Delay discounting for sucrose in alcohol-preferring and nonpreferring rats using a sipper tube within-sessions task.

BACKGROUND: Delay discounting (DD) is a measure of impulsivity that quantifies preference for a small reward delivered immediately over a large reward delivered after a delay. It has been hypothesized that impulsivity is an endophenotype associated with increased risk for development of alcohol use disorders (AUDs); however, a causal role of impulsivity is difficult to determine with human studies. We tested this hypothesis by assessing the degree of DD present in alcohol-naïve rats selectively bred for either high- or low-alcohol preference. METHODS: A novel adaptation of a within-sessions DD procedure was used to compare impulsivity differences between male alcohol-preferring (P) and nonpreferring (NP) rat lines (n = 6 per line) using a 5% sucrose reward. Animals chose between 2 options: 2-second sipper tube access delivered immediately (small reward) or 8-second access after a variable delay (large reward). Each 50-minute session consisted of 5 blocks of ten 60-second trials. Within each session, the delay to the large reward increased in each block of trials. Delays were gradually increased over 3 sets to attain a final delay set of 3, 8, 15, 18, and 25 seconds. RESULTS: Prior to starting delays, there were no significant differences between lines in sucrose consumption or percent choice for the large reward, and both lines exhibited a clear preference for the large reward. After delays were initiated, choice for the large reward decreased as the delay to its presentation increased. Although discounting of the large, delayed reward was observed for both lines, the degree of discounting, or "impulsivity," was greater for P rats compared with NP rats. CONCLUSIONS: P rats are more impulsive for sucrose rewards before exposure to alcohol compared with NP rats. Thus, individuals genetically predisposed toward developing AUDs may be more likely to engage in impulsive decision making prior to alcohol exposure.

Altered circulating leukocytes and their chemokines in a clinical trial of therapeutic hypothermia for neonatal hypoxic ischemic encephalopathy*.

OBJECTIVES: To determine systemic hypothermia's effect on circulating immune cells and their corresponding chemokines after hypoxic ischemic encephalopathy in neonates. DESIGN: In our randomized, controlled, multicenter trial of systemic hypothermia in neonatal hypoxic ischemic encephalopathy, we measured total and leukocyte subset and serum chemokine levels over time in both hypothermia and normothermia groups, as primary outcomes for safety. SETTING: Neonatal ICUs participating in a Neurological Disorders and Stroke sponsored clinical trial of therapeutic hypothermia. PATIENTS: Sixty-five neonates with moderate to severe hypoxic ischemic encephalopathy within 6 hours after birth. INTERVENTIONS: Patients were randomized to normothermia of 37°C or systemic hypothermia of 33°C for 48 hours. MEASUREMENTS AND MAIN RESULTS: Complete and differential leukocyte counts and serum chemokines were measured every 12 hours for 72 hours. The hypothermia group had significantly lower median circulating total WBC and leukocyte subclasses than the normothermia group before rewarming, with a nadir at 36 hours. Only the absolute neutrophil count rebounded after rewarming in the hypothermia group. Chemokines, monocyte chemotactic protein-1 and interleukin-8, which mediate leukocyte chemotaxis as well as bone marrow suppression, were negatively correlated with their target leukocytes in the hypothermia group, suggesting active chemokine and leukocyte modulation by hypothermia. Relative leukopenia at 60-72 hours correlated with an adverse outcome in the hypothermia group. CONCLUSIONS: Our data are consistent with chemokine-associated systemic immunosuppression with hypothermia treatment. In hypothermic neonates, persistence of lower leukocyte counts after rewarming is observed in infants with more severe CNS injury.

Serum cytokines in a clinical trial of hypothermia for neonatal hypoxic-ischemic encephalopathy.

Inflammatory cytokines may mediate hypoxic-ischemic (HI) injury and offer insights into the severity of injury and the timing of recovery. In our randomized, multicenter trial of hypothermia, we analyzed the temporal relationship of serum cytokine levels in neonates with hypoxic-ischemic encephalopathy (HIE) with neurodevelopmental outcome at 12 months. Serum cytokines were measured every 12 hours for 4 days in 28 hypothermic (H) and 22 normothermic (N) neonates with HIE. Monocyte chemotactic protein-1 (MCP-1) and interleukins (IL)-6, IL-8, and IL-10 were significantly higher in the H group. Elevated IL-6 and MCP-1 within 9 hours after birth and low macrophage inflammatory protein 1a (MIP-1a) at 60 to 70 hours of age were associated with death or severely abnormal neurodevelopment at 12 months of age. However, IL-6, IL-8, and MCP-1 showed a biphasic pattern in the H group, with early and delayed peaks. In H neonates with better outcomes, uniform down modulation of IL-6, IL-8, and IL-10 from their peak levels at 24 hours to their nadir at 36 hours was observed. Modulation of serum cytokines after HI injury may be another mechanism of improved outcomes in neonates treated with induced hypothermia.