Reduced extracellular dopamine and increased responsiveness to novelty: Neurochemical and behavioral sequelae of intermittent hypoxia

Study Objectives: Vesicular monoamine transporter and dopamine D1-receptor protein expression are upregulated within the striatum of adults rats exposed to intermittent hypoxic insults as neonates. These observations prompted us to test the hypothesis that intermittent hypoxic insults, occurring during this period of critical brain development, lead to persistent reductions in extracellular levels of dopamine within the striatum. We also tested the hypothesis that post-hypoxic rats exhibit increased novelty-induced behavioral activation and increased basal levels of locomotor activity, two indexes of impaired dopaminergic functioning. Study Design: Extracellular levels of dopamine were measured over a 50-hour interval via in-vivo microdialysis. Responsivity to novelty and basal levels of locomotor activity were measured via cubicles equipped with infrared transmitters and photosensors. Interventions: Between postnatal days 7 and 11, rat pups were exposed to intermittent hypoxia (20-second bursts of hypoxic gas consisting of 10% oxygen balance nitrogen; 60 events/hour) or compressed air for 6 hours during their major sleep period. On postnatal day 35, locomotor activity was continuously recorded over a 72-hour period. On postnatal day 42, extracellular levels of dopamine were determined in microdialysis samples collected at 30-minute intervals continuously for 50 hours. Measurements and Results: Post-hypoxic rats exhibited heightened behavioral activation when placed into the novel environment of locomotor-recording cubicles. Following 24 hours of adaptation to the cubicles, post-hypoxic rats exhibited locomotor hyperactivity during each dark phase of the circadian cycle, their typical waking period. These same rats also demonstrated reduced levels of extracellular dopamine during both the dark and light phases of the circadian cycle. Conclusions: We demonstrate increased responsivity to novelty, locomotor hyperactivity, and reduced levels of extracellular dopamine within the striata of juvenile rats exposed to intermittent hypoxic insults between postnatal days 7 and 11. These data, in conjunction with our previous observations, support our hypothesis that intermittent hypoxic insults occurring during a period of critical brain development lead to sequestration of dopamine presynaptically within nigrostriatal axons. We postulate that neonatally occurring hypoxic insults are one potential pathogenic mechanism underlying disorders of minimal brain dysfunction, such as attention-deficit/hyperactivity disorder, characterized by executive dysfunction and hyper responsiveness to novel stimuli, which is responsive to agents promoting enhanced extracellular levels of synaptic dopamine.