EFFECTS OF LONG-TERM ANTIPSYCHOTIC TREATMENT ON ENKEPHALIN-IMMUNOREACTIVE NEURONS IN RATS PERINATALLY TREATED WITH PHENCYCLIDINE

  • Anja Kompanijec MFUB
  • Bojan Korica MFUB
  • Tihomir Stojkovic Institut za medicinsku i klinicku biohemiju, Medicinski fakultet, Univerzitet u Beogradu
DOI: https://doi.org/10.5937/mp74-39248
Keywords: schizophrenia, phencyclidine, haloperidol, risperidone, enkephalin

Abstract


Introduction: Schizophrenia is a chronic mental illness that affects 1% of the world population. The phencyclidine animal model of schizophrenia is based on the glutamate theory of the development of schizophrenia. Enkephalin is a neuropeptide with a role in the development of schizophrenia symptoms via the modulatory effect of neurotransmission. 

Aim: This study aimed to elucidate whether the long-term treatment with haloperidol and risperidone causes the difference in the appearance of enkephalin-immunoreactive neurons (EIN) in the brain of rats perinatally treated with phencyclidine (PCP).

Material and methods: Experimental Wistar rats were treated on postnatal days 2 (PN2), 6, 9, and 12 with either PCP (10 mg/kg) or saline. From PN35 to PN100 haloperidol (3 mg/kg) and risperidone (1 mg/kg) were administrated orally in drinking water. Animals were divided into six groups. The control group received saline and drinking water, PCP group received PCP and drinking water. Hal group received saline and haloperidol, PCP-Hal group PCP and haloperidol, while Ris group and PCP-Ris received saline or PCP and risperidone. All animals were sacrificed at PN100 and the cortex, hippocampus, striatum, and septal area were used to analyze the presence of EIN by immunohistochemistry.

Results: In the hippocampus, the number of EIN was significantly higher in the PCP group than in the control group. Antipsychotics had a potent effect in the septal area, where both of them decreased the area covered by the EIN compared to the control group. In the striatum, only haloperidol changed the level of EIN by increasing the area covered with these neurons compared to the covered area in the control group.

Conclusion: Long-term administration of antipsychotics caused the region-specific change in the distribution of enkephalin-immunoreactive neurons in the brain of a rat, perinatally treated with PCP.

References


  1. Jablensky A. Epidemiology of schizophrenia: the global burden of disease and disability. Eur Arch Psychiatry Clin Neurosci. 2000;250:274-85.

  2. Harrison PJ. The neuropathology of schizophrenia. A critical review of the data and their interpretation. 1999:593-624.

  3. Osimo EF, Beck K, Reis Marques T, Howes OD. Synaptic loss in schizophrenia: a meta-analysis and systematic review of synaptic protein and mRNA measures. Mol Psychiatry. 2018 Mar 6. doi: 10.1038/s41380-018-0041-5.

  4. Lakić A, Munjiza M, Timotijević I. Shizofrenija. U: Gašić Jašović M, Toševski Lečić. D. Urednici. Psihijatrija, udžbenik za studente medicine. Beograd, Univerzitet u Beogradu. Medicinski fakultet; 2014. p. 112-128.

  5. Bubeníková-Valesová V, Horácek J, Vrajová M, Höschl C. Models of schizophrenia in humans and animals based on inhibition of NMDA receptors. Neurosci Biobehav Rev. 2008;32:1014-23

  6. Morris BJ, Cochran SM, Pratt JA. PCP: from pharmacology modeling schizophrenia. Curr Opin Pharmacol. 2005;5:101-6. 9.

  7. Grayson, B., Barnes, S. A., Markou, A., Piercy, C., Podda, G., & Neill, J. C. (2015). Postnatal Phencyclidine (PCP) as a Neurodevelopmental Animal Model of Schizophrenia Pathophysiology and Symptomatology: A Review. Current Topics in Behavioral Neurosciences, 403–428. doi:10.1007/7854_2015_403

  8. Agarwal SM, Hahn MK, Taylor VH, Kowalchuk C, Costa-Dookhan KA, Remington GJ, et al. Antipsychotics, Metabolic Adverse Effects, and Cognitive Function in Schizophrenia. Front Psychiatry. 2018;9(December):1–12

  9. Crossley NA, Constante M, McGuire P, Power P. Efficacy of atypical v. typical antipsychotics in the treatment of early psychosis: Meta-analysis. Br J Psychiatry. 2010;196(6):434–9.

  10. Takahashi, A. (2016). Handbook of Hormones, 55–e7A–2. doi:10.1016/b978-0-12-801028-0.00117-3

  11. Henry MS, Gendron L, Tremblay ME, Drolet G (2017). "Enkephalins: Endogenous Analgesics with an Emerging Role in Stress Resilience". review. Neural Plasticity. 2017: 1546125. doi:10.1155/2017/1546125. PMC 5525068. PMID 28781901.

  12. Trezza V., Damsteegt R., Achterberg E.M., Vanderschuren L. Nucleus accumbens μ-opioid receptors mediate social reward. J. Neurosci. 2011;31:6362–6370DOIoi: 10.1523/JNEUROSCI.5492-10.2011.

  13. Javitt DC. Glutamate and Schizophrenia: Phencyclidine, N‐Methyl‐d‐Aspartate Receptors, and Dopamine–Glutamate Interactions. 2007;78(06):69–108.

  14. Hanania, T., & Johnson, K. M. (1999). “Regulation of NMDA-stimulated [14C]GABA and [3H]acetylcholine release by striatal glutamate and dopamine receptors“. Brain   Research, 844(1-2), 106–117. doi:10.1016/s0006-8993(99)01869-7

  15. Liao D, Lin H, Law PY, Loh HH (February 2005). "Mu-opioid receptors modulate the stability of dendritic spines". Proc. Natl. Acad. Sci. U.S.A. 102 (5): 1725–30. Bibcode:2005PNAS..102.1725L. doi:10.1073/pnas.0406797102. JSTOR 3374498. PMC 545084. PMID 15659552

  16. Börner C., Kraus J., Schröder H., Ammer H., Höllt V. Transcriptional regulation of the human μ-opioid receptor gene by interleukin-6. Mol. Pharmacol. 2004;66:1719–1726. doi: 10.1124/mol.104.003806.

  17. Lidsky T.I. Reevaluation of the mesolimbic hypothesis of antipsychotic drug action. Schizophr. Bull. 1995;21:67–74.

  18. Prensa L, Giménez-Amaya JM, Parent A (Nov 1999). "Chemical heterogeneity of the striosomal compartment in the human striatum". J Comp Neurol. 413 (4): 603–18. doi:10.1002/(SICI)1096-9861(19991101)413:4<603::AID-CNE9>3.0.CO;2-K. PMID 10495446.

  19. Yager LM, Garcia AF, Wunsch AM, Ferguson SM (August 2015). "The ins and outs of the striatum: Role in drug addiction". Neuroscience. 301: 529–541. doi:10.1016/j.neuroscience.2015.06.033. PMC 4523218. PMID 26116518.

  20. Broom DC, Jutkiewicz EM, Rice KC, Traynor JR, Woods JH (Sep 2002). "Behavioral effects of delta-opioid receptor agonists: potential antidepressants?". Japanese Journal of Pharmacology. 90 (1): 1–6. doi:10.1254/jjp.90.1. PMID 12396021.

  21. Torregrossa MM, Jutkiewicz EM, Mosberg HI, Balboni G, Watson SJ, Woods JH (Jan 2006). "Peptidic delta opioid receptor agonists produce antidepressant-like effects in the forced swim test and regulate BDNF mRNA expression in rats". Brain Research. 1069 (1): 172–81. doi:10.1016/j.brainres.2005.11.005. PMC 1780167. PMID 16364263.

  22. Huang EJ, Reichardt LF (2001). "Neurotrophins: roles in neuronal development and function". Annual Review of Neuroscience. 24: 677–736. doi:10.1146/annual.neuro.24.1.677. PMC 2758233. PMID 11520916.

  23. Caldeira MV, Melo CV, Pereira DB, Carvalho R, Correia SS, Backos DS, Carvalho AL, Esteban JA, Duarte CB (April 2007). "Brain-derived neurotrophic factor regulates the expression and synaptic delivery of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor subunits in hippocampal neurons". The Journal of Biological Chemistry. 282 (17): 12619–28. doi:10.1074/jbc.M700607200. PMID 17337442

  24. Slack SE, Pezet S, McMahon SB, Thompson SW, Malcangio M (October 2004). "Brain-derived neurotrophic factor induces NMDA receptor subunit one phosphorylation via ERK and PKC in the rat spinal cord". The European Journal of Neuroscience. 20 (7): 1769–78. doi:10.1111/j.1460-9568.2004.03656.x. PMID 15379998

  25. Connor M, Vaughan CW, Chieng B, Christie MJ (1996). "Nociceptin receptor coupling to a potassium conductance in rat locus coeruleus neurons in vitro". British Journal of Pharmacology. 119 (8): 1614–8. doi:10.1111/j.1476-5381.1996.tb16080.x. PMC 1915781. PMID 8982509.

Published
2023/11/29
Issue
Vol. 74 No. 3 (2023): Medicinski podmladak
Section
Original Scientific Paper