Schizophrenia and Depression, Two Poles of Endocannabinoid System Deregulation

Overview

Journal Transl Psychiatry

Specialties Psychiatry
Public Health

Date 2017 Dec 19

PMID 29249810

Citations 22

Authors

Maria Rodriguez-Munoz

Pilar Sanchez-Blazquez

Luis F Callado

J Javier Meana

Javier Garzon-Nino

Affiliations

Soon will be listed here.

Abstract

The activity of certain G protein-coupled receptors (GPCRs) and of glutamate N-Methyl-D-aspartate receptors (NMDARs) is altered in both schizophrenia and depression. Using postmortem prefrontal cortex samples from subjects with schizophrenia or depression, we observed a series of opposite changes in the expression of signaling proteins that have been implicated in the cross-talk between GPCRs and NMDARs. Thus, the levels of HINT1 proteins and NMDAR NR1 subunits carrying the C1 cytosolic segment were increased in depressives and decreased in schizophrenics, respect to matched controls. The differences in NR1 C1 subunits were compensated for via altered expression of NR1 subunits lacking the C1 segment; thus, the total number of NR1 subunits was comparable among the three groups. GPCRs influence the function of NR1 C1-containing NMDARs via PKC/Src, and thus, the association of mu-opioid and dopamine 2 receptors with NR1 C1 subunits was augmented in depressives and decreased in schizophrenics. However, the association of cannabinoid 1 receptors (CB1Rs) with NR1 C1 remained nearly constant. Endocannabinoids, via CB1Rs, control the presence of NR1 C1 subunits in the neural membrane. Thus, an altered endocannabinoid system may contribute to the pathophysiology of schizophrenia and depression by modifying the HINT1-NR1 C1/GPCR ratio, thereby altering GPCR-NMDAR cross-regulation.

Citing Articles

Cannabinoids: Role in Neurological Diseases and Psychiatric Disorders.

Kumar U Int J Mol Sci. 2025; 26(1.

PMID: 39796008 PMC: 11720483. DOI: 10.3390/ijms26010152.

Microglial morphological/inflammatory phenotypes and endocannabinoid signaling in a preclinical model of periodontitis and depression.

Robledo-Montana J, Diaz-Garcia C, Martinez M, Ambrosio N, Montero E, Marin M J Neuroinflammation. 2024; 21(1):219.

PMID: 39245706 PMC: 11382403. DOI: 10.1186/s12974-024-03213-5.

Endocannabinoid levels in plasma and neurotransmitters in the brain: a preliminary report on patients with a psychotic disorder and healthy individuals.

van Hooijdonk C, Balvers M, van der Pluijm M, Smith C, de Haan L, Schrantee A Psychol Med. 2024; 54(9):2189-2199.

PMID: 38389452 PMC: 11413354. DOI: 10.1017/S0033291724000291.

Circulating Endocannabinoids and N-Acylethanolamines in Individuals with Cannabis Use Disorder-Preliminary Findings.

Boachie N, Gaudette E, Bazinet R, Lin L, Tyndale R, Mansouri E Brain Sci. 2023; 13(10).

PMID: 37891745 PMC: 10605789. DOI: 10.3390/brainsci13101375.

DNA methylation and the opposing NMDAR dysfunction in schizophrenia and major depression disorders: a converging model for the therapeutic effects of psychedelic compounds in the treatment of psychiatric illness.

Flynn L, Gao W Mol Psychiatry. 2023; 28(11):4553-4567.

PMID: 37679470 PMC: 11034997. DOI: 10.1038/s41380-023-02235-4.

References

Perroy J, Raynaud F, Homburger V, Rousset M, Telley L, Bockaert J . Direct interaction enables cross-talk between ionotropic and group I metabotropic glutamate receptors. J Biol Chem. 2008; 283(11):6799-805. DOI: 10.1074/jbc.M705661200. View

Sanchez-Blazquez P, Rodriguez-Munoz M, Herrero-Labrador R, Burgueno J, Zamanillo D, Garzon J . The calcium-sensitive Sigma-1 receptor prevents cannabinoids from provoking glutamate NMDA receptor hypofunction: implications in antinociception and psychotic diseases. Int J Neuropsychopharmacol. 2014; 17(12):1943-55. DOI: 10.1017/S1461145714000029. View

Harrison P, Weinberger D . Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence. Mol Psychiatry. 2004; 10(1):40-68. DOI: 10.1038/sj.mp.4001558. View

Abi-Saab W, Seibyl J, DSouza D, Karper L, Gueorgueva R, Abi-Dargham A . Ritanserin antagonism of m-chlorophenylpiperazine effects in neuroleptic-free schizophrenics patients: support for serotonin-2 receptor modulation of schizophrenia symptoms. Psychopharmacology (Berl). 2002; 162(1):55-62. DOI: 10.1007/s00213-002-1057-7. View

Gorzalka B, Hill M . Putative role of endocannabinoid signaling in the etiology of depression and actions of antidepressants. Prog Neuropsychopharmacol Biol Psychiatry. 2010; 35(7):1575-85. DOI: 10.1016/j.pnpbp.2010.11.021. View

Catts V, Lai Y, Weickert C, Weickert T, Catts S . A quantitative review of the postmortem evidence for decreased cortical N-methyl-D-aspartate receptor expression levels in schizophrenia: How can we link molecular abnormalities to mismatch negativity deficits?. Biol Psychol. 2015; 116:57-67. DOI: 10.1016/j.biopsycho.2015.10.013. View

Pickel V, Chan J, Kearn C, Mackie K . Targeting dopamine D2 and cannabinoid-1 (CB1) receptors in rat nucleus accumbens. J Comp Neurol. 2006; 495(3):299-313. PMC: 1698281. DOI: 10.1002/cne.20881. View

De Marchi N, De Petrocellis L, Orlando P, Daniele F, Fezza F, Di Marzo V . Endocannabinoid signalling in the blood of patients with schizophrenia. Lipids Health Dis. 2003; 2:5. PMC: 194767. DOI: 10.1186/1476-511X-2-5. View

Rodriguez-Munoz M, Sanchez-Blazquez P, Herrero-Labrador R, Martinez-Murillo R, Merlos M, Vela J . The σ1 receptor engages the redox-regulated HINT1 protein to bring opioid analgesia under NMDA receptor negative control. Antioxid Redox Signal. 2015; 22(10):799-818. PMC: 4367239. DOI: 10.1089/ars.2014.5993. View

10.

Seifert J, Ossege S, Emrich H, Schneider U, Stuhrmann M . No association of CNR1 gene variations with susceptibility to schizophrenia. Neurosci Lett. 2007; 426(1):29-33. DOI: 10.1016/j.neulet.2007.08.008. View

11.

Liu Q, Bhat M, Bowen W, Cheng J . Signaling pathways from cannabinoid receptor-1 activation to inhibition of N-methyl-D-aspartic acid mediated calcium influx and neurotoxicity in dorsal root ganglion neurons. J Pharmacol Exp Ther. 2009; 331(3):1062-70. PMC: 2784707. DOI: 10.1124/jpet.109.156216. View

12.

Jiao H, Zhang L, Gao F, Lou D, Zhang J, Xu M . Dopamine D(1) and D(3) receptors oppositely regulate NMDA- and cocaine-induced MAPK signaling via NMDA receptor phosphorylation. J Neurochem. 2007; 103(2):840-8. DOI: 10.1111/j.1471-4159.2007.04840.x. View

13.

Rodriguez-Munoz M, Sanchez-Blazquez P, Vicente-Sanchez A, Berrocoso E, Garzon J . The mu-opioid receptor and the NMDA receptor associate in PAG neurons: implications in pain control. Neuropsychopharmacology. 2011; 37(2):338-49. PMC: 3242298. DOI: 10.1038/npp.2011.155. View

14.

Hohmann A, Briley E, Herkenham M . Pre- and postsynaptic distribution of cannabinoid and mu opioid receptors in rat spinal cord. Brain Res. 1999; 822(1-2):17-25. DOI: 10.1016/s0006-8993(98)01321-3. View

15.

Sanchez-Blazquez P, Rodriguez-Munoz M, Berrocoso E, Garzon J . The plasticity of the association between mu-opioid receptor and glutamate ionotropic receptor N in opioid analgesic tolerance and neuropathic pain. Eur J Pharmacol. 2013; 716(1-3):94-105. DOI: 10.1016/j.ejphar.2013.01.066. View

16.

Charney D . Monoamine dysfunction and the pathophysiology and treatment of depression. J Clin Psychiatry. 1998; 59 Suppl 14:11-4. View

17.

Rodriguez J, Mackie K, Pickel V . Ultrastructural localization of the CB1 cannabinoid receptor in mu-opioid receptor patches of the rat Caudate putamen nucleus. J Neurosci. 2001; 21(3):823-33. PMC: 6762333. View

18.

Shelton R, Sanders-Bush E, Manier D, Lewis D . Elevated 5-HT 2A receptors in postmortem prefrontal cortex in major depression is associated with reduced activity of protein kinase A. Neuroscience. 2008; 158(4):1406-15. PMC: 9208662. DOI: 10.1016/j.neuroscience.2008.11.036. View

19.

Yuen E, Jiang Q, Chen P, Gu Z, Feng J, Yan Z . Serotonin 5-HT1A receptors regulate NMDA receptor channels through a microtubule-dependent mechanism. J Neurosci. 2005; 25(23):5488-501. PMC: 6724987. DOI: 10.1523/JNEUROSCI.1187-05.2005. View

20.

Lu W, Xiong Z, Lei S, Orser B, Dudek E, Browning M . G-protein-coupled receptors act via protein kinase C and Src to regulate NMDA receptors. Nat Neurosci. 1999; 2(4):331-8. DOI: 10.1038/7243. View