Leptin is an adipose-derived hormone that acts on hypothalamic leptin receptors to regulate energy balance. Leptin receptors are also expressed in extrahypothalamic sites including the ventral tegmental area (VTA), critical to brain reward circuitry. We report that leptin targets DA and GABA neurons of the VTA, inducing phosphorylation of signal-transducer-and-activator-of-transcription-3 (STAT3). Retrograde tracing combined with pSTAT3 immunohistochemistry show leptin-responsive VTA neurons projecting to nucleus accumbens (NAc). Assessing leptin function in the VTA, we showed that ob/ob mice had diminished locomotor response to amphetamine and lacked locomotor sensitization to repeated amphetamine injections, both defects reversed by leptin infusion. Electrically stimulated DA release from NAc shell terminals was markedly reduced in ob/ob slice preparations, and NAc DA levels and TH expression were lower. These data define a role for leptin in mesoaccumbens DA signaling and indicate that the mesoaccumbens DA pathway, critical to integrating motivated behavior, responds to this adipose-derived signal.

Neonatal and adult animals of five species were exposed to 95+% O2. Survival time and changes in lung antioxidant enzyme activity (superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GP)) in response to hyperoxia were determined. Adult animals succumbed to O2 lung toxicity in 3--5 days. Neonatal rats, mice and rabbits showed minimal lung changes after 7 days of hyperoxic exposure and these same neonatal animals showed rapid and significant increases in lung antioxidant enzyme activities. In contrast, neonatal guinea pigs and hamsters had no lung antioxidant enzyme response to hyperoxia and these neonates died in 95+% O2 as readily as their respective parent animals. Results from an in vitro hyperoxic exposure system suggest that the lack of enzymic response of the guinea pig (and hamster) neonates to O2 challenge is due to an inherent pulmonary biochemical unresponsiveness rather than to a deficiency of a necessary "serum factor." The results of this species and age study support the important role of the lung antioxidant enzyme defense system in protection of the lung from O2-induced injury.

The association between dietary obesity and mesolimbic systems that regulate hedonic aspects of feeding is currently unresolved. In the present study, we examined differences in baseline and stimulated central dopamine levels in obesity-prone (OP) and obesity-resistant (OR) rats. OP rats were hyperphagic and showed a 20% weight gain over OR rats at wk 15 of age, when fed a standard chow diet. This phenotype was associated with a 50% reduction in basal extracellular dopamine, as measured by a microdialysis probe in the nucleus accumbens, a projection site of the mesolimbic dopamine system that has been implicated in food reward. Similar defects were also observed in younger animals (4 wk old). In electrophysiology studies, electrically evoked dopamine release in slice preparations was significantly attenuated in OP rats, not only in the nucleus accumbens but also in additional terminal sites of dopamine neurons such as the accumbens shell, dorsal striatum, and medial prefrontal cortex, suggesting that there may be a widespread dysfunction in mechanisms regulating dopamine release in this obesity model. Moreover, dopamine impairment in OP rats was apparent at birth and associated with changes in expression of several factors regulating dopamine synthesis and release: vesicular monoamine transporter-2, tyrosine hydroxylase, dopamine transporter, and dopamine receptor-2 short-form. Taken together, these results suggest that an attenuated central dopamine system would reduce the hedonic response associated with feeding and induce compensatory hyperphagia, leading to obesity.

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SummaryTo determine if some specific "preparation for birth" occurs in the developing lung to help assure its successful adaptation to a comparatively 02-rich world at birth, we measured the activities of the antioxidant enzymes in the developing lungs of rabbit fetuses from 10 d before parturition to several days after birth. Superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GP) activities showed similar maturational patterns with significant increases id activity, compared with earlier gestational levels, during the last 3-5 d before birth. During the final days in utero, SOD and CAT activities increased by -110% and lung GP activity by -200%. There were no parallel changes in lung Oz consumption demonstrable over this same prenatal period. High concentrations of 0 2 are toxic to the lungs of all species, including man. The principal biochemical defense against 02-induced lung damage is generally accepted to be the antioxidant enzymes-SOD, CAT, and the GP system-and the lipid membrane constituent, Vitamin E (8,15,17,41). Studies from our own and other laboratories have established positive correlations between relative resistance to hyperoxia and increased levels of some or all of the pulmonary antioxidant enzymes (4,8,(15)(16)(17)41). It was noted a few years ago that SOD, CAT, and GP activities were all higher in the lungs of newborn rats than in the lungs of 2-d premature rat fetuses (43). In another study, SOD activity in the lungs from a small sampling of premature infants (26-32 wk gestation) ( n = 3) was found to be substantially lower than the SOD activity in the lungs of full-term newborns (n = 4) (1). These findings, combined with the fact that at birth the newborn leaves a hypoxic uterine environment (fetal arterial Poz -20-25 mm Hg) (7, 29) to enter a relatively hyperoxic 21% Oz environment, have made us wonder if some specific "preparation for birth" occurs in the developing lung to help assure its successful adaptation to a comparatively 02-rich world at birth. To examine the question, we have measured the activities of the antioxidant enzymes in the developing lungs of rabbit fetuses at intervals from 10 d before parturition (gestation period = 31.5 d) to several days after birth. We report here the changes in these protective enzymes that occur over this extended developmental period. Abbreviations MATERIALS AND METHODSAnimals. Pregnant California-strain rabbits were obtained from K-W Farms, Tice, FL. The exact breeding times (2 1 h) were provided by the supplier.All the fetuses used were delivered on the same day by hysterotomy under ketamine:xylazine anesthesia (90 mg/kg: 10 mg/kg) (Ketalar, Parke-Davis, Moms Plains, NJ; Rompun, Payvet Division-Cutter Labs, Shawnee, KS). All the pups used were sacrificed by an overdose of sodium pentobarbital administered intraperitoneally. The timed-gestations were interrupted at 2 1, 22, 26, 28, and 30 d. The pups used were <1-h old, 3-4-d-old, and 5-6-d-old. Adult does used for lung enzyme studies were sacrificed by pentobarbital over...

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Brain-derived neurotrophic factor (BDNF) and its receptor, TrkB, play prominent roles in food intake regulation through central mechanisms. However, the neural circuits underlying their anorexigenic effects remain largely unknown. We showed previously that selective BDNF depletion in the ventromedial hypothalamus (VMH) of mice resulted in hyperphagic behavior and obesity. Here, we sought to ascertain whether its regulatory effects involved the mesolimbic dopamine system, which mediates motivated and reward-seeking behaviors including consumption of palatable food. We found that expression of BDNF and TrkB mRNA in the ventral tegmental area (VTA) of wild-type mice was influenced by consumption of palatable, high-fat food (HFF). Moreover, amperometric recordings in brain slices of mice depleted of central BDNF uncovered marked deficits in evoked release of dopamine in the nucleus accumbens (NAc) shell and dorsal striatum but normal secretion in the NAc core. Mutant mice also exhibited dramatic increases in HFF consumption, which were exacerbated when access to HFF was restricted. However, mutants displayed enhanced responses to D 1 receptor agonist administration, which normalized their intake of HFF in a 4 h food intake test. Finally, in contrast to deletion of Bdnf in the VMH of mice, which resulted in increased intake of standard chow, BDNF depletion in the VTA elicited excessive intake of HFF but not of standard chow and increased body weights under HFF conditions. Our findings indicate that the effects of BDNF on eating behavior are neural substratedependent and that BDNF influences hedonic feeding via positive modulation of the mesolimbic dopamine system.

Summarveither by denaturation of intracellular enzymes andlor nucleoNeonatal rats (4-7 days old) and adult rats (approximately 8 0 days old) were continuously exposed to either 96-98% oxygen or air. Examination of the lungs of neonatal rats, who survived 5 days of oxygen exposure with no evidence of respiratory distress, showed significant increases in the pulmonary superoxide dismutase (SOD) activity (peak value: 144% of airexposed controls), glutathione peroxidase (GP) activity (126%), glutathione reductase (GR) activity (122%), reduced glutathione (GSH) level (176%), and glucose-6-phosphate dehydrogenase activity (151%). Adult rats, most of whom succumbed within 3 days of oxygen exposure, did not show any significant increase in the activities of pulmonary SOD, GP, GR, and the level of GSH as compared to the air-exposed adult animals. Glucose-6-phosphate dehydrogenase was significantly elevated in the 72-hr oxygen-exposed adult rats. It. is concluded that increases in the lung complement of SOD, GR, GP, and GSH in the neonatal rat during oxygen challenge may provide the mechanism(s) for their increased tolerance to hyperoxia-induced lung injury as compared to the adults. SpeculationFurther knowledge about the role of the antioxidant defense mechanism(s) of the neonatal lung may have important implications in the pursuit of the etiology of neonatal respiratory disease and in the identification of agent@) that may minimize pulmonary toxicity associated with oxygen therapy.