Skip to main content

Advertisement

SpringerLink
Log in

Postnatal hypoxia evokes persistent changes within the male rat’s dopaminergic system

  • Hypoxia • Original Article
  • Published:
Sleep and Breathing Aims and scope Submit manuscript

Abstract

Purpose

Hypoxic insults occurring during the perinatal period remain the leading cause of permanent brain impairment. Severe cognitive and motor dysfunction, as seen in cerebral palsy, will occur in 4–10% of post-hypoxic newborns. Subtle cognitive impairment, apparent in disorders of minimal brain dysfunction will occur in > 3 million post-hypoxic newborns. Analyses of post-hypoxic rodent brains reveal reduced extracellular levels of dopamine, a key neurotransmitter of vigilance, execute function, and behavior. The purpose of this study was to assess whether synaptic levels of dopamine could be enhanced in post-hypoxic, hypodopaminergic rats.

Methods

Newborn male rats were exposed to subtle, repetitive hypoxic insults for 4–6 h per day, during postnatal days 7–11. During adolescence, we quantified dopamine content within the caudate nuclei. We then determined whether extracellular dopamine levels could be increased by injecting the psychostimulant d-amphetamine. We next assessed whether the post-hypoxic rat’s response to d-amphetamine would differentially impact place preference behavior when compared with littermate controls.

Results

Total tissue content of dopamine was significantly higher in post-hypoxic rats. Injection of d-amphetamine liberated that dopamine which subsequently enhanced extracellular levels. Post-hypoxic rats acquired conditioned place preference for d-amphetamine during the training days. During the testing day, total time spent in the amphetamine-pairing box did not differ between post-hypoxic and control littermates.

Conclusion

Postnatally occurring hypoxic insults promote remodeling of the dopaminergic system resulting in increased intracellular sequestering of this monoamine. That sequestered dopamine can be released using the psychostimulant d-amphetamine, which did not promote a conditioned place preference any greater than was observed in non-hypoxic littermate controls.

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

Similar content being viewed by others

References

  1. Inder TE, Volpe JJ (2000) Mechanisms of perinatal brain injury. Semin Neonatol 5(1):3–16

    Article  CAS  PubMed  Google Scholar 

  2. Shany E et al (2017) Diffusion tensor tractography of the cerebellar peduncles in prematurely born 7-year-old children. Cerebellum 16(2):314–325

    Article  PubMed  PubMed Central  Google Scholar 

  3. Murray AL et al (2014) Neonatal brain pathology predicts adverse attention and processing speed outcomes in very preterm and/or very low birth weight children. Neuropsychology 28(4):552–562

    Article  PubMed  PubMed Central  Google Scholar 

  4. Row BW et al (2002) Impaired spatial learning and hyperactivity in developing rats exposed to intermittent hypoxia. Pediatr Res 52(3):449–453

    Article  PubMed  Google Scholar 

  5. Veasey SC et al (2004) Long-term intermittent hypoxia in mice: protracted hypersomnolence with oxidative injury to sleep-wake brain regions. Sleep 27(2):194–201

    Article  PubMed  Google Scholar 

  6. Decker MJ et al (2003) Episodic neonatal hypoxia evokes executive dysfunction and regionally specific alterations in markers of dopamine signaling. Neuroscience 117(2):417–425

    Article  CAS  PubMed  Google Scholar 

  7. Decker MJ et al (2005) Reduced extracellular dopamine and increased responsiveness to novelty: neurochemical and behavioral sequelae of intermittent hypoxia. Sleep 28(2):169–176

    Article  PubMed  Google Scholar 

  8. Thome J et al (2012) Biomarkers for attention-deficit/hyperactivity disorder (ADHD). A consensus report of the WFSBP task force on biological markers and the World Federation of ADHD. World J Biol Psychiatry 13(5):379–400

    Article  PubMed  Google Scholar 

  9. Rosa D (2010) Minimal brain dysfunction. In: Clauss-Ehlers CS (ed) Encyclopedia of cross-cultural school psychology. Springer US, Boston, p 626

    Chapter  Google Scholar 

  10. Bradford MM (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72:248–254

    Article  CAS  PubMed  Google Scholar 

  11. Keating GL, Walker SC, Winn P (2002) An examination of the effects of bilateral excitotoxic lesions of the pedunculopontine tegmental nucleus on responding to sucrose reward. Behav Brain Res 134(1–2):217–228

    Article  PubMed  Google Scholar 

  12. Boksa P, El-Khodor BF (2003) Birth insult interacts with stress at adulthood to alter dopaminergic function in animal models: possible implications for schizophrenia and other disorders. Neurosci Biobehav Rev 27(1–2):91–101

    Article  CAS  PubMed  Google Scholar 

  13. Kohlhauser C, Mosgoeller W, Hoeger H, Lubec G, Lubec B (1999) Cholinergic, monoaminergic and glutamatergic changes following perinatal asphyxia in the rat. Cell Mol Life Sci 55:1491–1501

    Article  CAS  PubMed  Google Scholar 

  14. Pagida MA et al (2013) Vulnerability of the mesencephalic dopaminergic neurons of the human neonate to prolonged perinatal hypoxia: an immunohistochemical study of tyrosine hydroxylase expression in autopsy material. J Neuropathol Exp Neurol 72(4):337–350

    Article  CAS  PubMed  Google Scholar 

  15. Gross J et al (2000) Perinatal asphyxia induces region-specific long-term changes in mRNA levels of tyrosine hydroxylase and dopamine D1 and D2 receptors in rat brain. Mol Brain Res 79:110–117

    Article  CAS  PubMed  Google Scholar 

  16. Wang Y et al (1995) Ketamine antagonizes hypoxia-induced dopamine release in rat striatum. Brain Res 693(1–2):233–245

    Article  CAS  PubMed  Google Scholar 

  17. Oliva I, Fernandez M, Martin ED (2013) Dopamine release regulation by astrocytes during cerebral ischemia. Neurobiol Dis 58:231–241

    Article  CAS  PubMed  Google Scholar 

  18. Sarna GS et al (1990) Effect of transient cerebral ischaemia and cardiac arrest on brain extracellular dopamine and serotonin as determined by in vivo dialysis in the rat. J Neurochem 55(3):937–940

    Article  CAS  PubMed  Google Scholar 

  19. Akiyama Y et al (1991) Effects of hypoxia on the activity of the dopaminergic neuron system in the rat striatum as studied by in vivo brain microdialysis. J Neurochem 57(3):997–1002

    Article  CAS  PubMed  Google Scholar 

  20. Sulzer D, Zecca L (2000) Intraneuronal dopamine-quinone synthesis: a review. Neurotox Res 1(3):181–195

    Article  CAS  PubMed  Google Scholar 

  21. Lohr KM et al (2016) Vesicular monoamine transporter 2 (VMAT2) level regulates MPTP vulnerability and clearance of excess dopamine in mouse striatal terminals. Toxicol Sci 153(1):79–88

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Yu PL et al (2015) Regulation of intermittent hypoxia on brain dopamine in amphetaminized rats. Chin J Physiol 58(4):219–227

    Article  CAS  PubMed  Google Scholar 

  23. Koob GF (1992) Dopamine, addiction, and reward. Semin Neurosci 4(2):139–148

    Article  Google Scholar 

  24. Koob GF (1996) Hedonic valence, dopamine and motivation. Mol Psychiatry 1(3):186–189

    CAS  PubMed  Google Scholar 

  25. Spanagel R, Weiss F (1999) The dopamine hypothesis of reward: past and current status. Trends Neurosci 22(11):521–527

    Article  CAS  PubMed  Google Scholar 

  26. Koob GF (2000) Neurobiology of addiction. Toward the development of new therapies. Ann N Y Acad Sci 909:170–185

    Article  CAS  PubMed  Google Scholar 

  27. Koob GF et al (2004) Neurobiological mechanisms in the transition from drug use to drug dependence. Neurosci Biobehav Rev 27(8):739–749

    Article  CAS  PubMed  Google Scholar 

  28. Koob GF, Le Moal M (2001) Drug addiction, dysregulation of reward, and allostasis. Neuropsychopharmacology 24(2):97–129

    Article  CAS  PubMed  Google Scholar 

  29. Koob GF, Volkow ND (2016) Neurobiology of addiction: a neurocircuitry analysis. Lancet Psychiatry 3(8):760–773

    Article  PubMed  Google Scholar 

  30. Cadet JL, Bisagno V, Milroy CM (2014) Neuropathology of substance use disorders. Acta Neuropathol 127(1):91–107

    Article  CAS  PubMed  Google Scholar 

  31. Spyraki C, Fibiger HC, Phillips AG (1982) Dopaminergic substrates of amphetamine-induced place preference conditioning. Brain Res 253(1–2):185–193

    Article  CAS  PubMed  Google Scholar 

  32. Kameda SR et al (2013) Opposite effects of neonatal hypoxia on acute amphetamine-induced hyperlocomotion in adult and adolescent mice. Psychiatry Res 208(1):74–77

    Article  CAS  PubMed  Google Scholar 

  33. Spear LP (2000) The adolescent brain and age-related behavioral manifestations. Neurosci Biobehav Rev 24(4):417–463

    Article  CAS  PubMed  Google Scholar 

  34. Hryhorczuk C et al (2016) Dampened mesolimbic dopamine function and signaling by saturated but not monounsaturated dietary lipids. Neuropsychopharmacology 41(3):811–821

    Article  CAS  PubMed  Google Scholar 

  35. Laplante F et al (2012) Sex differences in the effects of perinatal anoxia on dopamine function in rats. Neurosci Lett 506(1):89–93

    Article  CAS  PubMed  Google Scholar 

  36. Broderick PA, Gibson GE (1989) Dopamine and serotonin in rat striatum during in vivo hypoxic-hypoxia. Metab Brain Dis 4(2):143–153

    Article  CAS  PubMed  Google Scholar 

  37. Decker MJ, Rye DB (2002) Emerging research: Neonatal intermittent hypoxia impairs dopamine signaling and executive functioning. Sleep Breath 6(4):205–210

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

We dedicate this work to our beloved laboratory colleague, Inez Solomon, deceased.

Author Contributors

All authors directly participated in the study and have reviewed and approved the final manuscript.

Funding

for this study was provided through the National Institutes of Health HL-72722 (M.J.D.) and NS-36695 and NS-40221 (D.B.R.) as well as the Department of Neurology, Emory University. The sponsors had no role in the design or conduct of this research.

Author information

Authors and Affiliations

  1. School of Nursing, Case Western Reserve University, Cleveland, OH, USA

    Michael J. Decker

  2. Department of Physiology and Biophysics, School of Medicine, Case Western Reserve University, Cleveland, OH, USA

    Michael J. Decker

  3. Department of Neurosciences, School of Medicine, Case Western Reserve University, Cleveland, OH, USA

    Michael J. Decker

  4. Department of Pathology, Carver College of Medicine, Iowa City, IA, USA

    Karra A. Jones

  5. Department of Neurology, Emory University, Atlanta, GA, USA

    Glenda L. Keating & David B. Rye

Authors
  1. Michael J. Decker
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Karra A. Jones
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Glenda L. Keating
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. David B. Rye
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Michael J. Decker.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Decker, M.J., Jones, K.A., Keating, G.L. et al. Postnatal hypoxia evokes persistent changes within the male rat’s dopaminergic system. Sleep Breath 22, 547–554 (2018). https://doi.org/10.1007/s11325-017-1558-6

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11325-017-1558-6

Keywords

Search

Navigation