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

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.