Ana Polache

• PhD
• University of Valencia

The alcohol use disorder (AUD) is a complex, chronic pathology with a high relapse rate. Resumption to alcohol intake after a long period of abstinence is one of the most severe handicaps of this pathological condition. Consequently, in the last decade, a wealth of studies has focused on the neurobiological mechanisms involved in various phases of...

Purpose Alcohol use disorders (AUDs) are influenced by factors that can initiate, maintain, or induce relapse. Chronic pain has been linked to AUD as both a risk factor and a consequence of prolonged alcohol exposure. Pain share common neurological pathways with AUDs, and, in fact, alters the functioning of the mesolimbic dopaminergic system sugges...

Rationale Using a preclinical model based on the Alcohol Deprivation Effect (ADE), we have reported that N-Acetylcysteine (NAC) can prevent the relapse-like drinking behaviour in long-term ethanol-experienced male rats. Objectives To investigate if chronic ethanol intake and protracted abstinence affect several glutamate transporters and whether N...

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...

Rationale Accumulating evidence suggests that chronic alcohol consumption is associated with excessive oxidative damage and neuroinflammatory processes and these events have been associated to early alcohol withdrawal. In the present research we wonder if brain oxidative stress and neuroinflammation remains altered during prolonged withdrawal situa...

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 stud...

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...

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 ho...

Recent 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 rel...

The 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 whereb...

The 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 whereb...

Recent 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 rel...

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, caus...

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. Howeve...

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 widel...

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 investiga...

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 i...

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 activatin...

Previous experiments in our laboratory have shown that D-penicillamine (DP) (acetaldehyde sequestering agent) is able to block the increase in ethanol consumption observed after a period of imposed deprivation (the so-called alcohol deprivation effect (ADE)), using a non-operant paradigm in Wistar rats. This study is aimed at investigating the robu...

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...

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 exist...

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 find...

Rationale Nowadays, very few approved anti-relapse treatments for alcoholism exist, and their overall efficacy can be considered moderate. An exciting rationale drug development opportunity for the treatment of chronic alcoholism is the use of acetaldehyde sequestering agents. Although these compounds are able to attenuate or prevent most of the be...

Previous studies in vivo have shown that salsolinol, the condensation product of acetaldehyde and dopamine, has properties that may contribute to alcohol abuse. Although opioid receptors, especially the μ-opioid receptors (MORs), may be involved, the cellular mechanisms mediating the effects of salsolinol have not been fully explored. In the curren...

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 t...

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...

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 origi...

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...

Microinjections of ethanol and acetaldehyde into ventral tegmental area (VTA) produce locomotor activation in rats through mechanisms dependent on the mu-opioid receptors. However, it is not clear how these drugs can interact with these receptors. It has been hypothesized that salsolinol could be the responsible for this interaction. The aim of the...

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...

A recently published study has shown that microinjections of ethanol, or its metabolite, acetaldehyde into the substantia nigra pars reticulata, are able to produce behavioral activation in rats. Another brain site that could participate in such effects is the ventral tegmental area (VTA). We have investigated the locomotor-activating effects of lo...

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...

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 microd...

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...

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 s...

IntroductionAnatomy and Physiology of the Human Gastrointestinal TractPathways of Drug AbsorptionFactors Affecting Drug Intestinal AbsorptionIntestinal Permeability Enhancement: Possibilities and LimitationsMethodologies for Studying Intestinal AbsorptionReferences

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 vei...

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 w...

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 expressio...

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 w...

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...

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 presenc...

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. Intestina...

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 incre...

The effects of acamprosate on the in vivo dopamine extracellular levels in the nucleus accumbens and the involvement of N-methyl-D-aspartate (NMDA) receptors in these effects were investigated. Microdialysis in freely moving rats was used to assess dopamine levels before and during simultaneous perfusion of acamprosate and/or different agonists or...

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...

The multiple pharmaceutical applications of chitosans have been reviewed in this paper. After describing its structure and physico-chemical properties, an overview of the use of this polymer in controlled release dosage forms as well as in other dosage forms to improve bioavailability and safety has been made. Furthermore, the capacity of chitosan...

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...

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 s...

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 abou...

Previous work from our laboratory on the effect, in rats, of chronic ethanol intake on the intestinal absorption of ciprofloxacin analogs suggested an increased polarity of the lipoidal membrane constituents without effects on the aqueous environment. The aim of the present study was to investigate the influence of acute ethanol intake on the absor...

Background: Previous work from our laboratory on the effect, in rats, of chronic ethanol intake on the intestinal absorption of ciprofloxacin analogs suggested an increased polarity of the lipoidal membrane constituents without effects on the aqueous environment. The aim of the present study was to investigate the influence of acute ethanol intake...

Taurine is a nonessential amino acid that plays a critical role in development. However, biosynthetic capacity is almost negligible in the fetus and must be supplied by the mother. Therefore, when maternal taurine status is depressed during gestation, fetal tissue taurine concentrations can also be compromised. In the present study, the effect of c...

The effect of leucovorin calcium on the intestinal absorption of methotrexate in rat small intestine was investigated using an in situ rat gut technique. First, the kinetic absorption in situ parameters for methotrexate in solution were obtained: Vm=21.54 (±2.22) μM/h; Km=10.51 (±1.08) μM; ka=0.26 (±0.03) h−1 and AIC=−188.63. The inhibitory effect...

The effect of chronic alcohol intake on the intestinal absorption of seven compounds belonging to a homologous series (ciprofloxacin derivatives) was evaluated using an in situ rat gut technique that measures the intrinsic absorption rates of the compounds both in control and chronic alcohol-fed rats. For chronic alcohol treatment, the animals were...

The effect of chronic alcohol intake on the intestinal absorption of seven compounds belonging to a homologous series (ciprofloxacin derivatives) was evaluated using an in situ rat gut technique that measures the intrinsic absorption rates of the compounds both in control and chronic alcohol-fed rats. For chronic alcohol treatment, the animals were...

Previous studies showed that the in situ absorption of baclofen in rat jejunum was inhibited by beta-alanine, a nonessential amino acid, and therefore mediated, at least in part, by some beta-amino acid carrier. In this paper a similar study was undertaken using taurine, a sulfonic beta-amino acid, in order to evaluate its effect and to establish a...

The present study evaluates the effect of chronic alcohol intake on the intestinal transport of methionine during pregnancy. For this purpose, we have used an in vitro technique that allows measurement of the unidirectional influx of the amino acids across the brush-border membrane of the rat mid-jejunum, and the basolateral membrane enzyme Na+, K+...

Previous studies showed that the absorption of the antispastic drug baclofen, in the rat middle intestine, is inhibited by β-alanine, γ-aminobutyric acid (GABA) and leucine. It was concluded that baclofen intestinal transport was mediated, at least in part, by the β-, γ- and α-amino acid carriers. We therefore focused our next studies on the analys...

The acute and chronic intake of alcohol induces to variation in the absorption of immediate principles and other essential elements, leading to the so-called secondary malnutrition. This is due, in part, to alterations in the gastrointestinal tract which are difficult to be identified, either microscopically or at subcellular level. However, the av...

The acute and chronic intake of alcohol induces to variation in the absorption of immediate principles and other essential elements, leading to the so-called secondary malnutrition. This is due, in part, to alterations in the gastrointestinal tract which are difficult to be identified, either microscopically or at subcellular level. However, the av...

The inhibitory effect of the essential α-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 th...

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 diffusi...

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 jeju...

The rat intestinal imino acid carrier is chloride independent, while in guinea pig and rabbit intestine it is chloride dependent. While non-alpha-amino acids do not significantly interact with guinea pig and rabbit imino acid carriers, inhibition studies had indicated that in rat small intestine beta-alanine, gamma-aminobutyric acid (GABA), and pro...

Intestinal transport of baclofen (beta-(p-chlorophenyl)-gamma-aminobutyric acid) in the rat has been examined in vitro. Influx of baclofen across the brush-border membrane (JmcBacl) and steady-state accumulation by everted segments of the intestine were measured. JmcBacl could be accounted for as the sum of a saturable process with a maximum rate o...

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 sp...

Contradictory results have been reported on intestinal beta-alanine absorption, although a generalized view is that it could be a passive, nonmediated process. Since previous data from our laboratory suggested that some competition arises between intestinal absorption of the gamma-amino acidic drug baclofen and beta-alanine, a rat jejunum in situ s...

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...