, Volume 51, Issue 2, pp 72–76 | Cite as

Effects of a Gut Microbiome Toxin, p-Cresol, on the Contents of the NMDA2B Receptor Subunit in the Nucl. Accumbens of Rats

  • G. Tevzadze
  • E. Zhuravliova
  • M. Meparishvili
  • T. Lortkipanidze
  • L. Shanshiashvili
  • Z. Kikvidze
  • D. MikeladzeEmail author

The effects of p-cresol on the levels of subunit 2RB of NMDA receptors and also of AMPA and GABAA receptors in the nucl. accumbens (NAc) of rats were studied. As was found, the content of the NR2B subunit of NMDA glutamate receptors is increased in p-cresol-treated rats, and this elevation is abrogated after intranasal administration of oxytocin. These effects of oxytocin were partly reversed after i.p. injections of naltrexone. We suggest that interplay between mesolimbic glutamatergic, oxytocinergic, and opioidergic systems in the NAc may be important in the development of p-cresol-dependent neurological disorders.


gut microbiome p-cresol autism NMDA receptor oxytocinergic and opioidergic systems 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    G. Tevzadze, N. Oniani, E. Zhuravliova, et al., “Effects of a gut microbiome toxin, p-cresol, on the indices of social behavior in rats,” Neurophysiology, 50, No. 5, 372–377 (2018).CrossRefGoogle Scholar
  2. 2.
    G. Tevzadze, Z. Nanobashvili, E. Zhuravliova, et al., “Effects of a gut microbiome toxin, p-cresol, on the susceptibility to seizures in rats,” Neurophysiology, 50, No. 6, 424–427 (2018).CrossRefGoogle Scholar
  3. 3.
    Y. Nomura, Y. Nagao, K. Kimura, et al., “Epilepsy in autism: A pathophysiological consideration,” Brain Dev., 32, 799–804 (2010).CrossRefGoogle Scholar
  4. 4.
    P. J. Morgane, J. R. Galler, and D.J. Mokler, “A review of systems and networks of the limbic forebrain/limbic midbrain,” Prog. Neurobiol, 75, 143–160 (2005).CrossRefGoogle Scholar
  5. 5.
    S. B. Floresco, “The nucleus accumbens: An interface between cognition, emotion, and action,” Annu. Rev. Psychol., 66, 25–52 (2015).CrossRefGoogle Scholar
  6. 6.
    G. S. Dichter, J. N. Felder, S. R. Green, et al., “Reward circuitry function in autism spectrum disorders,” SCAN, 7, 160–172 (2012).Google Scholar
  7. 7.
    V. Trezza, R. Damsteegt, E. J. Achterberg, and L. J. Vanderschuren, “Nucleus accumbens mu-opioid receptors mediate social reward,” J. Neurosci., 31, 6362–6370 (2011).CrossRefGoogle Scholar
  8. 8.
    R. A. Depue and J. V. Morrone-Strupinsky, “A neurobehavioral model of affiliative bonding: Implications for conceptualizing a human trait of affiliation,” Behav. Brain Sci., 28, 313–395 (2005).Google Scholar
  9. 9.
    S. N. Haber and B. Knutson, “The reward circuit: linking primate anatomy and human imaging,” Neuropsychopharmacology, 35, 4–26 (2010).CrossRefGoogle Scholar
  10. 10.
    M. Tops, S. L. Koole, H. Ijzerman, and F. T. A. Buisman-Pijlman, “Why social attachment and oxytocin protect against addiction and stress: insights from the dynamics between ventral and dorsal corticostriatal systems,” Pharmacol. Biochem. Behav., 11, 39–48 (2014).CrossRefGoogle Scholar
  11. 11.
    D. Oddi, W. E. Crusio, F. R. D’Amato, and S. Pietropaolo, “Monogenic mouse models of social dysfunction: implications for autism,” Behav. Brain Res., 251, 75–84 (2013).CrossRefGoogle Scholar
  12. 12.
    J. A. Becker, D. Clesse, C. Spiegelhalter, et al., “Autistic-like syndrome in mu opioid receptor null mice is relieved by facilitated mGluR4 activity,” Neuropsychopharmacology, 39, 2049–2060 (2014).CrossRefGoogle Scholar
  13. 13.
    H. J. Lee, A. H. Macbeth, J. H. Pagani, and W. S. III Young, “Oxytocin: the great facilitator of life,” Prog. Neurobiol., 88, 127–151 (2009).Google Scholar
  14. 14.
    V. Gigliucci, M. Leonzino, M. Busnelli, et al., “Region specific up-regulation of oxytocin receptors in the opioid Oprm1-/-mouse model of autism,” Front. Pediat., 2, 1-12 (2014).Google Scholar
  15. 15.
    I. D. Neumann, R. Maloumby, D. I. Beiderbeck, et al., “Increased brain and plasma oxytocin after nasal and peripheral administration in rats and mice,” Psychoneuroendocrinology, 38, 1985–1993 (2013).CrossRefGoogle Scholar
  16. 16.
    R. O. Solomonia, N. Kunelauri, E. Mikautadze, et al., “Mitochondrial proteins, learning and memory: biochemical specialization of a memory system,” Neuroscience, 27, 112–123 (2011).CrossRefGoogle Scholar
  17. 17.
    E. Y. Hsiao, S. W. McBride, S. Hsien, et al., “Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders,” Cell, 155, 1451–1463 (2013).CrossRefGoogle Scholar
  18. 18.
    S. A. Wakeford, N. Neal Hinvest, H. Ring H, and M. Brosnan, “Autistic characteristics in adults with epilepsy and perceived seizure activity,” Epilepsy Behav., 41, 203-207 (2014).Google Scholar
  19. 19.
    J. K. Nicholson, E. Holmes, J. Kinross, et al., “Host-gut microbiota metabolic interactions,” Science, 336, 1262–1267 (2012).CrossRefGoogle Scholar
  20. 20.
    A. M. Persico and V. Napolioni, “Urinary p-cresol in autism spectrum disorder,” Neurotoxicol. Teratol., 36, 82–90 (2013).CrossRefGoogle Scholar
  21. 21.
    A. Dobolyi, K. A. Kékesi, G. Juhász, et al., “Neuropeptides in epilepsy,” Current Med. Chem., 21, 1–24 (2014).CrossRefGoogle Scholar
  22. 22.
    J. P. Britt, F. Benaliouad, R. A. McDevitt, et al., “Synaptic and behavioral profile of multiple glutamatergic inputs to the nucleus accumbens,” Neuron, 76, 790–803 (2012).CrossRefGoogle Scholar
  23. 23.
    J. Kang and E. Kim, “Suppression of NMDA receptor function in mice prenatally exposed to valproic acid improve social deficits and repetitive behaviors,” Front. Mol. Neurosci., 8, 1–9 (2015).CrossRefGoogle Scholar
  24. 24.
    E.-J. Lee, S. Y. Choi, and E. Kim, “NMDA receptor dysfunction in autism spectrum disorders,” Current Opin. Pharmacol., 20, 8–13 (2015).CrossRefGoogle Scholar
  25. 25.
    T. Papouin and S.H.R. Oliet, “Organization, control and function of extrasynaptic NMDA receptors,” Phil. Trans. Roy. Soc. Ser. B, 369, 20130601 (2014).CrossRefGoogle Scholar
  26. 26.
    N. Khetrapal, “Overlap of autism and seizures: understanding cognitive comorbidity,” Mens Sana Monogr., 8, 122–128 (2010).CrossRefGoogle Scholar
  27. 27.
    P. M. Levisohn, “The autism-epilepsy connection,” Epilepsia, 48, 33–35 (2007).CrossRefGoogle Scholar
  28. 28.
    M. M. Zaatreh, “The epilepsy-autism link, a brain misfire that causes social challenges,” Everyday Health, Apr. (2014) website: http,//
  29. 29.
    M. B. Ramocki and H. Y. Zoghbi, “Failure of neuronal homeostasis results in common neuropsychiatric phenotypes,” Nature, 455, 912–918 (2008).CrossRefGoogle Scholar
  30. 30.
    G. Tevzadze, L. Shanshiashvili, and D. Mikeladze, “Children with epilepsy and autistic spectrum disorders show similarly high levels of urinary p-cresol,” JBPC, 17, 77–80 (2017).CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • G. Tevzadze
    • 1
  • E. Zhuravliova
    • 2
    • 4
  • M. Meparishvili
    • 2
  • T. Lortkipanidze
    • 2
  • L. Shanshiashvili
    • 2
    • 4
  • Z. Kikvidze
    • 3
  • D. Mikeladze
    • 2
    • 4
    Email author
  1. 1.4-D Research Institute, Institute of Chemical BiologyIlia State UniversityTbilisiGeorgia
  2. 2.Institute of Chemical BiologyIlia State UniversityTbilisiGeorgia
  3. 3.Institute of Ethnobiology and SocioecologyIlia State UniversityTbilisiGeorgia
  4. 4.Beritashvili Center of Experimental BiomedicineTbilisiGeorgia

Personalised recommendations