Tetrahydrobiopterin modulates the behavioral neuroinflammatory response to an LPS challenge in mice.

Tetrahydrobiopterin (BH4) is a necessary cofactor for the synthesis of monoamines from essential amino-acids, phenylalanine, tyrosine and tryptophan. The BH4 synthesis pathway is induced by inflammatory factors but highly regulated processes maintain levels in a physiological range. However, BH4 activity can be durably altered in inflammation-related pathologies, such as certain types of depression, potentially involving impairment of dopaminergic neurotransmission. The purpose of this study was to investigate the response of the brain BH4 pathway to the inflammatory stimulus induced by lipopolysaccharide (LPS) in mice. Brain expression of genes related to BH4 synthesis, levels of BH4, changes in L-aromatic amino acid precursors of monoamines and dopamine levels were determined. As secondary aim, the effect of acute BH4 supply under the inflammatory challenge was tested on these parameters and on the expression of inflammatory cytokines. Mice were also submitted to the sucrose preference test and to the open-field in order to asses hedonic and locomotor responses to LPS, in addition to their modulation by BH4 supply. The LPS challenge resulted in decreased striatal DA levels and increased Phenylalanine/Tyrosine ratio, suggesting reduced BH4 activity. BH4 supply was effective to increase striatal BH4 levels, to restore the LPS-induced decreased in DA levels in striatum and to dampen the LPS-induced expression of inflammatory cytokines. At the behavioral level, BH4 supply was able to restore the loss of locomotor response to amphetamine in the LPS treated mice, suggesting a modulation of the dopaminergic neurotransmission. These data suggest that BH4 can be considered as a potential add-on molecule, helping to maintain or restore dopaminergic neurotransmission in neuroinflammatory conditions..

Tetrahydrobioterin (BH4) Pathway: From Metabolism to Neuropsychiatry.

Tetrahydrobipterin (BH4) is a pivotal enzymatic cofactor required for the synthesis of serotonin, dopamine and nitric oxide. BH4 is essential for numerous physiological processes at periphery and central levels, such as vascularization, inflammation, glucose homeostasis, regulation of oxidative stress and neurotransmission. BH4 de novo synthesis involves the sequential activation of three enzymes, the major controlling point being GTP cyclohydrolase I (GCH1). Complementary salvage and recycling pathways ensure that BH4 levels are tightly kept within a physiological range in the body. Even if the way of transport of BH4 and its ability to enter the brain after peripheral administration is still controversial, data showed increased levels in the brain after BH4 treatment. Available evidence shows that GCH1 expression and BH4 synthesis are stimulated by immunological factors, notably pro-inflammatory cytokines. Once produced, BH4 can act as an anti- inflammatory molecule and scavenger of free radicals protecting against oxidative stress. At the same time, BH4 is prone to autoxidation, leading to the release of superoxide radicals contributing to inflammatory processes, and to the production of BH2, an inactive form of BH4, reducing its bioavailability. Alterations in BH4 levels have been documented in many pathological situations, including Alzheimer's disease, Parkinson's disease and depression, in which increased oxidative stress, inflammation and alterations in monoaminergic function are described. This review aims at providing an update of the knowledge about metabolism and the role of BH4 in brain function, from preclinical to clinical studies, addressing some therapeutic implications.

Tetrahydrobiopterin administration facilitates amphetamine-induced dopamine release and motivation in mice.

Dopamine (DA) is a critical neurotransmitter involved in motivational processes. Tetrahydrobiopterin (BH4) is an essential cofactor for tyrosine hydroxylase, the rate-limiting enzyme in DA synthesis. Decreases in BH4 levels are observed in several DA-related neuropsychiatric diseases involving impairment in motivation. Yet, whether BH4 could be used to treat motivational deficits has not been comprehensively investigated. To investigate the effects of exogenous BH4 administration on the dopaminergic system and related behaviors, we acutely injected mice with BH4 (50 mg/kg). Passage of BH4 through the blood brain barrier and accumulation in brain was measured using the in situ brain perfusion technique. DA release was then recorded using in-vivo micro-dialysis and motivation was evaluated through operant conditioning paradigms in basal condition and after an amphetamine (AMPH) injection. First, we showed that BH4 crosses the blood-brain barrier and that an acute peripheral injection of BH4 is sufficient to increase the concentrations of biopterins in the brain, without affecting BH4- and DA-related protein expression. Second, we report that this increase in BH4 enhanced AMPH-stimulated DA release in the nucleus accumbens. Finally, we found that BH4-induced DA release led to improved performance of a motivational task. Altogether, these findings suggest that BH4, through its action on the dopaminergic tone, could be used as a motivational enhancer.

Impact of perinatal exposure to high-fat diet and stress on responses to nutritional challenges, food-motivated behaviour and mesolimbic dopamine function.

BACKGROUND/OBJECTIVES: Energy-dense food exposure and stress during development have been suggested to contribute to obesity and metabolic disorders later in life. Although these factors are frequently associated, the effects of their combination have not yet been investigated. In this study, using an animal model, we examined the long-term impact of maternal high-fat diet (HFD) and early-life stress (ELS) on energy homoeostasis control and food motivation. METHODS: Body weight growth under HFD, adipose tissue, body weight control in response to fasting and refeeding, food-motivated behaviour and mesolimbic dopamine function were examined in adult male offspring exposed to maternal HFD (during gestation and lactation) and/or ELS (maternal separation 3 h per day from postnatal day 2 to 14). RESULTS: Maternal HFD or ELS alone had no significant effect on offspring body weight; however, the combination of these factors exacerbated body weight gain when animals were exposed to HFD after weaning. There are no other significant combinatory effects of these perinatal events. In contrast, independently of the maternal diet, ELS disrupted body weight control during a fasting-refeeding procedure, increased adipose tissue mass and altered lipid metabolism. Finally, maternal HFD and ELS both resulted in exacerbated food-motivated behaviour and blunted dopamine release in the nucleus accumbens during palatable food consumption. CONCLUSIONS: We report a synergistic effect of perinatal HFD exposure and stress on the susceptibility to gain weight under HFD. However, ELS has a stronger impact than maternal HFD exposure on energy homoeostasis and food motivation in adult offspring. Altogether, our results suggest a programming effect of stress and nutrition supporting the hypothesis of the developmental origin of health and disease.

Proton-proton correlations at small relative momentum in neon-nucleus collisions at E/A=400 and 800 MeV.

Proton-proton small angle correlations have been measured in neon-nucleus collisions, using the 4 pi detector Diogene, at 400 and 800 MeV per nucleon incident energies. Values of the size of the emitting region are obtained by comparison with the Koonin formula, taking into account the biases of the apparatus. The dependence of the density on target mass and incident energy is also analysed.

The Diogene 4 pi detector at Saturne.

Diogene, an electronic 4 pi detector, has been built and installed at the Saturne synchrotron in Saclay. The forward angular range (0 degree-6 degrees) is covered by 48 time-of-flight scintillator telescopes that provide charge identification. The trajectories of fragments emitted at larger angles are recorded in a cylindrical 0.4-m3 Pictorial Drift Chamber (PDC) surrounding the target. The PDC is inside a 1-T magnetic field; the axis of the PDC cylinder and the magnetic field are parallel to the beam. Good identification has been obtained for both positive and negative pi mesons and for hydrogen and helium isotopes. Multiplicities in relativistic nucleus-nucleus reactions up to 40 have been detected, limited mainly by the present electronics.