The fibroblast growth factor system and mood disorders.

Recent evidence now suggests the involvement of the fibroblast growth factor (FGF) system in mood disorders. Specifically, several members of the FGF family have been shown to be dysregulated in individuals with major depression. In this review, we will introduce the FGF system in terms of structure and function during development, in adulthood, and in various regions and cell types. We will also review the FGF system as a mediator of neural plasticity. Furthermore, this review will summarize animal as well as human studies. The majority of animal studies have focused on stress, environmental enrichment, pharmacological manipulations, and the hippocampus. By contrast, human studies have focused on volumetric measurements, antidepressant literature, and, most recently, post-mortem microarray experiments. In summary, a reduced tone in the FGF system might alter brain development or remodeling and result in a predisposition or vulnerability to mood disorders, including major depression.     

Intracerebroventricular self-administration of commonly abused anabolic-androgenic steroids in male hamsters (Mesocricetus auratus): nandrolone, drostanolone, oxymetholone, and stanozolol

Previous studies by the authors have shown voluntary intracerebroventricular (icv) testosterone self-administration in hamsters (Mesocricetus auratus). Here, the authors compared icv self-administration of 4 anabolic steroids (drostanolone, nandrolone, oxymetholone, and stanozolol) at 0.1, 1.0, and 2.0 microg/microl, each for 8 days. Males (n=8/group) showed the highest levels of operant behavior for injectable steroids (drostanolone, nandrolone) compared with orally active androgens (oxymetholone, stanozolol). For nandrolone, responses on the active and inactive nose-pokes averaged 22.3 +/- 4.6/4 hr and 10.7 +/- 2.0/4 hr, respectively. Responding for drostanolone was similar. Males self-administering oxymetholone or stanozolol did not prefer the active nose-poke. These data demonstrate that injectable androgens are more reinforcing than oral steroids.     

Brief report: illness uncertainty and dispositional self-focus in adolescents and young adults with childhood-onset asthma

OBJECTIVE: To investigate differences in self-focused attention between college students with childhood-onset asthma and a group of healthy controls and to determine whether self-focused attention mediates the relationship between illness uncertainty and psychological distress among individuals with asthma. METHODS: Forty-two adolescent and young adult participants with childhood-onset asthma and 40 age- and gender-matched healthy participants completed measures of self-focused attention, perceived illness uncertainty, psychological distress, and health status. RESULTS: Adolescents and young adults with childhood-onset asthma evidenced an increased tendency to engage in private self-focus compared to age- and gender-matched peers without a chronic illness history. Self-focused attention also mediated the relationship between perceived illness uncertainty and psychological distress among those with asthma. CONCLUSIONS: The need for self-monitoring in asthma management may result in an increased propensity to self-focus, which may result in heightened levels of psychological distress.     

Cocaine interacts with the novelty-seeking trait to modulate FGFR1 gene expression in the rat

The present study sought to determine the interaction between the novelty-seeking trait and cocaine treatment on gene expression in the fibroblast growth factor (FGF) system. Specifically, we assessed the regulation of FGFR1 in response to cocaine in animals that were selectively bred on the basis of their locomotor response to a novel environment. High-responder (HR) rats are those that exhibit increased locomotor response and exploratory behavior in a novel environment and low-responder (LR) rats are those that exhibit lower levels of exploratory behavior and are less active. Both phenotypes received daily injections of either cocaine (15 mg/kg, i.p.) or saline for 7 consecutive days. Animals were sacrificed 45 min following their last injection and FGFR1 gene expression was assessed in the hippocampus and prefrontal cortex by mRNA in situ hybridization. HR-bred rats exhibited increased FGFR1 mRNA in the hippocampus compared to LR-bred rats. Furthermore, cocaine decreased FGFR1 mRNA in the hippocampus and increased FGFR1 mRNA in the prefrontal cortex. Finally, HR and LR rats differed in their response to cocaine between brain regions. In the hippocampus, cocaine decreased gene expression in HR-bred rats without affecting LR-bred rats, whereas in the prefrontal cortex cocaine increased gene expression in LR-bred rats without affecting HR-bred rats. These results suggest that cocaine interacts with the novelty-seeking trait to alter gene expression. Thus, the FGF system may contribute to individual differences in the response to drugs of abuse.     

Evaluation of the Novel Combination of High-Dose Daptomycin plus Trimethoprim-Sulfamethoxazole against Daptomycin-Nonsusceptible Methicillin-Resistant Staphylococcus aureus Using an In Vitro Pharmacokinetic/Pharmacodynamic Model of Simulated Endocardial Vegetations

Daptomycin-nonsusceptible (DNS) Staphylococcus aureus is found in difficult-to-treat infections, and the optimal therapy is unknown. We investigated the activity of high-dose (HD) daptomycin plus trimethoprim-sulfamethoxazole de-escalated to HD daptomycin or trimethoprim-sulfamethoxazole against 4 clinical DNS methicillin-resistant S. aureus (MRSA) isolates in an in vitro pharmacokinetic/pharmacodynamic model of simulated endocardial vegetations (10⁹ CFU/g). Simulated regimens included HD daptomycin at 10 mg/kg/day for 14 days, trimethoprim-sulfamethoxazole at 160/800 mg every 12 h for 14 days, HD daptomycin plus trimethoprim-sulfamethoxazole for 14 days, and the combination for 7 days de-escalated to HD daptomycin for 7 days and de-escalated to trimethoprim-sulfamethoxazole for 7 days. Differences in CFU/g (at 168 and 336 h) were evaluated by analysis of variance (ANOVA) with a Tukey''s post hoc test. Daptomycin MICs were 4 μg/ml (SA H9749-1, vancomycin-intermediate Staphylococcus aureus; R6212, heteroresistant vancomycin-intermediate Staphylococcus aureus) and 2 μg/ml (R5599 and R5563). Trimethoprim-sulfamethoxazole MICs were ≤0.06/1.19 μg/ml. HD daptomycin plus trimethoprim-sulfamethoxazole displayed rapid bactericidal activity against SA H9749-1 (at 7 h) and R6212 (at 6 h) and bactericidal activity against R5599 (at 72 h) and R5563 (at 36 h). A ≥8 log₁₀ CFU/g decrease was observed with HD daptomycin plus trimethoprim-sulfamethoxazole against all strains (at 48 to 144 h), which was maintained with de-escalation to HD daptomycin or trimethoprim-sulfamethoxazole at 336 h. The combination for 14 days and the combination for 7 days de-escalated to HD daptomycin or trimethoprim-sulfamethoxazole was significantly better than daptomycin monotherapy (P < 0.05) and trimethoprim-sulfamethoxazole monotherapy (P < 0.05) at 168 and 336 h. Combination therapy followed by de-escalation offers a novel bactericidal therapeutic alternative for high-inoculum, serious DNS MRSA infections.     

Fibroblast growth factor-2 (FGF2) augmentation early in life alters hippocampal development and rescues the anxiety phenotype in vulnerable animals

Individuals with mood disorders exhibit alterations in the fibroblast growth factor system, including reduced hippocampal fibroblast growth factor-2 (FGF2). It is difficult, however, to pinpoint whether these alterations are a cause or consequence of the disorder. The present study asks whether FGF2 administered the day after birth has long-lasting effects on hippocampal development and emotionality. We show that early-life FGF2 shifts the pace of neurogenesis, with an early acceleration around weaning followed by a deceleration in adulthood. This, in turn, results in a denser dentate gyrus with more neurons. To assess the impact of early-life FGF2 on emotionality, we use rats selectively bred for differences in locomotor response to novelty. Selectively bred low-responder (bLR) rats show low levels of novelty-induced locomotion and exhibit high levels of anxiety- and depression-like behavior compared with their selectively bred high-responder counterparts. Early-life FGF2 decreased anxiety-like behavior in highly anxious bLRs without altering other behaviors and without affecting high-responder rats. Laser capture microscopy of the dentate gyrus followed by microarray analysis revealed genes that were differentially expressed in bLRs exposed to early-life FGF2 vs. vehicle-treated bLRs. Some of the differentially expressed genes that have been positively associated with anxiety were down-regulated, whereas genes that promote cell survival were up-regulated. Overall, these results show a key role for FGF2 in the developmental trajectory of the hippocampus as well as the modulation of anxiety-like behavior in adulthood, and they point to potential downstream targets for the treatment of anxiety disorders.     

A micropuncture study of the relationship between flow-rate through the loop of Henle and sodium concentration in the early distal tubule

Summary In the rat kidney, single loops of Henle were perfused with 0.9% NaCl at different perfusion rates after the single nephron filtrate was blocked by injection of oil into the proximal convolution proximal to the infusion site. Samples collected from an early distal segment had higher sodium concentrations at high perfusion rates. This increased sodium concentration with increased perfusion rate is consistent with the hypothesis that sodium concentration at the macula densa site of the nephron provides a stimulus for a feedback mechanism regulating glomerular filtration rate through the renin containing juxtaglomerular cells in juxtaposition with the macula densa cells and the afferent glomerular arteriole.

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Zusammenfassung In Rattennieren wurden einzelne Henlesche Schleifen mit 0,9% Natriumchloridlösung mit unterschiedlichen Stromstärken perfundiert. Das proximale Konvolut war glomerulumnah mit Öl gefüllt, um eine Beimengung von glomerulär filtrierter Flüssigkeit zur Perfusionslösung zu vermeiden. Die Natriumkonzentration am Beginn des distalen Konvolutes der perfundierten Nephrone stieg mit steigender Perfusionsstromstärke an. Unter der Voraussetzung einer mit dem Glomerulumfiltrat ansteigenden Stromstärke in der Henleschen Schleife stehen die vorliegenden Befunde mit der Hypothese in Einklang, daß die Natriumkonzentration an den Macula densa-Zellen einen regulierenden Faktor für das Glomerulumfiltrat darstellt.

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With 3 Figures in the Text

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Supported by the Deutsche Forschungsgemeinschaft and the U. S. Department of the Army, European Research Office.