Central dopamine (DA) pathways are vulnerable to perinatal metabolic insults, potentially leading to adverse, long-term effects upon DA signaling with associated pathologic behaviors. This has been demonstrated in models emulating insults that occur in the setting of unambiguous clinical compromise such as placental dysfunction, prolonged labor, and cardiorespiratory resuscitation. More insidious mechanisms might include intermittent apnea and hypoxia, present in 59 percent-84 percent of premature infants. To establish that such """"""""subtle"""""""" insults indeed lead to clinically significant alterations in DA signaling, we exposed infant rats to a short, 3-day course of intermittent hypoxia. Preliminary results demonstrate disturbances of sleep-wake architecture, excessive locomotion, and impairments in working memory that persist up to two months post insult. These behavioral changes mimic attention deficit hyperactivity disorder (ADHD), and are consistent with that which might be expected from hyper- or hypo-dopaminergic functioning in DA responsive prefrontal and striatal circuits, respectively. This was confirmed in these same animals by Western-blot analysis of expression patterns of proteins involved in central DA signaling (e.g., dopamine and vesicular monoamine transporters, tyrosine hydroxylase, and D1 receptor). We propose to extend these preliminary observations by: 1) adding additional experimental cases; 2) assessing sleep-wake homeostasis, locomotion and working memory in conjunction with in vivo analysis of mesotelencephalic DA neurotransmission; and 3) extending like assessments to both male and female rats from two separate strains selected for differences in hypoxic sensitivity. The proposed studies will establish the degree to which intermittent hypoxia, prevalent among premature infants, is pathogenic to maturing mesotelencephalic DA pathways and the cellular and subcellular mechanisms accounting for the observed pathologic phenotypes. Such new knowledge will advance our understanding of DA's modulation of sleep and wakefulness, locomotion, and executive functioning, with a longer-term goal of promoting development of interventions to preserve and maximize mesotelencephalic DA neurotransmission during and following hypoxic insults
