Sex differences in the murine HPA axis after acute and repeated restraint stress.

Chronic stress and stress-related mental illnesses such as major depressive disorder (MDD) constitute some of the leading causes of disability worldwide with a higher prevalence in women compared to men. However, preclinical research into stress and MDD is heavily biased toward using male animals only. Aberrant activity of the hypothalamic-pituitary-adrenal (HPA) axis has been linked to the development of MDD and several animal models of MDD have been established based on HPA axis dysregulation.

Advancements in NMDA Receptor-Targeted Antidepressants: From d-Cycloserine Discovery to Preclinical Efficacy of Lu AF90103.

The discovery of d-cycloserine (), a partial agonist of the NMDA receptor that exhibits antidepressant effects without the psychotomimetic effects of ketamine, has fueled interest in new NMDA-targeting antidepressants. Our objective was to identify potent partial agonists mirroring , particularly tailored for the GluN2B subtype of the NMDA receptor. Through a structure-based drug design approach, we discovered compound .

Ultrafast proton release reaction and primary photochemistry of phycocyanobilin in solution observed with fs-time-resolved mid-IR and UV/Vis spectroscopy.

Deactivation processes of photoexcited (λ = 580 nm) phycocyanobilin (PCB) in methanol were investigated by means of UV/Vis and mid-IR femtosecond (fs) transient absorption (TA) as well as static fluorescence spectroscopy, supported by density-functional-theory calculations of three relevant ground state conformers, PCB, PCB and PCB, their relative electronic state energies and normal mode vibrational analysis. UV/Vis fs-TA reveals time constants of 2.0, 18 and 67 ps, describing decay of PCB*, of PCB* and thermal re-equilibration of PCB, PCB and PCB, respectively, in line with the model by Dietzek et al.

In vitro and in vivo characterization of Lu AA41178: A novel, brain penetrant, pan-selective Kv7 potassium channel opener with efficacy in preclinical models of epileptic seizures and psychiatric disorders.

Activation of the voltage-gated Kv7 channels holds therapeutic promise in several neurological and psychiatric disorders, including epilepsy, schizophrenia, and depression. Here, we present a pharmacological characterization of Lu AA41178, a novel, pan-selective Kv7.2-7.

Real-time observation of molecular flattening and intersystem crossing in [(DPEPhos)Cu(i)(PyrTet)] via ultrafast UV/Vis- and mid-IR spectroscopy on solution and solid samples.

The primary photo-induced processes in the mononuclear, heteroleptic Cu(i) complex [(DPEPhos)Cu(PyrTet)] (1), relevant for OLED applications, were investigated in various solvents and in solid state samples via femtosecond (fs) time resolved UV/Vis and fs time resolved mid-IR transient absorption spectroscopy (TA) with MLCT excitation around 340 nm. UV/Vis fs-TA on 1 in solution reveals (i) a severe blue-shift of excited state absorption on the time scale of a few picoseconds (τ) that is not observed in solids, and (ii), on the time scale of several tens of picoseconds (τ), a process with very similar dynamics in all samples. Mid-IR fs-TA in solution indicates structural changes with τ.

Effect of ADHD medication in male C57BL/6J mice performing the rodent Continuous Performance Test.

Rationale: The rodent Continuous Performance Test (rCPT) is a novel rodent paradigm to assess attention and impulsivity that resembles the human CPT. This task measures the rodents' ability to discriminate between target and non-target stimuli. The effect of attention-deficit/hyperactivity disorder (ADHD) medication on rCPT performance in mice remains to be fully characterized.

Photophysical dynamics of a binuclear Cu(i)-emitter on the fs to μs timescale, in solid phase and in solution.

Understanding subtle aspects of photophysical behavior is the key to design and synthesize new and improved luminescent materials. We contribute to this with an in-depth photophysical characterization of the binuclear copper complex Cu(i)-NHetPHOS-tris-m-tolylphosphine (1), a member of a recently established emitter class for ultra-efficient, printed organic light-emitting diodes (OLEDs). To this end we studied 1 in solution and in solid form, i.

Acute dosing of vortioxetine strengthens event-related brain activity associated with engagement of attention and cognitive functioning in rats.

Studies of the antidepressant vortioxetine have demonstrated beneficial effects on cognitive dysfunction associated with depression. To elucidate how vortioxetine modulates neuronal activity during cognitive processing we investigated the effects of vortioxetine (3 and 10mg/kg) in rats performing an auditory oddball (deviant target) task. We investigated neuronal activity in target vs non-target tone responses in vehicle-treated animals using electroencephalographic (EEG) recordings.

Adapted wavelet transform improves time-frequency representations: a study of auditory elicited P300-like event-related potentials in rats.

Objective: Active auditory oddball paradigms are simple tone discrimination tasks used to study the P300 deflection of event-related potentials (ERPs). These ERPs may be quantified by time-frequency analysis. As auditory stimuli cause early high frequency and late low frequency ERP oscillations, the continuous wavelet transform (CWT) is often chosen for decomposition due to its multi-resolution properties.

Targeting α4β2 nicotinic acetylcholine receptors in central nervous system disorders: perspectives on positive allosteric modulation as a therapeutic approach.

The nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels broadly involved in regulating neurotransmission in the central nervous system (CNS) by conducting cation currents through the membrane of neurons. Many different nAChR subtypes exist with each their functional characteristics, expression pattern and pharmacological profile. The focus of the present MiniReview is on the heteromeric α4β2 nAChR, as activity at this subtype contributes to cognitive functioning through interactions with multiple neurotransmitter systems and is implicated in various CNS disorders, for example schizophrenia and Alzheimer's disease.

Neuropharmacological modulation of the P3-like event-related potential in a rat two-tone auditory discrimination task with modafinil and NS9283, a positive allosteric modulator of α4β2 nAChRs.

The P300 (P3) event-related potential (ERP) is a neurophysiological signal believed to reflect cognitive processing of salient cues, and is thus used as a measure of attention and working memory. Additionally, P3 amplitude and latency is altered in neurological diseases and can be pharmacologically modulated. As P3-like ERPs can be recorded in rodents, it may serve as a potential translational biomarker of value for drug discovery.

Selective potentiation of (α4)3(β2)2 nicotinic acetylcholine receptors augments amplitudes of prefrontal acetylcholine- and nicotine-evoked glutamatergic transients in rats.

Prefrontal glutamate release evoked through activation of α4β2* nicotinic acetylcholine receptors (nAChRs) situated on thalamic glutamatergic afferents mediates cue detection processes and thus contributes to attentional performance. However, little is known about the respective contributions of the high sensitivity and low sensitivity (LS) stoichiometries of the α4β2 nAChR, (α4)2(β2)3 and (α4)3(β2)2, to these processes. In the present study we employed glutamate-sensitive microelectrodes and the (α4)3(β2)2-selective positive allosteric modulator (PAM) NS9283 to investigate the importance of the LS α4β2 nAChR for glutamate release in the rat medial prefrontal cortex (mPFC).

Unravelling the mechanism of action of NS9283, a positive allosteric modulator of (α4)3(β2)2 nicotinic ACh receptors.

Background And Purpose: Strong implications in major neurological diseases make the neuronal α4β2 nicotinic ACh receptor (nAChR) a highly interesting drug target. In this study, we present a detailed electrophysiological characterization of NS9283, a potent positive allosteric modulator acting selectively at 3α:2β stoichiometry of α2* and α4* nAChRs.

Experimental Approach: The whole-cell patch-clamp technique equipped with an ultra-fast drug application system was used to perform electrophysiological characterization of NS9283 modulatory actions on human α4β2 nAChRs stably expressed in HEK293 cells (HEK293-hα4β2).

Activation of store-operated I(CRAC) by hydrogen peroxide.

Reactive oxygen species (ROS) such as hydrogen peroxide (H2O2) play a role in both innate immunity as well as cellular injury. H2O2 induces changes in intracellular calcium ([Ca(2+)]i) in many cell types and this seems to be at least partially mediated by transient receptor potential melastatin 2 (TRPM2) in cells that express this channel. Here we show that low concentrations of H2O2 induce the activation of the Ca(2+)-release activated Ca(2+) current I(CRAC).

[Freiburg intervention program for ambulatory therapy of obesity in childhood (FITOC)].

In this study we first try to answer the question, whether it is possible to make a successful treatment for obese children in an interdisciplinary program. Second it is asked whether a transfer of this program to further regions in Germany leads to comparable results. In FITOC children from the age of 8-11 years and over the 97.

Amino acid residues of heparin cofactor II required for stimulation of thrombin inhibition by sulphated polyanions.

A variety of sulphated polyanions in addition to heparin and dermatan sulphate stimulate the inhibition of thrombin by heparin cofactor II (HCII). Previous investigations indicated that the binding sites on HCII for heparin and dermatan sulphate overlap but are not identical. In this study we determined the concentrations (IC50) of various polyanions required to stimulate thrombin inhibition by native recombinant HCII in comparison with three recombinant HCII variants having decreased affinity for heparin (Lys-173-->Gln), dermatan sulphate (Arg-189-->His), or both heparin and dermatan sulphate (Lys-185-->Asn).

Synthesis of apolipoprotein A-1 in pig brain microvascular endothelial cells.

In an approach toward the identification of hitherto unknown proteins involved in the function of the blood-brain barrier, we constructed a pig brain microvessel-derived cDNA library that is enriched in blood-brain barrier specific sequences by means of subtractive cloning. Sequence analysis of selected clones revealed that one of the cDNAs encoded porcine apolipoprotein (apo) A-1. The identity of apo A-1 mRNA was further confirmed by in vitro translation of RNA from brain microvascular endothelial cells and subsequent immunoprecipitation with an antibody against human apo A-1.