Behavioral pharmacology of 5-HT1A receptor ligands:Studies on the mechanism of action

Theorieën in de biologische psychiatrie over het ontstaan, de expressie en de farmacotherapie van angsttoestanden, impulsiviteitstoornissen (bijv. pathologische agressie en verslaving) en depressie, kennen veelal een centrale rol toe aan het neurotransmitter serotonine [5-hydroxytryptofaan: 5-HT; een chemische stof die de electrische boodschap doorgeeft tussen de presynaptische cel (waar 5-HT wordt aangemaakt) en de postsynaptische cel (waar 5-HT zijn werking uitoefend)]. Alhoewel de meeste klinische en door dierexperimenteel onderzoek verkregen evidentie enerzijds wijst op een hypoaktief serotonerg systeem in zowel pathologische agressie als depressie, en anderzijds op een hyperaktief systeem in angsttoestanden, is de precieze rol van 5-HT bij deze psychische ziekten nog omstreden. De ontdekking van een zevental verschillende 5-HT receptoren (bindingsplaatsen) in de hersenen van zoogdieren, en de ermee gepaard gaande synthese en ontwikkeling van stoffen die een aantal van deze receptoren selectief en met hoge affiiteit binden, stellen ons in staat de (dys)funktie van 5-HT in deze ziekten beter te begrijpen

Reversal learning and associative memory impairments in a BACHD rat model for Huntington disease

Chorea and psychiatric symptoms are hallmarks of Huntington disease (HD), a neurodegenerative disorder, genetically characterized by the presence of expanded CAG repeats (&gt;35) in the HUNTINGTIN (HTT) gene. HD patients present psychiatric symptoms prior to the onset of motor symptoms and we recently found a similar emergence of non motor and motor deficits in BACHD rats carrying the human full length mutated HTT (97 CAG-CAA repeats). We evaluated cognitive performance in reversal learning and associative memory tests in different age cohorts of BACHD rats. Male wild type (WT) and transgenic (TG) rats between 2 and 12 months of age were tested. Learning and strategy shifting were assessed in a cross-maze test. Associative memory was evaluated in different fear conditioning paradigms (context, delay and trace). The possible confound of a fear conditioning phenotype by altered sensitivity to a 'painful' stimulus was assessed in a flinch-jump test. In the cross maze, 6 months old TG rats showed a mild impairment in reversal learning. In the fear conditioning tasks, 4, 6 and 12 months old TG rats showed a marked reduction in contextual fear conditioning. In addition, TG rats showed impaired delay conditioning (9 months) and trace fear conditioning (3 months). This phenotype was unlikely to be affected by a change in 'pain' sensitivity as WT and TG rats showed no difference in their threshold response in the flinch-jump test. Our results suggest that BACHD rats have a profound associative memory deficit and, possibly, a deficit in reversal learning as assessed in a cross maze task. The time course for the emergence of these symptoms (i.e., before the occurrence of motor symptoms) in this rat model for HD appears similar to the time course in patients. These data suggest that BACHD rats may be a useful model for preclinical drug discovery.</p

Phosphodiesterase Type 4 Inhibition in CNS Diseases

Phosphodiesterases (PDEs) have been an interesting drug target for many diseases. Although a vast number of mainly preclinical studies demonstrates beneficial effects of PDE inhibitors for central nervous system (CNS) diseases, no drugs are currently available for CNS indications. In this review, we discuss the rationale of PDE4 inhibitors for different CNS diseases, including memory impairments, striatal disorders, multiple sclerosis (MS), and acquired brain injury (ABU). However, clinical development has been problematic due to mechanism-based adverse effects of these drugs in humans. Our increased understanding of factors influencing the conformational state of the PDE4 enzyme and of how to influence the binding affinity of PDE4 subtype inhibitors, holds promise for the successful development of novel selective PDE4 inhibitors with higher efficacy and fewer adverse effects

Meta-analysis of published cerebrospinal fluid proteomics data identifies and validates metabolic enzyme panel as Alzheimer's disease biomarkers

To develop therapies for Alzheimer's disease, we need accurate in vivo diagnostics. Multiple proteomic studies mapping biomarker candidates in cerebrospinal fluid (CSF) resulted in little overlap. To overcome this shortcoming, we apply the rarely used concept of proteomics meta-analysis to identify an effective biomarker panel. We combine ten independent datasets for biomarker identification: seven datasets from 150 patients/controls for discovery, one dataset with 20 patients/controls for down-selection, and two datasets with 494 patients/controls for validation. The discovery results in 21 biomarker candidates and down-selection in three, to be validated in the two additional large-scale proteomics datasets with 228 diseased and 266 control samples. This resulting 3-protein biomarker panel differentiates Alzheimer's disease (AD) from controls in the two validation cohorts with areas under the receiver operating characteristic curve (AUROCs) of 0.83 and 0.87, respectively. This study highlights the value of systematically re-analyzing previously published proteomics data and the need for more stringent data deposition

Near-infrared [Fe II] emission from supernova remnants and the supernova rate of starburst galaxies

In an effort to better calibrate the supernova rate of starburst galaxies as determined from near-IR [Fe II] features, we report on a [Fe II] 1.644 microns line-imaging survey of a sample of 42 optically-selected SNRs in M33. A wide range of [Fe II] luminosities are observed within our sample (from less than 6 to 695 L_sun). Our data suggest that the bright [Fe II] SNRs are entering the radiative phase and that the density of the local ISM largely controls the amount of [Fe II] emission. We derive the following relation between the [Fe II] 1.644 microns line luminosity of radiative SNRs and the electronic density of the postshock gas, n_e: L_[Fe II] (L_sun) ~ 1.1 n_e (cm^-3). We also find a correlation in our data between L_[Fe II] and the metallicity of the shock-heated gas, but the physical interpretation of this result remains inconclusive, as our data also show a correlation between the metallicity and n_e. The dramatically higher level of [Fe II] emission from SNRs in the central regions of starburst galaxies is most likely due to their dense environments, although metallicity effects might also be important. The typical [Fe II]-emitting lifetime of a SNR in the central regions of starburst galaxies is found to be of the order of 10^4 yr. On the basis of these results, we provide a new empirical relation allowing the determination of the current supernova rate of starburst galaxies from their integrated near-IR [Fe II] luminosity.Comment: 13 pages, 5 figures; accepted for publication in MNRA

Metallicity in the merger Seyfert galaxy NGC 6240

We have calculated the physical conditions throughout the NLR of the merger Seyfert galaxy NGC 6240 by modelling the observed optical and infrared line ratios. We have found that the optical spectra are emitted by clouds photoionised by the power-law radiation flux from the AGN (or AGNs), and heated mainly by the shock accompanying the propagation of the clouds outwards. The infrared line ratios are emitted from clouds ejected from a starburst which photoionises the gas by the black-body radiation flux corresponding to a stellar colour temperature of about 50,000 K. Both the flux from the AGN and the ionization parameters are low. The most characteristic physical parameters are the relatively high shock velocities (>400 km/s) and low preshock densities (about 40-60 cm-3) of the gas. The C/H, N/H, O/H relative abundances are higher than solar by a factor lower or about 1.5. We suggest that those high relative abundances indicate trapping of H into H2 molecules rather than high metallicities. Adopting an initial grain radius of 1 micron, the dust temperatures calculated in the clouds reached by the power-law radiation flux and by the black-body radiation flux are 81 K and 68 K, respectively.Comment: 14 pages, 5 figures, accepted for publication in MNRA

Gating Kinetics of Single Large-Conductance Ca2+-Activated K+ Channels in High Ca2+ Suggest a Two-Tiered Allosteric Gating Mechanism✪

The Ca2+-dependent gating mechanism of large-conductance calcium-activated K+ (BK) channels from cultured rat skeletal muscle was examined from low (4 μM) to high (1,024 μM) intracellular concentrations of calcium (Ca2+i) using single-channel recording. Open probability (Po) increased with increasing Ca2+i (K0.5 11.2 ± 0.3 μM at +30 mV, Hill coefficient of 3.5 ± 0.3), reaching a maximum of ∼0.97 for Ca2+i ∼ 100 μM. Increasing Ca2+i further to 1,024 μM had little additional effect on either Po or the single-channel kinetics. The channels gated among at least three to four open and four to five closed states at high levels of Ca2+i (>100 μM), compared with three to four open and five to seven closed states at lower Ca2+i. The ability of kinetic schemes to account for the single-channel kinetics was examined with simultaneous maximum likelihood fitting of two-dimensional (2-D) dwell-time distributions obtained from low to high Ca2+i. Kinetic schemes drawn from the 10-state Monod-Wyman-Changeux model could not describe the dwell-time distributions from low to high Ca2+i. Kinetic schemes drawn from Eigen's general model for a ligand-activated tetrameric protein could approximate the dwell-time distributions but not the dependency (correlations) between adjacent intervals at high Ca2+i. However, models drawn from a general 50 state two-tiered scheme, in which there were 25 closed states on the upper tier and 25 open states on the lower tier, could approximate both the dwell-time distributions and the dependency from low to high Ca2+i. In the two-tiered model, the BK channel can open directly from each closed state, and a minimum of five open and five closed states are available for gating at any given Ca2+i. A model that assumed that the apparent Ca2+-binding steps can reach a maximum rate at high Ca2+i could also approximate the gating from low to high Ca2+i. The considered models can serve as working hypotheses for the gating of BK channels