Anti-Alcohol and Anxiolytic Properties of a New Chemical Entity, GET73

N-[(4-trifluoromethyl)benzyl]4-methoxybutyramide (GET73) is a newly synthesized compound structurally related to the clinically used, alcohol-substituting agent, gamma-hydroxybutyric acid (GHB). The present study was designed to assess whether GET73 may share with GHB the capacity to reduce alcohol intake in rats. Additionally, the effect of treatment with GET73 on anxiety-related behaviors and cognitive tasks in rats was investigated. A series of in vitro binding assays investigated the capacity of GET73 to bind to the GHB binding site and multiple other receptors. GET73 (10−9–10−3 M) failed to inhibit [3H]GHB binding at both high- and low-affinity GHB recognition sites in rat cortical membranes. GET73 displayed minimal, if any, binding at dopamine, serotonin, GABA, and glutamate receptors in membranes from different rat brain areas. Acute treatment with low-to-moderate, non-sedative doses of GET73 (5–50 mg/kg, i.g. or i.p.) (a) reduced alcohol intake and suppressed “alcohol deprivation effect” (a model of alcohol relapse) in selectively bred, Sardinian alcohol-preferring (sP) rats, (b) exerted anxiolytic effects in Sprague-Dawley (SD) and sP rats exposed to the Elevated Plus Maze test, and (c) tended to induce promnestic effects in SD rats exposed to a modified water version of the Hebb–Williams maze test. Although the mechanism of GET73 action is currently unknown, the results of the present study suggest that GET73 has a multifaceted pharmacological profile, including the capacity to reduce alcohol drinking and anxiety-related behaviors in rats

NMDARs Mediate the Role of Monoamine Oxidase A in Pathological Aggression

This is the publisher's version, also available electronically from http://www.jneurosci.org/content/32/25/8574Converging evidence shows that monoamine oxidase A (MAO A), the key enzyme catalyzing serotonin (5-hydroxytryptamine; 5-HT) and norepinephrine (NE) degradation, is a primary factor in the pathophysiology of antisocial and aggressive behavior. Accordingly, male MAO A-deficient humans and mice exhibit an extreme predisposition to aggressive outbursts in response to stress. As NMDARs regulate the emotional reactivity to social and environmental stimuli, we hypothesized their involvement in the modulation of aggression mediated by MAO A. In comparison with WT male mice, MAO A KO counterparts exhibited increases in 5-HT and NE levels across all brain regions, but no difference in glutamate concentrations and NMDAR binding. Notably, the prefrontal cortex (PFC) of MAO A KO mice exhibited higher expression of NR2A and NR2B, as well as lower levels of glycosylated NR1 subunits. In line with these changes, the current amplitude and decay time of NMDARs in PFC was significantly reduced. Furthermore, the currents of these receptors were hypersensitive to the action of the antagonists of the NMDAR complex (dizocilpine), as well as NR2A (PEAQX) and NR2B (Ro 25-6981) subunits. Notably, systemic administration of these agents selectively countered the enhanced aggression in MAO A KO mice, at doses that did not inherently affect motor activity. Our findings suggest that the role of MAO A in pathological aggression may be mediated by changes in NMDAR subunit composition in the PFC, and point to a critical function of this receptor in the molecular bases of antisocial personality

The aggression and behavioral abnormalities associated with monoamine oxidase A deficiency are rescued by acute inhibition of serotonin reuptake

The termination of serotonin (5-hydroxytryptamine, 5-HT) neurotransmission is regulated by its uptake by the 5-HT transporter (5-HTT), as well as its degradation by monoamine oxidase (MAO)-A. MAO-A deficiency results in a wide set of behavioral alterations, including perseverative behaviors and social deficits. These anomalies are likely related to 5-HTergic homeostatic imbalances; however, the role of 5-HTT in these abnormalities remains unclear. To ascertain the role of 5-HTT in the behavioral anomalies associated to MAO-A deficiency, we tested the behavioral effects of its blocker fluoxetine on perseverative, social and aggressive behaviors in transgenic animals with hypomorphic or null-allele MAO-A mutations. Acute treatment with 5-HTT blocker fluoxetine (10 mg/kg, i.p.) reduced aggressive behavior in MAO-A knockout (KO) mice and social deficits in hypomorphic MAO-ANeo mice. Furthermore, this treatment also reduced perseverative responses (including marble burying and water mist-induced grooming) in both MAO-A mutant genotypes. Both MAO-A mutant lines displayed significant reductions in 5-HTT expression across the prefrontal cortex, amygdala and striatum, as quantified by immunohistochemical detection; however, the down-regulation of 5-HTT in MAO-ANeo mice was more pervasive and widespread than in their KO counterparts, possibly indicating a greater ability of the hypomorphic line to enact compensatory mechanisms with respect to 5-HT homeostasis. Collectively, these findings suggest that the behavioral deficits associated with low MAO-A activity may reflect developmental alterations of 5-HTT within 5-HTergic neurons. Furthermore, the translational implications of our results highlight 5-HT reuptake inhibition as an interesting approach for the control of aggressive outbursts in MAO-A deficient individuals

Enhanced endocannabinoid-mediated modulation of rostromedial tegmental nucleus drive onto dopamine neurons in sardinian alcohol-preferring rats

The progressive predominance of rewarding effects of addictive drugs over their aversive properties likely contributes to the transition from drug use to drug dependence. By inhibiting the activity of DA neurons in the VTA, GABA projections from the rostromedial tegmental nucleus (RMTg) are well suited to shift the balance between drug-induced reward and aversion. Since cannabinoids suppress RMTg inputs to DA cells and CB1 receptors affect alcohol intake in rodents, we hypothesized that the endocannabinoid system, by modulating this pathway, might contribute to alcohol preference. Here we found that RMTg afferents onto VTA DA neurons express CB1 receptors and display a 2-arachidonoylglycerol (2-AG)-dependent form of short-term plasticity, that is, depolarization-induced suppression of inhibition (DSI). Next, we compared rodents with innate opposite alcohol preference, the Sardinian alcohol-preferring (sP) and alcohol-nonpreferring (sNP) rats. We found that DA cells from alcohol-naive sP rats displayed a decreased probability of GABA release and a larger DSI. This difference was due to the rate of 2-AG degradation. In vivo, we found a reduced RMTg-induced inhibition of putative DA neurons in sP rats that negatively correlated with an increased firing. Finally, alcohol failed to enhance RMTg spontaneous activity and to prolong RMTg-induced silencing of putative DA neurons in sP rats. Our results indicate functional modifications of RMTg projections to DA neurons that might impact the reward/aversion balance of alcohol attributes, which may contribute to the innate preference observed in sP rats and to their elevated alcohol intak

Predisposition to Alcohol Drinking and Alcohol Consumption Alter Expression of Calcitonin Gene-Related Peptide, Neuropeptide Y, and Microglia in Bed Nucleus of Stria Terminalis in a Subnucleus-Specific Manner

Excessive alcohol consumption is often linked to anxiety states and has a major relay center in the anterior part of bed nucleus of stria terminalis (BNST). We analyzed the impact of (i) genetic predisposition to high alcohol preference and consumption, and (ii) alcohol intake on anterior BNST, namely anterolateral (AL), anteromedial (AM), and anteroventral (lateral + medial subdivisions: AVl, AVm) subnuclei. We used two rat lines selectively bred for low- and high-alcohol preference and consumption, named Sardinian alcohol-non preferring (sNP) and -preferring (sP), respectively, the latter showing also inherent anxiety-related behaviors. We analyzed the modulation of calcitonin gene-related peptide (CGRP; exerting anxiogenic effects in BNST), neuropeptide Y (NPY; exerting mainly anxiolytic effects), and microglia activation (neuroinflammation marker, thought to increase anxiety). Calcitonin gene-related peptide-immunofluorescent fibers/terminals did not differ between alcohol-naive sP and sNP rats. Fiber/terminal NPY-immunofluorescent intensity was lower in BNST-AM and BNST-AVm of alcohol-naive sP rats. Activation of microglia (revealed by morphological analysis) was decreased in BNST-AM and increased in BNST-AVm of alcohol-naive sP rats. Prolonged (30 consecutive days), voluntary alcohol intake under the homecage 2-bottle “alcohol vs. water” regimen strongly increased CGRP intensity in BNST of sP rats in a subnucleus-specific manner: in BNST-AL, BNST-AVm, and BNST-AM. CGRP area sum, however, decreased in BNST-AM, without changes in other subnuclei. Alcohol consumption increased NPY expression, in a subnucleus-specific manner, in BNST-AL, BNST-AVl, and BNST-AVm. Alcohol consumption increased many size/shapes parameters in microglial cells, indicative of microglia de-activation. Finally, microglia density was increased in ventral anterior BNST (BNST-AVl, BNST-AVm) by alcohol consumption. In conclusion, genetic predisposition of sP rats to high alcohol intake could be in part mediated by anterior BNST subnuclei showing lower NPY expression and differential microglia activation. Alcohol intake in sP rats produced complex subnucleus-specific changes in BNST, affecting CGRP/NPY expression and microglia and leading to hypothesize that these changes might contribute to the anxiolytic effects of voluntarily consumed alcohol repeatedly observed in sP rats

The SEGUE Stellar Parameter Pipeline. I. Description and Initial Validation Tests

We describe the development and implementation of the SEGUE (Sloan Extension for Galactic Exploration and Understanding) Stellar Parameter Pipeline (SSPP). The SSPP derives, using multiple techniques, radial velocities and the fundamental stellar atmospheric parameters (effective temperature, surface gravity, and metallicity) for AFGK-type stars, based on medium-resolution spectroscopy and $ugriz$ photometry obtained during the course of the original Sloan Digital Sky Survey (SDSS-I) and its Galactic extension (SDSS-II/SEGUE). The SSPP also provides spectral classification for a much wider range of stars, including stars with temperatures outside of the window where atmospheric parameters can be estimated with the current approaches. This is Paper I in a series of papers on the SSPP; it provides an overview of the SSPP, and initial tests of its performance using multiple data sets. Random and systematic errors are critically examined for the current version of the SSPP, which has been used for the sixth public data release of the SDSS (DR-6).Comment: 64 pages, 8 tables, 12 figures, submitted to the Astronomical Journa

The SEGUE Stellar Parameter Pipeline. III. Comparison with High-Resolution Spectroscopy of SDSS/SEGUE Field Stars

We report high-resolution spectroscopy of 125 field stars previously observed as part of the Sloan Digital Sky Survey and its program for Galactic studies, the Sloan Extension for Galactic Understanding and Exploration (SEGUE). These spectra are used to measure radial velocities and to derive atmospheric parameters, which we compare with those reported by the SEGUE Stellar Parameter Pipeline (SSPP). The SSPP obtains estimates of these quantities based on SDSS ugriz photometry and low-resolution (R = 2000) spectroscopy. For F- and G-type stars observed with high signal-to-noise ratios (S/N), we empirically determine the typical random uncertainties in the radial velocities, effective temperatures, surface gravities, and metallicities delivered by the SSPP to be 2.4 km/s, 130 K (2.2%), 0.21 dex, and 0.11 dex, respectively, with systematic uncertainties of a similar magnitude in the effective temperatures and metallicities. We estimate random errors for lower S/N spectra based on numerical simulations.Comment: 37 pages, 6 tables, 6 figures, submitted to the Astronomical Journa

The ACS Nearby Galaxy Survey Treasury IX. Constraining asymptotic giant branch evolution with old metal-poor galaxies

In an attempt to constrain evolutionary models of the asymptotic giant branch (AGB) phase at the limit of low masses and low metallicities, we have examined the luminosity functions and number ratio between AGB and red giant branch (RGB) stars from a sample of resolved galaxies from the ACS Nearby Galaxy Survey Treasury (ANGST). This database provides HST optical photometry together with maps of completeness, photometric errors, and star formation histories for dozens of galaxies within 4 Mpc. We select 12 galaxies characterized by predominantly metal-poor populations as indicated by a very steep and blue RGB, and which do not present any indication of recent star formation in their color--magnitude diagrams. Thousands of AGB stars brighter than the tip of the RGB (TRGB) are present in the sample (between 60 and 400 per galaxy), hence the Poisson noise has little impact in our measurements of the AGB/RGB ratio. We model the photometric data with a few sets of thermally pulsing AGB (TP-AGB) evolutionary models with different prescriptions for the mass loss. This technique allows us to set stringent constraints to the TP-AGB models of low-mass metal-poor stars (with M<1.5 Msun, [Fe/H]<~-1.0). Indeed, those which satisfactorily reproduce the observed AGB/RGB ratios have TP-AGB lifetimes between 1.2 and 1.8 Myr, and finish their nuclear burning lives with masses between 0.51 and 0.55 Msun. This is also in good agreement with recent observations of white dwarf masses in the M4 old globular cluster. These constraints can be added to those already derived from Magellanic Cloud star clusters as important mileposts in the arduous process of calibrating AGB evolutionary models.Comment: To appear in ApJ, a version with better resolution is in http://stev.oapd.inaf.it/~lgirardi/rgbagb.pd

The infrared JHK light curves of RR Lyr

We present infrared JHK time series photometry of the variable star RR Lyr, that allow us to construct the first complete and accurate infrared light curves for this star. The derived mean magnitudes are =6.74 +/- 0.02, =6.60 +/- 0.03 and =6.50 +/- 0.02. The magnitude is used to estimate the reddening, the mass, the mean luminosity and temperature of this variable star. The use of these RR Lyr data provide a more accurate absolute calibration of the P-L_K-[Fe/H] relation, and a distance modulus (m-M)_0=18.48 +/- 0.11 to the globular cluster Reticulum in the LMC.Comment: 6 pages, 2 figures, accepted for publication by MNRA