Peripheral administration of lactate produces antidepressant-like effects.

In addition to its role as metabolic substrate that can sustain neuronal function and viability, emerging evidence supports a role for l-lactate as an intercellular signaling molecule involved in synaptic plasticity. Clinical and basic research studies have shown that major depression and chronic stress are associated with alterations in structural and functional plasticity. These findings led us to investigate the role of l-lactate as a potential novel antidepressant. Here we show that peripheral administration of l-lactate produces antidepressant-like effects in different animal models of depression that respond to acute and chronic antidepressant treatment. The antidepressant-like effects of l-lactate are associated with increases in hippocampal lactate levels and with changes in the expression of target genes involved in serotonin receptor trafficking, astrocyte functions, neurogenesis, nitric oxide synthesis and cAMP signaling. Further elucidation of the mechanisms underlying the antidepressant effects of l-lactate may help to identify novel therapeutic targets for the treatment of depression

Erythropoietin restores glutathione peroxidase activity in 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine-induced neurotoxicity in C57BL mice and stimulates murine astroglial glutathione peroxidase production in vitro

Recently, we have reported that erythropoietin (Epo) provides neuroprotection in 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP)-induced neurotoxicity in vivo. In the present study, we investigated the effects of single Epo administration on brain antioxidant enzyme (superoxide dismutase (SOD) and glutathion peroxidase (GSHPx)) activities in this model in C57BL/6 mice. We found that MPTP treatment decreased GSHPx activity in both substantia nigra and striatum, and Epo restores nigral GSHPx activity decreased by MPTP. SOD enzyme activity was not significantly changed by MPTP and Epo treatment. Further, Epo stimulated astroglial GSHPx production in neonatal murine astroglial cell culture suggesting that the possible cell source for the stimulation of GSHPx activity by Epo in the MPTP-induced neurotoxicity model are astroglia. In conclusion, modulation of the astroglial antioxidant defense system might be one of the mechanisms by which Epo exerts a beneficial effect in MPTP-induced Parkinsonism. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved

Diurnal rhythms in quinpirole-induced locomotor behaviors and striatal D2/D3 receptor levels in mice

Dopaminergic drugs, including the D2/D3 agonist quinpirole, produce lasting changes in the brain that lead to altered behavioral responses. The action of these drugs is dosing time-dependent; in fruit flies, behavioral response to quinpirole shows a marked circadian variability. Here we demonstrate diurnal rhythm-dependent variations both in quinpirole-induced locomotor behaviors and in striatal D2 and D3 protein levels in mice. We found opposing diurnal rhythms in striatal D2 and D3 protein levels, resulting in a high D2/D3 ratio during the day and a low D2/D3 ratio at night. Protracted quinpirole treatment differentially altered striatal D2/D3 rhythms depending on the time of injection (i.e., day or night). When quinpirole-induced locomotor activity was analyzed for 90 min, we found hypomotility after the first day or nighttime drug injection. By the seventh injection, daytime quinpirole treatment produced clear hyperactivity while nighttime quinpirole treatment continued to induce a significant initial hypoactivity followed by a hyperactivity period. Our data indicate that quinpirole-induced long-term alterations in the brain include dosing time-dependent changes in dopamine receptor rhythms. Therefore, we propose that diurnal mechanisms, which participate in drug-induced long-term changes in the dopamine system, are important for the development of dopaminergic behaviors. (c) 2004 Elsevier Inc. All rights reserved

Involvement of the pineal gland in diurnal cocaine reward in mice

Contribution of circadian mechanisms to the psychostimulant-induced behaviors has been suggested. The pineal gland is important component of circadian mechanisms. Using pinealectomized mice and sham-operated controls, we tested the contribution of pineal gland to the rewarding effects of cocaine in conditioned place preference test. Experiments were performed both during the day and at night. Controls with intact pineal glands demonstrated significant decrease in cocaine-induced conditioned place preference at night compared to daytime, whereas pinealectomized mice did not show any diurnal differences. Circadian mechanisms regulated by the pineal gland thus appear critically involved in cocaine-induced reward. (C) 2004 Elsevier B.V. All rights reserved

Effects of footshock stress on superoxide dismutase and glutathione peroxidase enzyme activities and thiobarbituric acid reactive substances levels in the rat prefrontal cortex and striatum

Mild footshock stress results in an increase dopamine metabolism in the prefrontal cortex. Increases in either the intensity or duration of stress enhance dopamine metabolism in the nucleus accumbens and striatum, as well as in the prefrontal cortex. Dopamine is metabolized by monoamine oxidase with hydrogen peroxide as a product. In this study we have demonstrated that while very mild (0.2 mA) footshock stress did not change glutathione peroxidase activity in the rat prefrontal cortex and striatum, more intense (1.6 mA) footshock stress increased glutathione peroxidase activity at 0, 15, 30 and 60 min after the footshock in the prefrontal cortex and at 30 min after the footshock in the striatum. Stress did not change superoxide dismutase activity and thiobarbituric acid reactive substances levels. These results indicate that increased dopamine metabolism induced by footshock stress is probably responsible for the increase of glutathione peroxidase activity. (C) 2000 Elsevier Science Ireland Ltd. All rights reserved

Heat shock protein 70 expression in neonatal rats after hypoxic stress

Objectives: The tissue damage due to hypoxia in newborns is to some-extent age-dependent; organs of premature babies are more vulnerable to hypoxic insult than full-term neonates. The aim of this immunohistochemical study was to investigate the role of heat shock protein 70 (HSP70), a stress-inducible protein, in developing the response to hypoxia in premature newborns. Methods: Postnatal day-7 rats (corresponding to a human fetus of 32-34 weeks' gestation) and day-12 rats (corresponding to a full-term newborn infant) (n = 7) were subjected to mild hypoxia at 33°C. Control rats (n = 7) for each group breathed room air for 4 h. After 4 h of recovery, the animals were killed, and brains, hearts and kidneys were removed for immunohistochemical staining. Results: Immunohistochemically, HSP70 expression was found to be induced in the hippocampus and myocardium after exposure to hypoxia. The level of HSP70 expression in the hippocampus after hypoxic stress was significantly higher in the 12-day rats than in the 7-day rats (p = 0.03). However, HSP70 expression in the myocardium did not show any significant difference between the two groups. In addition, no significant induction of HSP70 expression was apparent in the kidney of rats exposed to hypoxia or in any organ of the control animals. Conclusions: We conclude that diminished HSP70 expression in the hippocampus of premature newborns may play a critical role in developing the response to hypoxic stress. However, HSP70 expression in the heart and the kidney after exposure to hypoxia did not appear to be related to fetal maturity