Skip to main content
Log in

Effects of Buspirone on the Behavioral Responses of Adult Male and Female Rats Exposed to Stressors at Neonatal Age

  • Published:
Neuroscience and Behavioral Physiology Aims and scope Submit manuscript

The long-term influences of chronic injections of the type 1A serotonin (5-HT1A) receptor agonist buspirone in the pubertal period of development of male and female rats exposed to pain/stress in the first two days of life on measures of anxiety and depression-like behavior and the cognitive domain were studied in adult animals. The data presented here provide evidence of long-term impairments to the behavioral measures assessed – levels of anxiety, severity of depression-like behavior, cognitive capacities – in adult male and female rats subjected to repeated pain/stress. Buspirone improved the behaviors of interest impaired by the harmful treatments. These results indicate that 5-HT1A receptors are involved in the protective effects of buspirone and, perhaps, in blocking the development of affective disorders and abnormalities in the cognitive domain due to buspirone administration during the critical adolescent period of development. The anxiolytic and antidepressant effects of buspirone were apparent as greater improvements in behavioral indicators in females than males.

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

Access this article

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

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. I. P. Butkevich and V. A. Mikhailenko, “Harmful treatments at early age alter pain sensitivity in adult female rats, correction with buspirone,” Ros. Fiziol. Zh., 102, No. 10, 1146–1155 (2016).

    CAS  Google Scholar 

  2. I. P. Butkevich, V. A. Mikhailenko, E. A. Vershinina, and N. A. Ulanova, “Differences in adaptive types of behavior in male and female rats at the adolescent period of development after exposure to inflammatory pain or stress in the neonatal state,” Zh. Evolyuts. Biokhim. Fiziol., 5, No. 4, 266–275 (2015).

    Google Scholar 

  3. I. P. Butkevich, V. A. Mikhailenko, Yu. A. Lavrova, and N. A. Ulanova, “repeated pain on inflammation in neonatal males alter adaptive behavior in the adolescent period of development,” Ros. Fiziol. Zh., 100, No. 11, 1241–1251 (2014).

    CAS  Google Scholar 

  4. P. R. Albert and L. M. Fiori, “Transcriptional dys-regulation in anxiety and major depression: 5-HT1A gene promoter architecture as a therapeutic opportunity,” Curr. Pharm. Des., 20, 3738–3750 (2014), doi: https://doi.org/10.2174/13816128113196660740.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. P. R. Albert and B. L. François, “Modifying 5-HT1A receptor gene expression as a new target for antidepressant therapy,” Front. Neurosci., 4, 35 (2010), doi: https://doi.org/10.3389/fnins.2010.00035.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. N. Alenina and F. Klempin, “The role of serotonin in adult hippocampal neurogenesis,” Behav. Brain Res., 227, 49–57 (2015).

    Article  CAS  Google Scholar 

  7. V. C. Z. Anseloni, F. He, S. I. Novikova, et al., “Alterations in stress-associated behaviors and neurochemical markers in adult rats after neonatal short-lasting local inflammatory insult,” Neuroscience, 131, No. 3, 635–645 (2005).

    Article  CAS  PubMed  Google Scholar 

  8. M. Banqueri, M. Mendez, and J. L. Arias, “Behavioral effects in adolescence and early adulthood in two length models of maternal separation in male rats,” Behav. Brain Res., 324, No. 1, 77–86 (2017), doi: https://doi.org/10.1016/j.bbr.2017.02.006.

    Article  PubMed  Google Scholar 

  9. N. N. Burke, C. Y. Fan, and T. Trang, “Microglia in health and pain: impact of noxious early life events,” Exp. Physiol., 101, No. 8, 1003–1021 (2016).

    Article  PubMed  Google Scholar 

  10. I. P. Butkevich, V. A. Mikhailenko, E. A. Vershinina, et al., “Long-term effects of chronic buspirone during adolescence reduce the adverse influences of neonatal inflammatory pain and stress on adaptive behavior in adult male rats,” Front. Behav. Neurosci., 11, 11 (2017), doi: https://doi.org/10.3389/fnbeh.2017.00011.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. I. P. Butkevich, V. A. Mikhailenko, E. A. Vershinina, et al., “Buspirone before prenatal stress protects against adverse effects of stress on emotional and inflammatory pain-related behavior in infant rats: age and sex differences,” Brain Res., 1419, 76–84 (2011), doi: https://doi.org/10.1016/j.brainres.2011.08.068.

    Article  CAS  PubMed  Google Scholar 

  12. C. M. Chau, I. L. Cepeda, A. M. Devlin, et al., “The Val66Met brain-derived neurotrophic factor gene variant interacts with early pain exposure to predict cortisol dys-regulation in 7-year-old children born very preterm: Implications for cognition,” Neuroscience, 342, No. 7, 188–199 (2017), doi: https://doi.org/10.1016/j.neuroscience.2015.08.044. Epub 2015 Aug 28.

  13. T. Deak, M. Quinn, J. A. Cidlowski, et al., “Neuro-immune mechanisms of Stress: sex differences, developmental plasticity, and implications for pharmacotherapy of Stress-related disease,” Stress, 18, No. 4, 367–380 (2015), doi: https://doi.org/10.3109/10253890.2015.1053451.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. C. H. Do Prado, T. Narahari, F. H. Holland, et al., “Effects of early adolescent environmental enrichment on cognitive dysfunction, prefrontal cortex development, and inflammatory cytokines after early life stress,” Dev. Psychobiol., 58, No. 4, 482–491 (2016), doi: https://doi.org/10.1002/dev.21390.2015.

    Article  PubMed  Google Scholar 

  15. M. Fitzgerald, “The developmental of nociceptive circuits,” Nat. Rev. Neurosci., 6, 507–520 (2005).

    Article  CAS  PubMed  Google Scholar 

  16. R. Grassi-Oliveira, J. A. Honeycutt, F. H. Holland, et al., “Cognitive impairment effects of early life stress in adolescents can be predicted with early bio-markers: Impacts of sex, experience, and cytokines,” Psychoneuroendocrinology, 71, 19–30 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. L. R. Hammerslag and J. M. Gulley, “Sex differences in behavior and neural development and their role in adolescent vulnerability to substance use,” Behav. Brain Res., 298, Part A, 15–26 (2016), doi: https://doi.org/10.1016/j.bbr.2015.04.008.2015.

  18. Y. O. Henderson, N. C. Victoria, K. Inoue, et al., “Early life inflammatory pain induces long-lasting deficits in hippocampal-dependent spatial memory in male and female rats,” Neurobiol. Learn. Mem, 118, 30–41 (2016), doi: https://doi.org/10.1016/j.nlm.2014.10.010.Feb2015.

    Article  Google Scholar 

  19. H. S. Jørgensen, “Studies on the neuroendocrine role of serotonin,” Dan. Med. Bull., 54, No. 4, 266–288 (2007).

    PubMed  Google Scholar 

  20. E. Kirilly, X. Gonda, and G. Bagdy, “Antidepressants, stressors and the serotonin 1A receptors,” Neuropsychopharmacol. Hung., 17, No. 2, 81–89 (2015).

    PubMed  Google Scholar 

  21. E. Lacivita, P. DiPilato, P. De Giorgio, et al., “The therapeutic potential of 5-HT1A receptors: a patent review,” Ep. Opin. Ther. Pat., 22, No. 8, 887–902 (2012).

    Article  CAS  Google Scholar 

  22. J. L. LaPrairie and A. Z. Murphy, “Long term impact of neonatal injury in male and female rats: sex differences, mechanisms and clinical implications,” Front. Neuroendocrinol., 31, 193–202 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  23. M. Lima, J. Malheiros, A. Negrigo, et al., “Sex-related long-term behavioral and hippocampal cellular alterations after nociceptive stimulation throughout postnatal development in rats,” Neuropharmacology, 77, 268–276 (2014).

    Article  CAS  PubMed  Google Scholar 

  24. M. Loi, J. C. Mossink, G. F. Meerhoff, et al., “Effects of early-life stress on cognitive function and hippocampal structure in female rodents,” Neuroscience, 342, 101–119 (2017), doi: https://doi.org/10.1016/j.neuroscience.2015.08.024.2015.

    Article  CAS  PubMed  Google Scholar 

  25. C. M. McCormick, B. F. Furcy, Child Meredith, et al., “Neonatal sex hormones have ‘organizational’ effects on the hypothalamic-pituitary-adrenal axis of male rats,” Brain Res. Dev. Brain Res., 105, 295–307 (1998).

    Article  CAS  PubMed  Google Scholar 

  26. C. M. McCormick and M. R. Green, “From the stressed adolescent to the anxious and depressed adult: investigations in rodent model,” Neuroscience, 249, 242–257 (2013), doi: https://doi.org/10.1016/j.neuroscience.2012.08.06.

    Article  CAS  PubMed  Google Scholar 

  27. M. Mori, Y. Murata, A. Matsuo, et al., “Chronic treatment with the 5-HT1A receptor partial agonist tandospirone increases hippocampal neurogenesis,” Neurol. Ther., 3, No. 1, 67–77 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  28. L. H. Nelson, and K. M. Lenz, “The immune system as a novel regulator of sex differences in brain and behavioral development,” J. Neurosci. Res., 95, No. 1–2, 447–461 (2017), doi: 0.1002/jnr.3821.

  29. N. K. Popova and V. S. Naumenko, “5-HT1A receptor as a key player in the brain 5-HT system,” Rev. Neurosci., 24, No. 2, 191–204 (2013).

    CAS  PubMed  Google Scholar 

  30. R. D. Porsolt, M. LePichon, and M. Jalfre, “Depression: a new animal model sensitive to antidepressant treatments,” Nature, 266, 730–732 (1977).

    Article  CAS  Google Scholar 

  31. K. Ren, V. Anseloni, S. P. Zou, et al., “Characterization of basal and re-inflammation-associated long-term alteration in Pain responsivity following short-lasting neonatal local inflammatory insult,” Pain, 110, 588–596 (2004).

    Article  CAS  PubMed  Google Scholar 

  32. D. Rice and S. Barone, Jr., “Critical periods of vulnerability for the developing nervous system: evidence from humans and animal models,” Environ. Health Perspect., 108, No. 3, 511–533 (2000).

    PubMed  PubMed Central  Google Scholar 

  33. J. W. Richardson-Jones, C. P. Craige, T. H. Nguyen, et al., “Serotonin-1A autoreceptors are necessary and sufficient for the normal formation of circuits underlying innate anxiety,” J. Neurosci., 31, No. 16, 6008–6018 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. P. S. Rojas and J. L. Fiedler, “What do we really know about 5-HT1A receptor signaling in neuronal cells?” Front. Cell Neurosci., 10, 272 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. B. A. Samuels, I. Mendez-David, C. Faye, et al., “Serotonin 1A and serotonin 4 receptors: essential mediators of the neurogenic and behavioral actions of antidepressants,” Neuroscientist, 22, No. 1, 26–45 (2016).

    Article  CAS  PubMed  Google Scholar 

  36. M. V. Schmidt, “Animal models for depression and the mismatch hypothesis of disease,” Psychoneuroendocrinology, 36, 330–338 (2011).

    Article  PubMed  Google Scholar 

  37. J. M. Schwarz and S. D. Bilbo, “Sex, glia and development: interactions in health and disease,” Horm. Behav., 62, 243–253 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. H. Sharifi , A. M. Nayebi, S. Farajnia, and R. Haddadi, “Effect of chronic administration of bus-pirone and fluoxetine on inflammatory cytokines in 6-hydroxydopamine-lesioned rats,” Drug Res. (Stuttg.), 65, No. 8, 393–397 (2015), doi: https://doi.org/10.1055/s-0034-1374615.

    Article  CAS  Google Scholar 

  39. V. C. Sousa, J. Vital, A. R. Costenla, et al., “Maternal separation impairs long term-potentiation in CA1-CA3 synapses and hippocampal-dependent memory in old rats,” Neurobiol. Aging, 35, No. 7, 1680-1685 (2014), doi:https://doi.org/10.1016/j.neurobiolaging.2014.

    Article  PubMed  Google Scholar 

  40. N. C. Victoria and A. Z. Murphy, “Exposure to early life pain: long term consequences and contributing mechanisms,” Curr. Opin. Behav. Sci., 7, 61–68 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  41. N. C. Victoria and A. Z. Murphy, “The long-term impact of early life pain on adult responses to anxiety and stress: historical perspectives and empirical evidence,” Dev. Neurobiol., 275, 261–273 (2016), doi: https://doi.org/10.1016/j.expneurol.2015.

    Article  Google Scholar 

  42. S. M. Walker, S. Beggs, and M. L. Baccei, “Persistent changes in peripheral and spinal nociceptive processing after early tissue injury,” Exp. Neurol., 275, Part 2, 253–260 (2016).

  43. S. M. Walker, J. Meredith-Middleton, C. Cooke-Yarborough, and M. Fitzgerald, “Neonatal inflammation and primary afferent terminal plasticity in the rat dorsal horn,” Pain, 105, 185–195 (2003).

    Article  PubMed  Google Scholar 

  44. P. M. Whitaker-Azmitia, M. Druse, P. Walker, and J. M. Lauder, “Serotonin as a developmental signal,” Behav. Brain Res., 73, No. 1–2, 19–29 (1996), doi: https://doi.org/10.1016/0166-4328(96)00071-x.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to V. A. Mikhailenko.

Additional information

Translated from Rossiiskii Fiziologicheskii Zhurnal imeni I. M. Sechenova, Vol. 103, No. 6, pp. 658–670, June, 2017.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Mikhailenko, V.A., Butkevich, I.P. & Vershinina, E.A. Effects of Buspirone on the Behavioral Responses of Adult Male and Female Rats Exposed to Stressors at Neonatal Age. Neurosci Behav Physi 49, 315–322 (2019). https://doi.org/10.1007/s11055-019-00734-y

Download citation

  • Received:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11055-019-00734-y

Keywords

Navigation