Glutamate and opioid antagonists modulate dopamine levels evoked by innately attractive male chemosignals in the nucleus accumbens of female rats

Sexual chemosignals detected by vomeronasal and olfactory systems mediate intersexual attraction in rodents, and act as a natural reinforcer to them. The mesolimbic pathway processes natural rewards, and the nucleus accumbens receives olfactory information via glutamatergic projections from the amygdala. Thus, the aim of this study was to investigate the involvement of the mesolimbic pathway in the attraction toward sexual chemosignals. Our data show that female rats with no previous experience with males or their chemosignals display an innate preference for male-soiled bedding. Focal administration of the opioid antagonist b-funaltrexamine into the posterior ventral tegmental area does no…

The Effects of N-Acetylcysteine on the Rat Mesocorticolimbic Pathway: Role of mGluR5 Receptors and Interaction with Ethanol

N-acetylcysteine (NAC) is a prodrug that is marketed as a mucolytic agent and used for the treatment of acetaminophen overdose. Over the last few decades, evidence has been gathered that suggests the potential use of NAC as a new pharmacotherapy for alcohol use disorder (AUD), although its mechanism of action is already being debated. In this paper, we set out to assess both the potential involvement of the glutamate metabotropic receptors (mGluR) in the possible dual effect of NAC administered at two different doses and NAC’s effect on ethanol-induced activation. To this aim, 30 or 120 mg/kg of NAC was intraperitoneally administered to rats with the presence or absence of the negative allo…

Salsolinol and ethanol-derived excitation of dopamine mesolimbic neurons: new insights

Evidence supporting the essential role of brain-derived ethanol metabolites in the excitation of dopamine (DA) midbrain neurons has multiplied in the last 10–15 years. The pioneer and influential behavioral studies by CM Aragon and colleagues (see Correa et al., 2012 for a complete review) and more recent data (Sanchez-Catalan et al., 2009; Marti-Prats et al., 2010, 2013) have repeatedly demonstrated the crucial role displayed by acetaldehyde (ACD) in the locomotor and other behavioral responses elicited by ethanol. Although these experiments mainly used an indirect measure (exploratory locomotion) as an index of the excitation of DA neurons in the ventral tegmental area (VTA), results stro…

Opposite motor responses elicited by ethanol in the posterior VTA: The role of acetaldehyde and the non-metabolized fraction of ethanol

Recent electrophysiological evidence suggests that ethanol simultaneously exerts opposite effects on the activity of dopamine (DA) neurons in the ventral tegmental area (VTA) through two parallel mechanisms, one promoting and the other reducing the GABA release onto VTA DA neurons. Here we explore the possible behavioural implications of these findings by investigating the role displayed by acetaldehyde (the main metabolite of ethanol) and the non-metabolized fraction of ethanol in motor activity of rats. We analyse the appearance of motor activation or depression after intra-VTA administration of ethanol in rats subjected to different pharmacological pre-treatments designed to preferential…

Effect Of Inflammatory Pain On Alcohol-Induced Dopamine Release In The Nucleus Accumbens: Behavioural Implications In Rat Models

AbstractRecent studies have drawn the attention to the link between Alcohol Use Disorder (AUD) and the presence of pain. Indeed, the correct management of pain in patients with a previous history of AUD has been reported to decrease the risk of relapse in alcohol drinking, suggesting that in this prone population, pain may increase the vulnerability to relapse. Previous data in male rats revealed that inflammatory pain desensitizes mu opioid receptors (MORs) in the ventral tegmental area (VTA) and increases intake of high doses of heroine. Due to the relevant role of MORs in alcohol effects, we hypothesize that pain may also alter alcohol reinforcing properties and therefore affect alcohol …

Local salsolinol modulates dopamine extracellular levels from rat nucleus accumbens: shell/core differences.

Salsolinol (SAL), a condensation product of dopamine and acetaldehyde that appears in the rat and human brain after ethanol ingestion, has been largely implicated in the aetiology of alcoholism. Although the behavioural consequences of systemic or intracerebral SAL administrations have been described, the neurochemical effects of pharmacologically relevant doses of SAL and other tetrahydroisoquinolines (THIQs) in the brain areas involved in alcohol addiction are practically unknown. To gain an insight into this topic, male Wistar rats were stereotaxically implanted with one concentric microdialysis probe in either the shell or the core of the nucleus accumbens (NAc). Treatments involved loc…

Quantitative in vivo microdialysis in pharmacokinetic studies: some reminders.

This paper reviews the empirical methods of quantitative microdialysis that have been used to interpret the results obtained from pharmacokinetic studies. The concept of extraction efficiency or recovery and the properties of recovery in vivo (variation with flow rate, time dependency and influence of the mode of administration) are considered. The most frequently used methods for determining recovery in vivo are described and evaluated in the light of recent theoretical studies. Specifically, we review the variation of flow rate method, the very slow flow method, the no net flux method and the delivery and retrodialysis methods. Special emphasis is placed on the description of each method,…

Renal and nonrenal clearances of ceftriaxone at the steady-state and its relation to plasma protein binding

Abstract The effect of the saturable plasma protein binding of ceftriaxone on the elimination of this drug was studied under steady-state conditions in the rat. A concentration-dependent increase in the total, renal and nonrenal clearances of total drug (bound + unbound) was observed, and it was related to the increase in the ex vivo unbound fraction of ceftriaxone as the plasma concentration increased. The nonrenal clearance of the unbound ceftriaxone showed a statistically significant decrease as the plasma concentration of the unbound drug at the steady state increased, which indicates that the nonrenal elimination of the drug (mainly by biliary excretion) is a saturable process. Renal c…

Pre-Clinical Studies with D-Penicillamine as a Novel Pharmacological Strategy to Treat Alcoholism: Updated Evidences

Ethanol, as other drugs of abuse, is able to activate the ventral tegmental area dopamine (VTA-DA) neurons leading to positively motivational alcohol-seeking behavior and use, and, ultimately to ethanol addiction. In the last decades, the involvement of brain-derived acetaldehyde (ACD) in the ethanol actions in the mesolimbic pathway has been widely demonstrated. Consistent published results have provided a mechanistic support to the use of ACD inactivating agents to block the motivational and reinforcing properties of ethanol. Hence, in the last years, several pre-clinical studies have been performed in order to analyze the effects of the sequestering ACD agents in the prevention of ethano…

Competition and R&D in retail banking under expense preference behaviour

Cost-reducing R&D activities are examined in the context of a retail banking sector where some entities exhibit an expense preference. The results reveal that the effects from R&D interact with the effects in the previous literature in shaping the equilibrium configuration.

Intestinal absorption enhancement via the paracellular route by fatty acids, chitosans and others: a target for drug delivery.

Peroral delivery of hydrophilic drugs is one of the greatest challenges in biopharmaceutical research. Hydrophilic drugs usually present low bioavailability after oral administration. One of the causes of this low bioavailability is their poor intestinal permeation through the paracellular pathway. This pathway is actually restricted by the presence of tight junctions at the apical side of the enterocytes. In the last few years, great interest has been focused on the structure and cellular regulation of tight junctions, materializing in more in-depth knowledge of this intestinal barrier. Simultaneously, and on the basis of this understanding, continuous efforts are being made to develop age…

Impaired alcohol-induced dopamine release in the nucleus accumbens in an inflammatory pain model: behavioral implications in male rats

ABSTRACT Recent studies have drawn the attention to the link between alcohol use disorder and the presence of pain. Indeed, the correct management of pain in patients with a previous history of alcohol use disorder has been reported to decrease the risk of relapse in alcohol drinking, suggesting that in this prone population, pain may increase the vulnerability to relapse. Previous data in male rats revealed that inflammatory pain desensitizes mu-opioid receptors in the ventral tegmental area and increases intake of high doses of heroin. Owing to the relevant role of mu-opioid receptors in alcohol effects, we hypothesize that pain may also alter alcohol reinforcing properties and therefore …

Disposition ofd-penicillamine, a promising drug for preventing alcohol-relapse. Influence of dose, chronic alcohol consumption and age: studies in rats

Pharmacokinetic studies concerning d-penicillamine (an acetaldehyde sequestering agent) are scarce and have not evaluated the influence of chronic ethanol consumption and age on its disposition. Since recent preclinical studies propose d-penicillamine as a promising treatment for alcohol relapse, the main aim of the present work was to evaluate the influence of these two factors on d-penicillamine disposition in order to guide future clinical studies on the anti-relapse efficacy of this drug in alcoholism. Additionally, the effect of the administered dose was also evaluated. To this end, three studies were carried out. Study 1 assessed the influence of dose on d-penicillamine disposition, w…

Revisiting the controversial role of salsolinol in the neurobiological effects of ethanol: old and new vistas.

The possible involvement of salsolinol (Sal), an endogenous condensation product of ACD (the first metabolite of ethanol) and dopamine, in the neurochemical basis underlying ethanol action has been repeatedly suggested although it has not been unequivocally established, still being a controversial matter of debate. The main goal of this review is to evaluate the presumed contribution of Sal to ethanol effects summarizing the reported data since the discovery in the 1970s of Sal formation in vitro during ethanol metabolism until the more recent studies characterizing its behavioral and neurochemical effects. Towards this end, we first analyze the production and detection of Sal, in different…

Physiological pharmacokinetic model for ceftazidime disposition in the rat and its application to prediction of plasma concentrations in humans

Abstract A physiological pharmacokinetic model for the disposition of ceftazidime in the rat was developed. The model is composed of 10 compartments which represent most of the organs and tissues of the body. Ceftazidime concentration-time profiles in the organs and tissues represented in the model were simulated and compared with the observed concentration-time data after i.v. administration of 5 and 20 mg of antibiotic. The model gave an acceptable description of the observed data. The steady-state volume of distribution and total clearance of ceftazidime in healthy humans predicted from data obtained in the rat (0.21 l/kg and 113 ml/min, respectively) were similar to the values reported …

Compact, cost-effective and field-portable microscope prototype based on MISHELF microscopy

AbstractWe report on a reduced cost, portable and compact prototype design of lensless holographic microscope with an illumination/detection scheme based on wavelength multiplexing, working with single hologram acquisition and using a fast convergence algorithm for image processing. All together, MISHELF (initials coming from Multi-Illumination Single-Holographic-Exposure Lensless Fresnel) microscopy allows the recording of three Fresnel domain diffraction patterns in a single camera snap-shot incoming from illuminating the sample with three coherent lights at once. Previous implementations have proposed an illumination/detection procedure based on a tuned (illumination wavelengths centered…

Systemic administration of D-penicillamine prevents the locomotor activation after intra-VTA ethanol administration in rats.

Although recently published studies seem to confirm the important role displayed by acetaldehyde (ACH), the main metabolite of ethanol, in the behavioral effects of ethanol, the origin of ACH is still a matter of debate. While some authors confer more importance to the central (brain metabolism) origin of ACH, others indicate that the hepatic origin could be more relevant. In this study we have addressed this topic using an experimental approach that combines local microinjections of ethanol into the ventral tegmental area (VTA) (which guarantees the brain origin of the ACH) to induce motor activation in rats together with systemic administration (i.p.) of several doses (0, 12.5, 25 and 50 …

Low bioavailability of amoxicillin in rats as a consequence of presystemic degradation in the intestine.

Several studies have been carried out to elucidate the causes of the low oral bioavailability of amoxicillin in rats. The hepatic first-pass effect of the antibiotic was estimated by comparing the area under the plasma drug concentration-versus-time curve from time zero to infinity (AUC0-infinity) obtained after injecting the drug into a mesenteric vein with the AUC0-infinity value obtained after injecting the drug into the jugular vein of conscious rats. No hepatic first-pass effect was detected. The bioavailability of amoxicillin after intraduodenal administration was only 51%, and the fraction of the dose remaining in the intestine at the end of the experiment was 4.5%. This was far less…

BASIC RESEARCH AND DEVELOPMENT IN VERTICAL MARKETS*

This paper considers the role of basic research and development (R&D) investment in vertical markets in which an incumbent owner of a basic technological input faces potential competition. We identify the conditions under which the socially optimal investment in basic research involves entry by new firms. Our main insight is that there is a role for public investment in R&D that appears to have been overlooked in the existing literature. This role draws on the idea that basic R&D adds to the credibility of the threat of the potential development of alternative technologies by reducing their implementation costs.

Competition, risk taking, and governance structures in retail banking

This paper investigates the extent to which the linkages between bank performance and governance structure affect deposits market competition and risk taking incentives when commercial banks compete with organizations with objectives different from profit maximization. These organizations include savings banks whose corporate and ownership structure yields an objective function that can incorporate labour expenses. It is found that such objective function enables the savings banks to capture a greater market share of bank deposits and to take on relatively less risk in their portfolio of investments. The empirical evidence from the Spanish retail banking sector documents these conclusions.

Disposition of acamprosate in the rat: Influence of probenecid

The purpose of the present study was to investigate the disposition of acamprosate (calcium bis acetyl-homotaurine) in the rat. Initially, we studied the linearity of acamprosate disposition and the fraction of acamprosate excreted unchanged in the urine of the animals. Rats received 9.3, 36.6 or 73.3 mg/kg of the drug as an intravenous bolus. The statistical analysis of the pharmacokinetic parameters did not reveal any significant difference, indicating that acamprosate disposition was linear within the range of the doses assayed. On average, 95% of the administered dose was excreted unchanged in the urine of the animals in the 0-6 h post-administration period indicating that renal excreti…

Improved effect of the combination naltrexone/D-penicillamine in the prevention of alcohol relapse-like drinking in rats

Opioid antagonists are licensed drugs for treating alcohol use disorders; nonetheless, clinical studies have evidenced their limited effectiveness. Preclinical findings indicate that opioid receptor (OR) antagonists, such as naltrexone (NTX), reduce the alcohol deprivation effect (ADE). However, a detailed analysis of published data shows the existence of a delayed increase in ethanol consumption after continuous OR blockade, a phenomenon originally called as ‘delayed ADE’. We have recently reported that D-penicillamine (DP) is able to prevent ADE through a mechanism dependent on the inactivation of acetaldehyde, the main metabolite of ethanol. Hypothetically, OR activation would be trigge…

Hippocampal dopamine receptors modulate the motor activation and the increase in dopamine levels in the rat nucleus accumbens evoked by chemical stimulation of the ventral hippocampus.

A number of studies have shown that chemical stimulation (using N-methyl-D-aspartate (NMDA) infusions) or electrical stimulation of the ventral hippocampus (VH) elicits locomotor activation and sustained increases in nucleus accumbens (NAc) dopamine (DA) levels in rodents. How DA neurotransmission in NAc is involved in these effects has also been well established. However, the modulatory role of the DA receptors located in VH is not yet fully understood. The purpose of this study was to characterize the role played by VH D1 and D2 subtype receptors in both the locomotor activation and NAc DA increases induced by NMDA stimulation of the VH. This was assessed by studying how retrodialysis app…

Cytotoxic effect of As(III) in Caco-2 cells and evaluation of its human intestinal permeability.

Inorganic arsenic has been classified as a carcinogen for humans (Group I). However, its transit across the human intestinal epithelium has not been characterized. Using Caco-2 cells, the thiol-redox balance and apparent permeability coefficients (P(app)) for As(III) in the apical to basolateral (AP-BL) and basolateral to apical (BL-AP) direction were evaluated. After As(III) exposure, GSH-induced synthesis was observed, increasing the GSH/GSSG ratio by elevating the As(III) concentration. The AP-BL permeabilities decreased as the As(III) concentrations increased, indicating the existence of a mediated transport mechanism. The (BL-AP)/(AP-BL) permeability ratios were higher than unity, sugg…

Four channels multi-illumination single-holographic-exposure lensless Fresnel (MISHELF) microscopy

Abstract MISHELF microscopy [Opt. Express 23, 21352 (2015)] has been recently reported as the background technology of a new concept of compact, cost-effective and field-portable lensless microscope [Sci. Rep. 7, 43291 (2017)] based on wavelength multiplexing and a fast and robust algorithm for twin image minimization and noise reduction. In this manuscript, MISHELF microscopy is expanded beyond its actual configuration by considering 4 illumination/detection channels while retaining its working principle concerning single-shot, twin image mitigation and noise averaging. Proof of principle validation of the proposed improvement is conducted through experiments with a resolution test target …

Superresolved phase-shifting Gabor holography by CCD shift

Holography in the Gabor regime is restricted to weak diffraction assumptions. Otherwise, diffraction prevents an accurate recovery of the object's complex wavefront. We have recently proposed a modified Gabor-like setup to extend Gabor's concept to any sample provided that it be non-diffusive. However, the resolution of the final image becomes limited as a consequence of the additional elements considered in the proposed setup. In this paper we present an experimental approach to overcome such a limitation in which the former configuration is used while the CCD camera is shifted to different off-axis positions in order to generate a synthetic aperture. Thus, once the whole image set is reco…

Distribution and differential induction of CYP2E1 by ethanol and acetone in the mesocorticolimbic system of rat

Aims: The expression of cytochrome P4502E1 (CYP2E1) in the brain has been demonstrated in several regions, nevertheless there is a lack of specific studies on the constitutive expression and induction at the mesocorticolimbic system, the most relevant brain pathway in the context of drug addiction and alcoholism. Hence, we have performed a detailed study of the CYP2E1 expression and induction in three key areas of the mesocorticolimbic system of the rat brain: prefrontal cortex (PFC), nucleus accumbens (NAc), and ventral tegmental area (VTA). Methods: Expression levels of CYP2E1 were analyzed by Western blot. The induction of the enzyme in the selected brain areas by chronic acetone (1% v/v…

Efficacy of N-acetylcysteine in the prevention of alcohol relapse-like drinking: Study in long-term ethanol-experienced male rats

Alcohol use disorders are chronic and highly relapsing disorders, thus alcoholic patients have a high rate of recidivism for drug use even after long periods of abstinence. The literature points to the potential usefulness of N-acetylcysteine (NAC) in the management of several substance use disorders probably due to its capacity to restore brain homeostasis of the glutamate system disrupted in addiction. However, there is little evidence in the case of alcohol. The aim of this study was to explore the potential anti-relapse efficacy of NAC using the alcohol deprivation effect (ADE) model in long-term experienced rats. Two experiments were performed in male Wistar rats to: (a) test the effic…

Absorption of Drugs after Oral Administration

After oral administration, drugs must be absorbed through the gastrointestinal tract to achieve the systemic circulation and exert their pharmacological effects. The successful formulation of an optimized oral drug delivery system requires a detailed consideration and a good understanding of the intestinal absorption process, its possibilities and limitations. This article gives an overview and update on the concepts, possibilities, and limitations of drug absorption after oral administration. Keywords: oral administration; drug absorption; oral drug delivery system; gastrointestinal tract; intestinal absorption

Acamprosate blocks the increase in dopamine extracellular levels in nucleus accumbens evoked by chemical stimulation of the ventral hippocampus.

Recently, we have shown that acamprosate is able to modulate extracellular dopamine (DA) levels in the nucleus accumbens (NAc) and may act as an antagonist of N-methyl-D-aspartate (NMDA) receptors. Neurochemical studies show that chemical stimulation (using NMDA) of the ventral subiculum (vSub) of the hippocampus produces robust and sustained increases in extracellular DA levels in the NAc, an effect mediated through ionotropic glutamate (iGlu) receptors. The present study examines whether acamprosate locally infused in the NAc of rats could block or attenuate the increase in NAc extracellular DA elicited by chemical stimulation (with 5 mM NMDA) of the ventral subiculum of the hippocampus. …

Activation of MORs in the VTA induces changes on cFos expression in different projecting regions: Effect of inflammatory pain.

Abstract Chronic pain is a worldwide major health problem and many pain-suffering patients are under opioid based therapy. Epidemiological data show that pain intensity correlates with the risk of misuse of prescription opioids, and other drugs of abuse including alcohol. This increased vulnerability to suffer Substance Use Disorders could be, in part, caused by functional changes that occur over the mesocorticolimbic system, a brain pathway involved in reward processing and addiction. Previous data in rats revealed that inflammatory pain desensitizes mu opioid receptors (MORs) in the ventral tegmental area (VTA). As a consequence, pain alters dopamine release in the nucleus accumbens (NAc)…

Shell/core differences in mu- and delta-opioid receptor modulation of dopamine efflux in nucleus accumbens

The mu- and delta-opioid receptors located at the terminal level in nucleus accumbens are involved in the opiate modulation of dopamine release in this brain area. However, recent studies suggest that the effects of opioid drugs on the core subregion of nucleus accumbens may completely differ from those observed in the shell. We used in vivo microdialysis to simultaneously apply selective mu- and delta-opioid receptor agonists and to measure extracellular levels of dopamine in three subregions of the accumbens, namely shell, core, and the transition zone between them. The regional analysis of these subregions of the accumbens demonstrated that basal levels of dopamine and its metabolites we…

Kinetic study of acamprosate absorption in rat small intestine.

Acamprosate (calcium bis acetyl-homotaurine), a homotaurine derivative, a structural analogue of gamma-aminobutyric acid (GABA) and an upper homologue of taurine, is a relatively new drug used to prevent relapse in weaned alcoholics. When administered orally as enteric-coated tablets at relatively high doses, this drug has a bioavailability of about 11%; however, the intestinal absorption mechanism has not been studied in depth. The present study was therefore planned to characterize the intestinal transport of acamprosate in the rat and the effect of chronic alcohol treatment on this process, quantifying its kinetic parameters and investigating possible inhibitors. Using an in vitro techni…

Dose-dependent induction of CPP or CPA by intra-pVTA ethanol: Role of mu opioid receptors and effects on NMDA receptors.

AbstractThe neurobiological mechanisms underlying alcohol motivational properties are still not fully understood, however, the mu-opioid receptors (MORs) have been evidenced as central elements in the manifestation of the alcohol reinforcing properties. Drug-associated environmental stimuli can trigger alcohol relapse and promote alcohol consumption whereby N-methyl-D-aspartate (NMDA) receptors play a pivotal role. Here we sought to demonstrate, for the first time, that ethanol induces conditioned place preference or aversion (CPP or CPA) when administered locally into the ventral tegmental area (VTA) and the associated role of MORs. We further analyzed the changes in the expression and mRN…

Assessment and modulation of acamprosate intestinal absorption: comparative studies using in situ, in vitro (CACO-2 cell monolayers) and in vivo models.

The purpose of this study was to explore the intestinal absorption mechanism of acamprosate and to attempt to improve the bioavailability (BA) of the drug through modulation of its intestinal absorption using two enhancers (polysorbate 80 and sodium caprate) based on in situ, in vitro and in vivo models and comparing the results obtained. Intestinal transport of the drug, in the absence and in presence of polysorbate 80 (0.06, 0.28 and 9.6 mM) or sodium caprate (13 and 16 mM) was measured by using an in situ rat gut technique and Caco-2 cell monolayers. Additionally, the effect of sodium caprate on drug oral bioavailability, measured as urinary recovery, was quantified by performing in vivo…

Quantitative In Vivo Microdialysis in Pharmacokinetic Studies

SY26-4REVIEWING THE NEUROBIOLOGICAL EFFECTS OF SALSOLINOL: ROLE OF THE MU OPIOID RECEPTORS

During the last decades Salsolinol (SAL), a condensation product from dopamine (DA) and acetaldehyde that appears in the brain of humans and rodents as a consequence of brain metabolism of ethanol, has been proposed as a key component in the development of alcohol use disorders. Although evidence has been published …

Pharmacology of Acamprosate: An Overview

In the last years important advances have been made in the development of drugs for the treatment of alcohol addiction. Acamprosate (calcium bis‐acetylhomotaurine) is one of the better established drugs in this field on the European market. This review focuses first on the pharmacokinetics of acamprosate. The published data and the recent advances in our knowledge on the mechanisms involved in the intestinal absorption and elimination of this drug are summarized. The importance of pharmacokinetics for the proper clinical use of acamprosate is highlighted. The anti‐relapse as well as the well‐known effects of acamprosate on ethanol intake are discussed. The recent experiments in animal model…

Evidence of a flip-flop phenomenon in acamprosate pharmacokinetics: an in vivo study in rats.

The pharmacokinetics of acamprosate were examined in the rat after oral and intravenous administration in order to detect the possible presence of a flip-flop phenomenon. Rats received 9.3 or 73.3 mg/kg of the drug as an intravenous bolus. The same doses were orally administered via gastric intubation. Plasma samples were taken from the jugular vein for determination of acamprosate concentration by liquid scintillation counting. The drug content was also quantified in urine and faeces. The acamprosate bioavailability was close to 20%, the amount recovered in the faeces being around 80% of the administered dose. The terminal slope of the oral plasma curve was significantly lower than that ob…

Kinetics of zinc transport in vitro in rat small intestine and colon: interaction with copper.

The present study was planned to investigate the kinetic transport of zinc, in the intact intestine of the rat, in order to establish if more than one transporter is involved as well as the existence of a preferent sector in the cation uptake. Using an in vitro technique, the influx of zinc across the brush border membrane in three sectors of the small intestine (proximal, mid and distal) and in the colon of the rat was measured at six different concentrations (from 0.0007 to 11 mM). The kinetic study showed that intestinal transport of zinc occurs by a saturable process in the small intestine. The K(m) value obtained in the proximal segment (10.78+/-4.40 mM) is clearly higher than those ob…

Synthetic Aperture Lensless Digital Holographic Microscopy (SALDHM) for Superresolved Biological Imaging

Lensless digital holographic microscopy (LDHM) relates with the capability to achieve microscopic imaging working without lenses in the regime of holography. LDHM uses an extremely simplified setup and provides micron-range lateral and depth resolutions in three-dimensional (3D) imaging. Typically, LDHM uses a pinhole to provide spherical divergent illumination over the sample. Then, two different basic schemes are usually adopted for providing holographic recording. The first one assumes the interference between two in-line waves since diffraction by the sample can be considered as a perturbation of the reference wave. The second scheme uses an external reference beam in an off-line config…

Induction of conditioned place preference and dopamine release by salsolinol in posterior VTA of rats: involvement of μ-opioid receptors.

Salsolinol (Sal), locally administered into the posterior VTA (pVTA) of rats, produces psychomotor responses and reinforcing effects, probably, through the activation of μ-opioid receptors (MORs). The neurochemical correlates of these phenomena are, however, practically unknown. In this paper, we explore the neurochemical events and the mechanisms involved in these behaviors. To do that, we test the ability of Sal, directly microinjected into the pVTA, to induce conditioned place preference (CPP) and to increase dopamine levels in the nucleus accumbens shell. Bilateral injections of 30 pmol of Sal induced a strong CPP (rats spent around 70% of the total test time), a result that could be ex…

Regional differences in mu-opioid receptor-dependent modulation of basal dopamine transmission in rat striatum

Abstract The nigrostriatal dopamine system is implicated in the regulation of reward and motor activity. Dopamine (DA) release in dorsal striatum (DS) is controlled by the firing rate of DA neurons in substantia nigra pars compacta. However, influences at terminal level, such as those involving activation of mu opioid receptors (MORs), can play a key role in determining DA levels in striatum. Nonetheless, published data also suggest that the effect of opioid drugs on DA levels may differ depending on the DS subregion analyzed. In this study, in vivo microdialysis in rats was used to explore this regional dependence. Changes in basal DA levels induced by local retrodialysis application of DA…

Single-exposure super-resolved interferometric microscopy by RGB multiplexing in lensless configuration

Abstract Single-Exposure Super-Resolved Interferometric Microscopy (SESRIM) reports on a way to achieve one-dimensional (1-D) superresolved imaging in digital holographic microscopy (DHM) by a single illumination shot and digital recording. SESRIM provides color-coded angular multiplexing of the accessible sample׳s range of spatial frequencies and it allows their recording in a single CCD (color or monochrome) snapshot by adding 3 RGB coherent reference beams at the output plane. In this manuscript, we extend the applicability of SESRIM to the field of digital in-line holographic microscopy (DIHM), that is, working without lenses. As consequence of the in-line configuration, an additional r…

Resolution and field of view improvement in digital holography using a VCSEL source array

We describe a new implementation capable to produce superresolution (SR) and object field of view (FOV) improvement in digital lensless Fourier holography. The method provides synthetic aperture (SA) generation using angular multiplexing incoming from a Vertical Cavity Surface Emitting Laser (VCSEL) source array. SR imaging in a single exposure is obtained after proper digital processing of a multiplexed hologram coming from the incoherent addition of multiple sub-holograms, each one corresponding with a different source of the VCSEL array. FOV improvement in addition with SR imaging is achieved by recording a set of individual holograms obtained by sequential activation of the VCSEL source…

Brain metabolism of ethanol and alcoholism: an update.

It has long been suggested that some of the neuropharmacological, neurochemical and behavioural effects of ethanol are mediated by its first metabolite, acetaldehyde. In spite of the well documented psychoactivity of acetaldehyde, the precise role of this compound in alcohol abuse remains a matter of intense debate among scientists devoted to the study of alcoholism. Very frequently, the main drawback has been related to the presence of adequate levels of acetaldehyde or its derivatives inside the brain after ethanol ingestion. Since penetration into the central nervous system from blood of peripherically derived acetaldehyde is very low due to the high aldehyde dehydrogenase activity at th…

Hippocampal dopamine receptors modulate cFos expression in the rat nucleus accumbens evoked by chemical stimulation of the ventral hippocampus

Recently, we have shown that D1 and D2 receptors in the ventral hippocampus (VH) modulate both the locomotor activation and the increase in dopamine (DA) levels in the rat nucleus accumbens (NAc) induced by NMDA stimulation of the VH. In the present study we analyze the possible role of VH D1 and D2 receptors in the modulation of the cFos expression in NAc (core and shell subregions) and in dorsal striatum. This was assessed by immunohistochemical analysis of cFos expression in the rat brains after retro-dialysis application of NMDA (50mM, 10 min) into VH, in absence and in presence of either the D1/D5 receptor antagonist SCH 23390 (100 and 250 microM, 60 min) or the D2 receptor antagonist …

Nonlinearities in amoxycillin pharmacokinetics. I. Disposition studies in the rat.

Several features of amoxycillin pharmacokinetics in man are not well known in spite of the extensive clinical use of the antibiotic. In this paper it is demonstrated that amoxycillin disposition kinetics in rats is clearly nonlinear, and that this may be due mainly to its elimination mechanisms. At different intravenous bolus dose levels, and in steady-state perfusion studies, the most striking feature is an increased renal clearance as dose increases (from 3.5 to 7.0 mg kg-1 for intravenous bolus, and from 4.6 to 20.0 micrograms min-1 for intravenous perfusions). This phenomenon has been attributed to a saturation of the active renal tubular reabsorption of the antibiotic. When the intrave…

Induction of brain CYP2E1 changes the effects of ethanol on dopamine release in nucleus accumbens shell.

CYP2E1 is an important enzyme involved in the brain metabolism of ethanol that can be induced by chronic consumption of alcohol. Recent works have highlighted the importance of this system in the context of the behavioural effects of ethanol. Unfortunately, the underlying neurochemical events for these behavioural changes, has not been yet explored. In this work, we have started this exploration by analyzing the possible changes in the neurochemical response of the mesolimbic system to ethanol after pharmacological induction of brain CYP2E1. We have used the dopamine extracellular levels in nucleus accumbens (NAc) core and shell, measured by means of microdialysis in vivo, as an index of th…

SY09EXPLORING CURRENT AND PROMISING PHARMACOTHERAPIES IN THE TREATMENT OF ALCOHOLISM: CLINICAL AND PRECLINICAL EVIDENCESY09-1COMBINED THERAPIES DO MATTER: OPTIMIZING NALTREXONE ANTI-RELAPSE EFFECT

Naltrexone (NTX), a non-selective opioid receptor, is a licensed drug for treating alcohol use disorders almost from 20 years ago. During this time, more than 50 clinical trials have been conducted to evaluate its effects in patients suffering for alcoholism. Although these studies have confirmed its effectiveness, …

Dual motor responses elicited by ethanol in the posterior VTA: Consequences of the blockade of μ-opioid receptors

A recent hypothesis, based on electrophysiological and behavioural findings, suggests that ethanol simultaneously exerts opposed effects on the activity of dopamine (DA) neurons in the ventral tegmental area (VTA) through two parallel mechanisms, one promoting and the other reducing the GABA release onto VTA DA neurons. In this sense, the activating effects are mediated by salsolinol, a metabolite of ethanol, acting on the μ-opioid receptors (MORs) located in VTA GABA neurons. The inhibitory effects are, however, triggered by the non-metabolized fraction of ethanol which would cause the GABAA receptors-mediated inhibition of VTA DA neurons. Since both trends tend to offset each other, only…

Multi-illumination single-holographic-exposure lensless Fresnel (MISHELF) microscopy using 4 channels

MISHELF microscopy is generalized by considering 4 illumination/detection channels while retaining single-shot working principle, twin image mitigation and noise averaging. Proof of principle validation is included considering a resolution test target.

GOVERNANCE-BASED ACQUISITIONS AND RISK TAKING IN BANKING

We examine the market for corporate control in banking when strategic acquisitions are driven by the different governance structures of commercial and savings banks. In contrast to profit-maximizing entities, we show that savings institutions can have acquisition incentives from their peculiar governance and ownership structure. Governance-based acquisition incentives, which interact with the specifics of the loan market in affecting bank risk taking, can arise when acquisitions take place sequentially or simultaneously, and also when financial intermediaries affect risk taking directly through the target return of investments or indirectly through the loan interest rate.

Upward and Downward Limit Pricing: The Role of Post-Entry Competition

Under asymmetric information, entry-deterring strategies by an incumbent monopolist can consist of deviations from its static monopoly price through downward deviations termed downward limit pricing, or upward deviations termed upward limit pricing. Our analysis shows that the mode of post-entry competition influences the range of situations in which an incumbent adopts a strategy of downward limit pricing instead of an upward one: this range is greater under price than under output competition; it is decreasing in the degree of product differentiation; and with homogeneous product only downward limit pricing emerges under price competition, while upward limit pricing can still take place w…

Mystic Acetaldehyde: The Never-Ending Story on Alcoholism

After decades of uncertainties and drawbacks, the study on the role and significance of acetaldehyde in the effects of ethanol seemed to have found its main paths. Accordingly, the effects of acetaldehyde, after its systemic or central administration and as obtained following ethanol metabolism, looked as they were extensively characterized. However, almost 5 years after this research appeared at its highest momentum, the investigations on this topic have been revitalized on at least three main directions: (1) the role and the behavioral significance of acetaldehyde in different phases of ethanol self-administration and in voluntary ethanol consumption; (2) the distinction, in the central e…