signaling mediates oxytocin-driven social reward. Proc Natl Acad Sci U S A 112:14084–14089. https://doi.org/10.1073/pnas.1509795112

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Eisenstein SA, Holmes PV, Hohmann AG (2009) Endocannabinoid modulation of amphetamine sensitization is disrupted in a rodent model of lesion-induced dopamine dysregulation. Synapse 63:941–950. https://doi.org/10.1002/syn.20679

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. 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. https://doi.org/10.1097/00008877-200509000-00006

    Article  CAS  PubMed  Google Scholar 

  40. Stark T, Iannotti FA, Di Martino S et al (2022) Early blockade of CB1 receptors ameliorates schizophrenia-like alterations in the neurodevelopmental MAM model of schizophrenia biomolecules. Biomolecules 12:108. https://doi.org/10.3390/biom12010108

  41. Trezza V, Baarendse PJJ, Vanderschuren LJMJ (2010) The pleasures of play: pharmacological insights into social reward mechanisms. Trends Pharmacol Sci 31:463–469. https://doi.org/10.1016/j.tips.2010.06.008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Bergamaschi MM, Queiroz RHC, Chagas MHN et al (2014) Rimonabant effects on anxiety induced by simulated public speaking in healthy humans: a preliminary report. Hum Psychopharmacol Clin Exp 29:94–99. https://doi.org/10.1002/hup.2374

    Article  CAS  Google Scholar 

  43. Gunduz-Cinar O, Hill MN, McEwen BS, Holmes A (2013) Amygdala FAAH and anandamide: mediating protection and recovery from stress. Trends Pharmacol Sci 34:637–644. https://doi.org/10.1016/j.tips.2013.08.008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Bartel SJ, Sherry SB, Stewart SH (2020) Self-isolation: a significant contributor to Cannabis use during the Covid-19 pandemic. Subst Abus 41:409–412. https://doi.org/10.1080/08897077.2020.1823550

    Article  CAS  PubMed  Google Scholar 

  45. Stiles-Shields C, Archer J, Zhang J et al (2023) A scoping review of associations between Cannabis use and anxiety in adolescents and young adults. Child Psychiatry Hum Dev 54:639–658. https://doi.org/10.1007/s10578-021-01280-w

    Article  PubMed  Google Scholar 

  46. Jacobson MR, Watts JJ, Boileau I et al (2019) A systematic review of phytocannabinoid exposure on the endocannabinoid system: implications for psychosis. Eur Neuropsychopharmacol 29:330–348. https://doi.org/10.1016/j.euroneuro.2018.12.014

    Article  CAS  PubMed  Google Scholar 

  47. Maldonado R, Cabañero D, Martín-García E (2020) The endocannabinoid system in modulating fear, anxiety, and stress. Dialogues Clin Neurosci 22:229–239. https://doi.org/10.31887/DCNS.2020.22.3/rmaldonado

    Article  PubMed  PubMed Central  Google Scholar 

  48. Zovetti N, Rossetti MG, Perlini C et al (2021) Neuroimaging studies exploring the neural basis of social isolation. Epidemiol Psychiatr Sci 30:e29. https://doi.org/10.1017/S2045796021000135

    Article  PubMed  PubMed Central  Google Scholar 

  49. Cacioppo JT, Cacioppo S, Capitanio JP, Cole SW (2015) The neuroendocrinology of social isolation. Annu Rev Psychol 66:733–767. https://doi.org/10.1146/annurev-psych-010814-015240

    Article  PubMed  Google Scholar 

  50. Tan T, Wang W, Liu T et al (2021) Neural circuits and activity dynamics underlying sex-specific effects of chronic social isolation stress. Cell Rep 34:108874. https://doi.org/10.1016/j.celrep.2021.108874

    Article  CAS  PubMed  Google Scholar 

  51. Begni V, Sanson A, Pfeiffer N et al (2020) Social isolation in rats: effects on animal welfare and molecular markers for neuroplasticity. PLoS ONE 15:e0240439. https://doi.org/10.1371/journal.pone.0240439

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Meaney MJ (2010) Epigenetics and the biological definition of gene × environment interactions. Child Dev 81:41–79. https://doi.org/10.1111/j.1467-8624.2009.01381.x

    Article  PubMed  Google Scholar 

  53. Siuda D, Wu Z, Chen Y et al (2014) Social isolation-induced epigenetic changes in midbrain of adult mice. J Physiol Pharmacol 65:247–255

    CAS  PubMed  Google Scholar 

  54. Vanderschuren LJMJ, Achterberg EJM, Trezza V (2016) The neurobiology of social play and its rewarding value in rats. Neurosci Biobehav Rev 70:86–105. https://doi.org/10.1016/j.neubiorev.2016.07.025

    Article  PubMed  PubMed Central  Google Scholar 

  55. Baenninger LP (1967) Comparison of behavioural development in socially isolated and grouped rats. Anim Behav 15:312–323. https://doi.org/10.1016/0003-3472(67)90018-8

    Article  CAS  PubMed  Google Scholar 

  56. Panksepp J (1981) The ontogeny of play in rats. Dev Psychobiol 14:327–332. https://doi.org/10.1002/dev.420140405

    Article  CAS  PubMed  Google Scholar 

  57. Pellis SM, Pellis VC, Ham JR, Stark RA (2023) Play fighting and the development of the social brain: the rat’s tale. Neurosci Biobehav Rev 145:105037. https://doi.org/10.1016/j.neubiorev.2023.105037

    Article  PubMed  Google Scholar 

  58. Faul F, Erdfelder E, Lang A-G, Buchner A (2007) G*Power 3: a flexible statistical power analysis program for the social, behavioral, and biomedical sciences. Behav Res Methods 39:175–191. https://doi.org/10.3758/BF03193146

    Article  PubMed  Google Scholar 

  59. Kilkenny C, Browne W, Cuthill IC et al (2010) Animal research: reporting in vivo experiments: the ARRIVE guidelines. Br J Pharmacol 160:1577–1579. https://doi.org/10.1111/j.1476-5381.2010.00872.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Percie du Sert N, Hurst V, Ahluwalia A et al (2020) The ARRIVE guidelines 2.0: updated guidelines for reporting animal research. Br J Pharmacol 177:3617–3624. https://doi.org/10.1111/bph.15193

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Pucci M, Micioni Di Bonaventura MV, Vezzoli V et al (2019) Preclinical and clinical evidence for a distinct regulation of Mu opioid and Type 1 cannabinoid receptor genes expression in obesity. Front Genet. https://doi.org/10.3389/fgene.2019.00523

    Article  PubMed  PubMed Central  Google Scholar 

  62. Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2−ΔΔCT method. Methods 25:402–408. https://doi.org/10.1006/meth.2001.1262

    Article  CAS  PubMed  Google Scholar 

  63. D’Addario C, Bellia F, Benatti B et al (2019) Exploring the role of BDNF DNA methylation and hydroxymethylation in patients with obsessive compulsive disorder. J Psychiatr Res. https://doi.org/10.1016/j.jpsychires.2019.04.006

    Article  PubMed  Google Scholar 

  64. Li L-C, Dahiya R (2002) MethPrimer: designing primers for methylation PCRs. Bioinformatics 18(11):1427–1431. https://doi.org/10.1093/bioinformatics/18.11.1427

    Article  CAS  PubMed  Google Scholar 

  65. D’Addario C, Pucci M (2023) DNA methylation analysis of Cnr1 gene promoter. Methods Mol Biol 2576:373–384

    Article  PubMed  Google Scholar 

  66. Dahl JA, Collas P (2007) A quick and quantitative chromatin immunoprecipitation assay for small cell samples. Front Biosci 12:4925–4931. https://doi.org/10.2741/2438

    Article  CAS  PubMed  Google Scholar 

  67. Rozen S, Skaletsky H (2000) Primer3 on the WWW for general users and for biologist programmers. In: Bioinformatics methods and protocols. Humana Press, New Jersey, pp 365–386

  68. Ghashghaei HT, Hilgetag CC, Barbas H (2007) Sequence of information processing for emotions based on the anatomic dialogue between prefrontal cortex and amygdala. Neuroimage 34:905–923. https://doi.org/10.1016/j.neuroimage.2006.09.046

    Article  CAS  PubMed  Google Scholar 

  69. Banks SC, Piggott MP, Stow AJ, Taylor AC (2007) Sex and sociality in a disconnected world: a review of the impacts of habitat fragmentation on animal social interactions. Can J Zool 85:1065–1079. https://doi.org/10.1139/Z07-094

    Article  Google Scholar 

  70. Prater KE, Hosanagar A, Klumpp H et al (2013) ABERRANT AMYGDALA-FRONTAL CORTEX CONNECTIVITY DURING PERCEPTION OF FEARFUL FACES AND AT REST IN GENERALIZED SOCIAL ANXIETY DISORDER. Depress Anxiety 30:234–241. https://doi.org/10.1002/da.22014

    Article  PubMed  Google Scholar 

  71. Murray EA, Fellows LK (2022) Prefrontal cortex interactions with the amygdala in primates. Neuropsychopharmacology 47:163–179. https://doi.org/10.1038/s41386-021-01128-w

    Article  PubMed  Google Scholar 

  72. Packard K, Opendak M (2022) Rodent models of early adversity: impacts on developing social behavior circuitry and clinical implications. Front Behav Neurosci. https://doi.org/10.3389/fnbeh.2022.918862

    Article  PubMed  PubMed Central  Google Scholar 

  73. Davidson RJ, Pizzagalli D, Nitschke JB, Putnam K (2002) Depression: perspectives from affective neuroscience. Annu Rev Psychol 53:545–574. https://doi.org/10.1146/annurev.psych.53.100901.135148

    Article  PubMed  Google Scholar 

  74. Marcus DJ, Bedse G, Gaulden AD et al (2020) Endocannabinoid signaling collapse mediates stress-induced amygdalo-cortical strengthening. Neuron 105:1062-1076.e6. https://doi.org/10.1016/j.neuron.2019.12.024

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Howlett AC, Breivogel CS, Childers SR et al (2004) Cannabinoid physiology and pharmacology: 30 years of progress. Neuropharmacology 47:345–358. https://doi.org/10.1016/j.neuropharm.2004.07.030

    Article  CAS  PubMed  Google Scholar 

  76. Herkenham M, Lynn AB, Little MD et al (1990) Cannabinoid receptor localization in brain. Proc Natl Acad Sci USA 87:1932–1936. https://doi.org/10.1073/pnas.87.5.1932

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Achterberg EJM, van Swieten MMH, Driel NV et al (2016) Dissociating the role of endocannabinoids in the pleasurable and motivational properties of social play behaviour in rats. Pharmacol Res 110:151–158. https://doi.org/10.1016/j.phrs.2016.04.031

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Micale V, Di Marzo V, Sulcova A et al (2013) Endocannabinoid system and mood disorders: priming a target for new therapies. Pharmacol Ther 138:18–37. https://doi.org/10.1016/j.pharmthera.2012.12.002

    Article  CAS  PubMed  Google Scholar 

  79. Rubino T, Sala M, Viganò D et al (2007) Cellular mechanisms underlying the anxiolytic effect of low doses of peripheral δ9-tetrahydrocannabinol in rats. Neuropsychopharmacology 32:2036–2045. https://doi.org/10.1038/sj.npp.1301330

    Article  CAS  PubMed  Google Scholar 

  80. Rubino T, Realini N, Castiglioni C et al (2008) Role in anxiety behavior of the endocannabinoid system in the prefrontal cortex. Cereb Cortex 18:1292–1301. https://doi.org/10.1093/cercor/bhm161

    Article  CAS  PubMed  Google Scholar 

  81. Malone DT, Kearn CS, Chongue L et al (2008) Effect of social isolation on CB1 and D2 receptor and fatty acid amide hydrolase expression in rats. Neuroscience 152:265–272. https://doi.org/10.1016/j.neuroscience.2007.10.043

    Article  CAS  PubMed  Google Scholar 

  82. Tan Y, Singhal SM, Harden SW et al (2019) Oxytocin receptors are expressed by glutamatergic prefrontal cortical neurons that selectively modulate social recognition. J Neurosci 39:3249–3263. https://doi.org/10.1523/JNEUROSCI.2944-18.2019

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Wei D, Allsop S, Tye K, Piomelli D (2017) Endocannabinoid signaling in the control of social behavior. Trends Neurosci 40:385–396

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Arnsten AFT (2009) Stress signalling pathways that impair prefrontal cortex structure and function. Nat Rev Neurosci 10:410–422

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Blankman JL, Cravatt BF (2013) Chemical probes of endocannabinoid metabolism. Pharmacol Rev 65:849–871. https://doi.org/10.1124/pr.112.006387

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. 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. https://doi.org/10.1016/j.brainres.2010.04.031

    Article  CAS  PubMed  Google Scholar 

  87. Ceccarini J, Kuepper R, Kemels D et al (2015) [18F]MK-9470 PET measurement of cannabinoid CB 1 receptor availability in chronic cannabis users. Addict Biol 20:357–367. https://doi.org/10.1111/adb.12116

    Article  CAS  PubMed  Google Scholar 

  88. D’Souza DC, Cortes-Briones JA, Ranganathan M et al (2016) Rapid changes in Cannabinoid 1 receptor availability in Cannabis-dependent male subjects after abstinence from Cannabis. Biol Psychiatry Cogn Neurosci Neuroimaging 1:60–67. https://doi.org/10.1016/j.bpsc.2015.09.008

    Article  PubMed  PubMed Central  Google Scholar 

  89. Hirvonen J, Goodwin RS, Li C-T et al (2012) Reversible and regionally selective downregulation of brain cannabinoid CB1 receptors in chronic daily cannabis smokers. Mol Psychiatry 17:642–649. https://doi.org/10.1038/mp.2011.82

    Article  CAS  PubMed  Google Scholar 

  90. Spindle TR, Kuwabara H, Eversole A et al (2021) Brain imaging of cannabinoid type I (CB1) receptors in women with cannabis use disorder and male and female healthy controls. Addict Biol. https://doi.org/10.1111/adb.13061

    Article  PubMed  Google Scholar 

  91. Boileau I, Mansouri E, Williams B et al (2016) Fatty acid amide hydrolase binding in brain of cannabis users: imaging with the novel radiotracer [11C]CURB. Biol Psychiatry 80:691–701. https://doi.org/10.1016/j.biopsych.2016.04.012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Jacobson MR, Watts JJ, Da Silva T et al (2021) Fatty acid amide hydrolase is lower in young cannabis users. Addict Biol. https://doi.org/10.1111/adb.12872

    Article  PubMed  Google Scholar 

  93. Rhew IC, Cadigan JM, Lee CM (2021) Marijuana, but not alcohol, use frequency associated with greater loneliness, psychological distress, and less flourishing among young adults. Drug Alcohol Depend 218:108404. https://doi.org/10.1016/j.drugalcdep.2020.108404

    Article  PubMed  Google Scholar 

  94. Gulliver TL, Fowler K (2022) Exploring social context and psychological distress in adult Canadians with cannabis use disorder: to what extent do social isolation and negative relationships predict mental health? Psychiatr Q 93:311–323. https://doi.org/10.1007/s11126-021-09950-7

    Article  PubMed  Google Scholar 

  95. Patel RR, Patarino M, Kim K et al (2023) Social isolation recruits amygdala-cortical circuitry to escalate alcohol drinking. bioRxiv. https://doi.org/10.1101/2023.11.09.566421

    Article  PubMed  PubMed Central  Google Scholar 

  96. Huang H-S, Matevossian A, Whittle C et al (2007) prefrontal dysfunction in schizophrenia involves mixed-lineage leukemia 1-regulated histone methylation at GABAergic gene promoters. J Neurosci 27:11254–11262. https://doi.org/10.1523/JNEUROSCI.3272-07.2007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Yuan J, Jiang Q, Gong T et al (2021) Loss of grand histone H3 lysine 27 trimethylation domains mediated transcriptional activation in esophageal squamous cell carcinoma. NPJ Genom Med. https://doi.org/10.1038/s41525-021-00232-6

    Article  PubMed  PubMed Central  Google Scholar 

  98. Tsankova NM, Berton O, Renthal W et al (2006) Sustained hippocampal chromatin regulation in a mouse model of depression and antidepressant action. Nat Neurosci 9:519–525. https://doi.org/10.1038/nn1659

    Article  CAS  PubMed  Google Scholar 

  99. Hunter RG, McCarthy KJ, Milne TA et al (2009) Regulation of hippocampal H3 histone methylation by acute and chronic stress. Proc Natl Acad Sci USA 106:20912–20917. https://doi.org/10.1073/pnas.0911143106

    Article  PubMed  PubMed Central  Google Scholar 

  100. Ernst C, Chen ES, Turecki G (2009) Histone methylation and decreased expression of TrkB.T1 in orbital frontal cortex of suicide completers. Mol Psychiatry 14:830–832. https://doi.org/10.1038/mp.2009.35

    Article  CAS  PubMed  Google Scholar 

  101. Shogren-Knaak M, Ishii H, Sun J-M et al (1979) (2006) Histone H4–K16 acetylation controls chromatin structure and protein interactions. Science 311:844–847. https://doi.org/10.1126/science.1124000

    Article  CAS  Google Scholar 

  102. Viana Borges J, Souza de Freitas B, Antoniazzi V et al (2019) Social isolation and social support at adulthood affect epigenetic mechanisms, brain-derived neurotrophic factor levels and behavior of chronically stressed rats. Behav Brain Res 366:36–44. https://doi.org/10.1016/j.bbr.2019.03.025

    Article  PubMed  Google Scholar 

  103. Wu M-S, Li X-J, Liu C-Y et al (2022) Effects of histone modification in major depressive disorder. Curr Neuropharmacol 20:1261–1277. https://doi.org/10.2174/1570159X19666210922150043

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Brugnatelli V, Facco E, Zanette G (2021) Lifestyle interventions improving cannabinoid tone during COVID-19 lockdowns may enhance compliance with preventive regulations and decrease psychophysical health complications. Front Psychiatry. https://doi.org/10.3389/fpsyt.2021.565633

    Article  PubMed  PubMed Central  Google Scholar 

  105. Sedley L (2020) Advances in nutritional epigenetics—a fresh perspective for an old idea. Lessons learned, limitations, and future directions. Epigenet Insights 13:251686572098192. https://doi.org/10.1177/2516865720981924

    Article  Google Scholar 

  106. Davison JM, Mellott TJ, Kovacheva VP, Blusztajn JK (2009) gestational choline supply regulates methylation of histone H3, expression of histone methyltransferases G9a (Kmt1c) and Suv39h1 (Kmt1a), and DNA methylation of their genes in rat fetal liver and brain. J Biol Chem 284:1982–1989. https://doi.org/10.1074/jbc.M807651200

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Dobosy JR, Fu VX, Desotelle JA et al (2008) A methyl-deficient diet modifies histone methylation and alters Igf2 and H19 repression in the prostate. Prostate 68:1187–1195. https://doi.org/10.1002/pros.20782

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

This research was partially funded by the European Union—Next Generation EU. Project Code: ECS00000041; Project CUP: C43C22000380007; Project Title: Innovation, digitalization and sustainability for the diffused economy in Central Italy—VITALITY. The project was partly supported also by Rome Technopole, PNRR grant M4-C2-Inv. 1.5 CUP F83B22000040006 to VT. In particular, the behavioral experiments were funded by Rome Technopole.

Author information

Authors and Affiliations

  1. Department of Bioscience and Technology for Food, Agriculture and Environment, University of Teramo, Via Renato Balzarini, 1, 64100, Teramo, Italy

    Antonio Girella, Martina Di Bartolomeo, Enrico Dainese & Claudio D’Addario

  2. Department of Science, Roma Tre University, Rome, Italy

    Valeria Buzzelli & Viviana Trezza

  3. Neuroendocrinology, Metabolism and Neuropharmacology Unit, IRCSS Fondazione Santa Lucia, Rome, Italy

    Viviana Trezza

  4. Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden

    Claudio D’Addario

Authors
  1. Antonio Girella
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Martina Di Bartolomeo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Enrico Dainese
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Valeria Buzzelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Viviana Trezza
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Claudio D’Addario
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors contributed to the study conception and design. Conceptualization: Claudio D’Addario; methodology: Antonio Girella, Claudio D’Addario, Valeria Buzzelli, Viviana Trezza; formal analysis and investigation: Antonio Girella, Claudio D’Addario, Valeria Buzzelli, Viviana Trezza; writing—original draft preparation: Antonio Girella, Claudio D’Addario; funding acquisition: Claudio D’Addario, Enrico Dainese; Resources: Claudio D’Addario, Enrico Dainese, Viviana Trezza; supervision: Claudio D’Addario, Viviana Trezza, Martina Di Bartolomeo. All authors read and approved the final manuscript. We confirm that the manuscript has been read and approved by all named authors. We confirm that the order of authors listed in the manuscript has been approved by all named authors.

Corresponding author

Correspondence to Claudio D’Addario.

Ethics declarations

Conflict of interest

We wish to confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome.

Ethical Approval

We further confirm that any aspect of the work covered in this manuscript that has involved animal models has been conducted with the ethical approval of all relevant bodies and that such approvals are acknowledged within the manuscript.

Intellectual Property

We confirm that we have given due consideration to the protection of intellectual property associated with this work and that there are no impediments to publication, including the timing of publication, with respect to intellectual property. In so doing we confirm that we have followed the regulations of our institutions concerning intellectual property.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 357 KB)

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Girella, A., Di Bartolomeo, M., Dainese, E. et al. Fatty Acid Amide Hydrolase and Cannabinoid Receptor Type 1 Genes Regulation is Modulated by Social Isolation in Rats. Neurochem Res 49, 1278–1290 (2024). https://doi.org/10.1007/s11064-024-04117-9

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11064-024-04117-9

Keywords

Search

Navigation