0000000000040034
AUTHOR
Lucía Hipólito
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…
Pain-induced alterations in the dynorphinergic system within the mesocorticolimbic pathway: Implication for alcohol addiction.
Latest studies have revealed that pain negatively impacts on reward processing and motivation leading to negative affective states and stress. These states not only reduce quality of life of patients by increasing the appearance of psychiatric comorbidities, but also have an important impact on vulnerability to drug abuse, including alcohol. In fact, clinical, epidemiological but also preclinical studies have revealed that the presence of pain is closely related to alcohol use disorders (AUDs). All this evidence suggests that pain is a factor that increases the risk of suffering AUD, predicting heavy drinking behavior and relapse drinking in those patients with a previous history of AUD. Th…
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…
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 …
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 …
P-56LOCAL BLOCKADE OF THE MU OPIOID RECEPTOR REVEALS THE DUAL MOTOR EFFECT OF ETHANOL IN pVTA
Previous electrophysiological and behavioral data have revealed the existence of ethanol opposite effects (excitatory and inhibitory) on the posterior ventral tegmental area (pVTA) dopamine (DA) neurons activity. These activating and depressing effects of ethanol could be the result of two concurrent and opposing mechanisms, one increasing and the other reducing GABA release …
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…
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…
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-…
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 …
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 …
Kappa opioid receptor blockade in the nucleus accumbens shell prevents sex-dependent alcohol deprivation effect induced by inflammatory pain.
ABSTRACT Pain-induced negative affect reduces life quality of patients by increasing psychiatric comorbidities, including alcohol use disorders (AUDs). Indeed, clinical data suggest pain as a risk factor to suffer AUDs, predicting relapse drinking in abstinent patients. Here, we analyse the impact of pain on alcohol relapse and the role of kappa opioid receptor (KOR) activation in mediating these pain-induced effects because KORs play an important role in pain-driven negative affect and AUD. Female and male Sprague-Dawley rats underwent 2 alcohol intermittent access periods separated by a forced abstinence period. The complete Freund adjuvant model of inflammatory pain was introduced during…
Inflammatory Pain Promotes Increased Opioid Self-Administration: Role of Dysregulated Ventral Tegmental Area μ Opioid Receptors
Pain management in opioid abusers engenders ethical and practical difficulties for clinicians, often resulting in pain mismanagement. Although chronic opioid administration may alter pain states, the presence of pain itself may alter the propensity to self-administer opioids, and previous history of drug abuse comorbid with chronic pain promotes higher rates of opioid misuse. Here, we tested the hypothesis that inflammatory pain leads to increased heroin self-administration resulting from altered mu opioid receptor (MOR) regulation of mesolimbic dopamine (DA) transmission. To this end, the complete Freund's adjuvant (CFA) model of inflammation was used to assess the neurochemical and functi…
Pain-Induced Negative Affect Is Mediated via Recruitment of The Nucleus Accumbens Kappa Opioid System.
Negative affective states affect quality of life for patients suffering from pain. These maladaptive emotional states can lead to involuntary opioid overdose and many neuropsychiatric comorbidities. Uncovering the mechanisms responsible for pain-induced negative affect is critical in addressing these comorbid outcomes. The nucleus accumbens (NAc) shell, which integrates the aversive and rewarding valence of stimuli, exhibits plastic adaptations in the presence of pain. In discrete regions of the NAc, activation of the kappa opioid receptor (KOR) decreases the reinforcing properties of rewards and induces aversive behaviors. Using complementary techniques, we report that in vivo recruitment …
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…
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…
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…
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, …
The Life Cycle of the Mu-Opioid Receptor
Opioid receptors (ORs) are undisputed targets for the treatment of pain. Unfortunately, targeting these receptors therapeutically poses significant challenges including addiction, dependence, tolerance, and the appearance of side effects, such as respiratory depression and constipation. Moreover, misuse of prescription and illicit narcotics has resulted in the current opioid crisis. The mu-opioid receptor (MOR) is the cellular mediator of the effects of most commonly used opioids, and is a prototypical G protein-coupled receptor (GPCR) where new pharmacological, signalling and cell biology concepts have been coined. This review summarises the knowledge of the life cycle of this therapeutic …