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,…

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…

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…

Influence of gamma-aminobutyric acid on baclofen intestinal absorption.

Since previous studies suggested that baclofen absorption in the rat middle intestine was inhibited by beta-alanine and therefore mediated, at least in part, by the beta-aminoacid carrier, we focused our new studies on the analysis of the possible inhibition of the drug by a gamma-aminoacid model compound, gamma-aminobutyric acid (GABA). A rat jejunum in situ study was undertaken in order to evaluate the effect of GABA on baclofen absorption and to establish the inhibition model. Assays using isotonic perfusion solutions of 0.5 mM baclofen with starting GABA concentrations ranging from 0 to 100 mM are reported. The results show that the absorption rate pseudoconstants of the drug decrease a…

Partially competitive inhibition of intestinal baclofen absorption by beta-alanine, a nonessential dietary aminoacid.

In situ intestinal absorption of baclofen in the rat in the presence of beta-alanine has been investigated. Through the perfusion of 0.50 mM baclofen solutions containing variable concentrations of the aminoacid (from 5 to 100 mM), a partially competitive inhibition of baclofen absorption was characterized: absorption rate pseudoconstants of the spasmolytic drug decrease as beta-alanine concentration increases, until a limiting value is obtained (36.8 per cent of that found for baclofen alone). A computer method was developed in order to calculate parameters governing baclofen absorption in the presence of beta-aminoacid, with the following results: Vm = 11.22 mM h-1; Km = 7.42 mM; Ki = 2.4…

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…

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 …

Intestinal absorption pathway of gamma-aminobutyric acid in rat small intestine.

Intestinal absorption of gamma-aminobutyric acid (GABA), as a model compound for gamma-aminoacids, has not been extensively studied from the kinetic viewpoint. Since data from our laboratory suggested that some competition arises between intestinal absorption of beta-alanine and GABA and since our intent was to maintain the aqueous stagnant diffusion layer in order to approach absorption tests to in vivo physiological conditions, a rat jejunum in situ study was undertaken in order to gain an insight into the mechanism of GABA absorption. In the present paper, results from assays using isotonic perfusion solutions with starting GABA concentrations ranging from 1 to 50 mM are reported. They s…

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…

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…

Neuroimmune and Mu-Opioid Receptor Alterations in the Mesocorticolimbic System in a Sex-Dependent Inflammatory Pain-Induced Alcohol Relapse-Like Rat Model

Evidence concerning the role of alcohol-induced neuroinflammation in alcohol intake and relapse has increased in the last few years. It is also proven that mu-opioid receptors (MORs) mediate the reinforcing properties of alcohol and, interestingly, previous research suggests that neuroinflammation and MORs could be related. Our objective is to study neuroinflammatory states and microglial activation, together with adaptations on MOR expression in the mesocorticolimbic system (MCLS) during the abstinence and relapse phases. To do so, we have used a sex-dependent rat model of complete Freund’s adjuvant (CFA)-induced alcohol deprivation effect (ADE). Firstly, our results confirm that only CFA-…

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…

Crosstalk between Mu-Opioid receptors and neuroinflammation: Consequences for drug addiction and pain

Mu-Opioid Receptors (MORs) are well-known for participating in analgesia, sedation, drug addiction, and other physiological functions. Although MORs have been related to neuroinflammation their biological mechanism remains unclear. It is suggested that MORs work alongside Toll-Like Receptors to enhance the release of pro-inflammatory mediators and cytokines during pathological conditions. Some cytokines, including TNF-α, IL-1β and IL-6, have been postulated to regulate MORs levels by both avoiding MOR recycling and enhancing its production. In addition, Neurokinin-1 Receptor, also affected during neuroinflammation, could be regulating MOR trafficking. Therefore, inflammation in the central …

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…

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…

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 …

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…

Influence of leucine on intestinal baclofen absorption as a model compound of neutral α-aminoacids

The inhibitory effect of the essential alpha-aminoacid L-leucine on the intestinal absorption of the antispastic drug baclofen was examined by means of an in situ rat gut perfusion technique. When 0.5 mM baclofen solutions were perfused in the presence of increasing concentrations of the aminoacid (5-100 mM), the apparent absorption rate constant of the drug decreased as the initial leucine concentration increased. Higher leucine concentrations however did not completely abolish the absorption of the drug (at 100 mM of leucine, only 76% inhibition was observed). The interaction can be mathematically described as a complete competitive inhibition with a second component, K = 0.35 (+/- 0.08)h…

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…