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The cAMP signaling pathway has emerged as an important modulator of the pharmacological effects of ethanol. In this respect, the cAMP-dependent protein kinase has been shown to play an important role in the modulation of several ethanol-induced behavioral actions. Cellular levels of cAMP are maintained by the activity of adenylyl cyclases and phosphodiesterases. In the present work we have focused on ascertaining the role of PDE4 in mediating the neurobehavioral effects of ethanol. For this purpose, we have used the selective PDE4 inhibitor Ro 20-1724. This compound has been proven to enhance cellular cAMP response by PDE4 blockade and can be administered systemically. Swiss mice were injected intraperitoneally (i.p.) with Ro 20-1724 (0-5 mg/kg; i.p.) at different time intervals before ethanol (0-4 g/kg; i.p.) administration. Immediately after the ethanol injection, locomotor activity, loss of righting reflex, PKA footprint and enzymatic activity were assessed. Pretreatment with Ro 20-1724 increased ethanol-induced locomotor stimulation in a dose-dependent manner. Doses that increased locomotor stimulation did not modify basal locomotion or the suppression of motor activity produced by high doses of this alcohol. Ro 20-1724 did not alter the locomotor activation produced by amphetamine or cocaine. The time of loss of righting reflex evoked by ethanol was increased after pretreatment with Ro 20-1724. This effect was selective for the narcotic effects of ethanol since Ro 20-1724 did not affect pentobarbital-induced narcotic effects. Moreover, Ro 20-1724 administration increased the PKA footprint and enzymatic activity response elicited by ethanol. These data provide further evidence of the key role of the cAMP signaling pathway in the central effects of ethanol., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: Alcohol use disorders (AUDs) are emerging as a substance use disorder having various psychological and physical ill effects leading to hampering of individual's productivity and functioning. Aims: The aim of this study was to evaluate the efficacy of ketamine in enhancing confidence levels to abstain from alcohol. Methods: Eighteen patients were administered ketamine intravenously after detoxification; a total of three doses, with a 3-day gap between each. The Alcohol Abstinence Self-Efficacy Scale was used to measure their confidence in abstaining from alcohol. Results: The study revealed a significant increase in mean confidence scores after three ketamine sessions, with a final assessment showing a 51.98% increase in confidence from baseline. Conclusions: The study found that ketamine therapy significantly increased confidence levels in individuals with AUD to abstain from alcohol, with P = 0.05 threshold. However, the impact may wane over time, suggesting the need for additional support or maintenance treatments. [ABSTRACT FROM AUTHOR]

Studies presented in this chapter show that: (1) in the brain, ethanol is metabolized by catalase to acetaldehyde, which condenses with dopamine forming salsolinol; (2) acetaldehyde-derived salsolinol increases the release of dopamine mediating, via opioid receptors, the reinforcing effects of ethanol during the acquisition of ethanol consumption, while (3) brain acetaldehyde does not influence the maintenance of chronic ethanol intake, it is suggested that a learned cue-induced hyperglutamatergic system takes precedence over the dopaminergic system. However, (4) following a prolonged ethanol deprivation, the generation of acetaldehyde in the brain again plays a role, contributing to the increase in ethanol intake observed during ethanol re-access, called the alcohol deprivation effect (ADE), a model of relapse behavior; (5) naltrexone inhibits the high ethanol intake seen in the ADE condition, suggesting that acetaldehyde-derived salsolinol via opioid receptors also contributes to the relapse-like drinking behavior. The reader is referred to glutamate-mediated mechanisms that trigger the cue-associated alcohol-seeking and that also contribute to triggering relapse., (© 2023. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

The adverse use of alcohol is a serious global public health problem. Maternal alcohol consumption during pregnancy usually causes prenatal alcohol exposure (PAE) in the developing fetus, leading to a spectrum of disorders known as fetal alcohol spectrum disorders (FASD) and even fetal alcohol syndrome (FAS) throughout the lifelong sufferers. The prevalence of FASD is approximately 7.7 per 1,000 worldwide, and is even higher in developed regions. Generally, Ethanol in alcoholic beverages can impair embryonic neurological development through multiple pathways leading to FASD. Among them, the leading mechanism of FASDs is attributed to ethanol-induced neuroinflammatory damage to the central nervous system (CNS). Although the underlying molecular mechanisms remain unclear, the remaining multiple pathological mechanisms is likely due to the neurotoxic damage of ethanol and the resultant neuronal loss. Regardless of the molecular pathway, the ultimate outcome of the developing CNS exposed to ethanol is almost always the destruction and apoptosis of neurons, which leads to the reduction of neurons and further the development of FASD. In this review, we systematically summarize the current research progress on the pathogenesis of FASD, which hopefully provides new insights into differential early diagnosis, treatment and prevention for patents with FASD. [ABSTRACT FROM AUTHOR]

Rationale: Previous studies have shown that gonadal hormones influence opioid self-administration in female rodents, but very few studies have examined these effects in male rodents. Objectives: The purpose of this study was to examine the effects of chronic hormone treatment on intravenous heroin self-administration in gonadectomized male rats using both physiological and supraphysiological doses of testosterone, estradiol, or progesterone. Methods: Gonadectomized male rats were surgically implanted with intravenous catheters and trained to self-administer heroin on a fixed ratio (FR1) schedule of reinforcement. Using a between-subjects design, rats were treated daily with testosterone (0.175 or 1.75 mg, sc), estradiol (0.0005 or 0.005 mg, sc), progesterone, (0.0125 or 0.125 mg, sc), or their vehicles. After 14 days of chronic treatment, a dose–effect curve was determined for heroin (0.0003—0.03 mg/kg/infusion) over the course of one week. Results: Neither testosterone nor estradiol altered responding maintained by heroin. In contrast, the high dose of progesterone (0.125 mg) reduced responding maintained by all doses of heroin to saline-control levels. This dose of progesterone did not reduce responding maintained by food on a progressive ratio schedule in either food-restricted or food-sated rats. Conclusions: These data indicate that exogenous progesterone or a pharmacologically active metabolite selectively decreases heroin intake in male rodents, which may have therapeutic implications for men with opioid use disorder. [ABSTRACT FROM AUTHOR]

Ethanol metabolism plays an essential role in how the body perceives and experiences alcohol consumption, and evidence suggests that modulation of ethanol metabolism can alter the risk for alcohol use disorder (AUD). In this review, we explore how ethanol metabolism, mainly via alcohol dehydrogenase and aldehyde dehydrogenase 2 (ALDH2), contributes to drinking behaviors by integrating preclinical and clinical findings. We discuss how alcohol dehydrogenase and ALDH2 polymorphisms change the risk for AUD, and whether we can harness that knowledge to design interventions for AUD that alter ethanol metabolism. We detail the use of disulfiram, RNAi strategies, and kudzu/isoflavones to inhibit ALDH2 and increase acetaldehyde, ideally leading to decreases in drinking behavior. In addition, we cover recent preclinical evidence suggesting that strategies other than increasing acetaldehyde-mediated aversion can decrease ethanol consumption, providing other potential metabolism-centric therapeutic targets. However, modulating ethanol metabolism has inherent risks, and we point out some of the key areas in which more data are needed to mitigate these potential adverse effects. Finally, we present our opinions on the future of treating AUD by the modulation of ethanol metabolism. [ABSTRACT FROM AUTHOR]

Background: Caffeine is frequently consumed with ethanol to reduce the impairing effects induced by ethanol, including psychomotor slowing or incoordination. Both drugs modulate dopamine (DA)-related markers in accumbens (Acb), and Acb DA is involved in voluntary locomotion and locomotor sensitization. The present study determined whether caffeine can affect locomotion induced by acute and repeated ethanol administration in adult male CD-1 mice., Methods: Acute administration of caffeine (7.5 to 30.0 mg/kg) was evaluated for its effects on acute ethanol-induced (1.5 to 3.5 g/kg) changes in open-field horizontal locomotion, supported rearing, and rearing not supported by the wall. DA receptor-dependent phosphorylation markers were assessed: extracellular signal-regulated kinase (pERK), and dopamine-and cAMP-regulated phosphoprotein Mr32kDa phosphorylated at threonine 75 site (pDARPP-32-Thr75) in Acb core and shell. Acutely administered caffeine was also evaluated in ethanol-sensitized (1.5 g/kg) mice., Results: Acute ethanol decreased both types of rearing. Caffeine increased supported rearing but did not block ethanol -induced decreases in rearing. Both substances increased horizontal locomotion in a biphasic manner, and caffeine potentiated ethanol-induced locomotion. Although ethanol administered repeatedly induced sensitization of locomotion and unsupported rearing, acute administration of caffeine to ethanol-sensitized mice in an ethanol-free state resulted in blunted stimulant effects compared with those seen in ethanol-naïve mice. Ethanol increased pERK immunoreactivity in both subregions of the Acb, but coadministration with caffeine blunted this increase. There were no effects on pDARPP-32(Thr75) immunoreactivity., Conclusions: The present results demonstrated that, after the first administration, caffeine potentiated the stimulating actions of ethanol, but did not counteract its suppressant or ataxic effects. Moreover, our results show that caffeine has less activating effects in ethanol-sensitized animals., (© 2021 by the Research Society on Alcoholism.)

Chronic alcohol (ethyl alcohol, EtOH) binging has been associated with long-term neural adaptations that lead to the development of addiction. Many of the neurobiological features of EtOH abuse are shared with other forms of binging, like pathological feeding. The drinking-in-the-dark (DID) paradigm has been used extensively to study the neurobiology of EtOH binge-like drinking due to its ability to promote high intakes relevant to human behavior. DID can also generate high consumption of other tastants, but this procedure has not been fully adapted to study forms of binging behavior that are not alcohol-driven. In the present study, we used a modified version of DID that uses multiple bottle availability to promote even higher levels of EtOH drinking in male C57BL/6J mice and allows a thorough investigation of tastant preferences. We assessed whether administration of systemic naltrexone could reduce binging on EtOH, sucrose, and saccharin separately as well as in combination. Our multiple bottle DID procedure resulted in heightened levels of consumption compared with previously reported data using this task. We found that administration of the opioid receptor antagonist naltrexone reduced intakes of preferred, highly concentrated EtOH, sucrose, and saccharin. We also report that naltrexone was able to reduce overall intakes when animals were allowed to self-administer EtOH, sucrose, or saccharin in combination. Our modified DID procedure provides a novel approach to study binging behavior that extends beyond EtOH to other tastants (i.e. sucrose and artificial sweeteners), and has implications for the study of the neuropharmacology of binge drinking.

The ability of a suite of models contributing to the sixth phase of the Coupled Model Intercomparison Project (CMIP6) to simulate observed large-scale atmospheric circulation patterns over the Pacific Northwest of North America is evaluated. Twelve representative patterns of 500-hPa geopotential height (Z500) anomalies are identified using the self-organizing map method applied to reanalysis. CMIP6 Z500 anomalies from simulations of the historical period are mapped to each reanalysis-derived pattern, and the resulting differences between patterns, as well as differences in frequency of pattern occurrence, are quantified. In general, models are able to simulate the range of Z500 patterns with reasonable fidelity, although model skill varies across the 25-member ensemble. Surface temperature and precipitation anomalies associated with each Z500 pattern are found to also be reasonably simulated by the models, with some biases noted. This boosts confidence that the models are simulating temperature and precipitation patterns for the correct physical reasons. The models exhibit a range of skill at simulating pattern occurrence frequency and pattern persistence, with more agreement in winter than summer. Results indicate that the CMIP6 models are appropriate for assessing future projections of key atmospheric circulation patterns and their impacts on temperature and precipitation over the region. [ABSTRACT FROM AUTHOR]

Schizophrenia is a neurological disorder that alters the behavior and affects the quality of life of a patient. It is characterized by hallucinations, disorganized behavior, cognitive dysfunction, hyperlocomotion, and loss of the reward system. Schizophrenia constitutes three symptoms' domains, viz. positive, negative and cognitive. Typical and atypical antipsychotics do not fully resolve all the symptoms' domains thus paving the way to the genesis of the glutamatergic hypothesis, i.e. N-methyl-d-aspartate (NMDA) receptor hypofunction in the pathophysiology of schizophrenia. Positive modulation of NMDA receptors by enhancing co-agonist, glycine effect is proposed to produce a therapeutic effect in schizophrenia. Hence, sarcosine (N-methyl glycine), natural amino acid, and a glycine transporter inhibitor (GlyT-1) which also acts on NMDA receptors were used in the present study. The present study unravels the role of sarcosine in the attenuation of ketamine-induced three symptom domains in a rat model through modulation of oxidative stress, mitochondrial dysfunction, and neuroinflammatory pathways. The animal model of schizophrenia was established by injecting ketamine intraperitoneal (ip) at a 30 mg/kg dose for 10 consecutive days, after which sarcosine (300, 600 mg/kg, ip) as a treatment was given for 7 days followed by behavioral, biochemical, molecular, and histopathological analysis. It was revealed that sarcosine reversed ketamine-induced behavioral impairments. Moreover, sarcosine ameliorated oxidative and nitrosative stress, mitochondrial dysfunction, and neuroinflammation and showed protective effects in histopathological examination by hematoxylin and eosin staining. Hence, conclusively, sarcosine was regarded to attenuate the behavioural symptoms of schizophrenia by alleviating oxidative stress, neuroinflammation, and mitochondrial dysfunction established by the ketamine. [ABSTRACT FROM AUTHOR]

Activation of nociceptin opioid peptide receptors (NOP, a.k.a. opioid-like receptor-1, ORL-1) by the ligand nociceptin/orphanin FQ, leads to G protein-dependent regulation of Cav2.2 (N-type) voltage-gated calcium channels (VGCCs). This typically causes a reduction in calcium currents, triggering changes in presynaptic calcium levels and thus neurotransmission. Because of the widespread expression patterns of NOP and VGCCs across multiple brain regions, the dorsal horn of the spinal cord, and the dorsal root ganglia, this results in the alteration of numerous neurophysiological features. Here we review the regulation of N-type calcium channels by the NOP-nociceptin system in the context of neurological conditions such as anxiety, addiction, and pain. [ABSTRACT FROM AUTHOR]

Rationale: The role of ethanol-derived acetaldehyde has not been examined yet on performance in a model of operant oral self-administration. However, previous studies reported that an acetaldehyde-sequestering agent, d-penicillamine (DP) and an inhibitor of catalase-mediated acetaldehyde production, 3-amino-1,2,4-triazole (3-AT) reduce voluntary ethanol consumption. Objectives: The aim of our investigation was to evaluate the effects of DP and 3-AT on acquisition and maintenance of oral operant ethanol self-administration. Methods: Using operant chambers, rats learned to nose poke in order to receive ethanol solution (5-10 % v/ v) under an FR1 schedule of reinforcement in which discrete light and tone cues were presented during ethanol delivery. Results: DP and 3-AT impair the acquisition of ethanol self-administration, whereas its maintenance is not affected neither by drug given alone for both 10 or 5 % ethanol nor by drugs association for 5 % ethanol. Moreover, when the concentration of ethanol was diminished from 10 to 5 %, rats increased the rate of self-administration behaviour. Conclusions: These findings suggest that brain acetaldehyde plays a critical role during acquisition of operant self-administration in ethanol-naïve rats. In contrast, during the maintenance phase, acetaldehyde could contribute to ethanol self-administration by a combined mechanism: On one hand, its lack (by DP or 3-AT) might result in further ethanol-seeking and taking and, on the other, inhibition of ethanol metabolism (by 3-AT) might release an action of the un-metabolised fraction of ethanol that does not overall result in compromising maintenance of ethanol self-administration. [ABSTRACT FROM AUTHOR]

Schizophrenia is a common psychiatric disorder that exhibits a variety of symptoms. The exact etiology and pathogenesis are still doubtful. However, genetic and environmental factors seem to have a role. Years ago, the role of the immune system was focused on auto-antibodies, cytokines, different types of immune cells and immune genes. The Toll-like receptors (TLR) are a cornerstone of the innate immune system, particularly TLR4. TLR4 primarily recognises gram-negative lipopolysaccharides bacteria. This case-control study, for the first time to our knowledge, examined the role of TLR4 gene polymorphisms in 142 Egyptian schizophrenic patients and 175 healthy controls. Using polymerase chain reaction-restriction fragment length polymorphism (PCR–RFLP), four single nucleotide polymorphisms (SNPs) were investigated in the TLR4 gene rs11536889, rs10759931, rs1927911, and rs1927914. The Positive and Negative Syndrome Scale (PANSS) was used in diagnosis and assessment. A statistically significant association was observed between rs11536889, rs1927911 and rs1927914, but no association was found between rs10759931. There was no association between the different SNP genotypes and PANSS, except between rs1927914 and general psychopathologic symptoms. This study shows a strong association between TLR4 rs11356889 and rs1927911 minor alleles and schizophrenia. These findings could be additional evidence for the immune system's role in schizophrenia development. However, more studies with a more significant sample number, TLR4 protein assessment, and a larger number of SNPs are recommended. [ABSTRACT FROM AUTHOR]

Ethanol excites dopamine ( DA) neurons in the posterior ventral tegmental area ( pVTA). This effect is responsible for ethanol's motivational properties and may contribute to alcoholism. Evidence indicates that catalase-mediated conversion of ethanol into acetaldehyde in pVTA plays a critical role in this effect. Acetaldehyde, in the presence of DA, condensates with it to generate salsolinol. Salsolinol, when administered in pVTA, excites pVTA DA cells, elicits DA transmission in nucleus accumbens and sustains its self-administration in pVTA. Here we show, by using ex vivo electrophysiology, that ethanol and acetaldehyde, but not salsolinol, failed to stimulate pVTA DA cell activity in mice administered α-methyl-p-tyrosine, a DA biosynthesis inhibitor that reduces somatodendritic DA release. This effect was specific for ethanol and acetaldehyde since morphine, similarly to salsolinol, was able to excite pVTA DA cells in α-methyl-p-tyrosine-treated mice. However, when DA was bath applied in slices from α-methyl-p-tyrosine-treated mice, ethanol-induced excitation of pVTA DA neurons was restored. This effect requires ethanol oxidation into acetaldehyde given that, when H2 O2-catalase system was impaired by either 3-amino-1,2,4-triazole or in vivo administration of α-lipoic acid, ethanol did not enhance DA cell activity. Finally, high performance liquid chromatography-tandem mass spectrometry analysis of bath medium detected salsolinol only after co-application of ethanol and DA in α-methyl-p-tyrosine-treated mice. These results demonstrate the relationship between ethanol and salsolinol effects on pVTA DA neurons, help to untangle the mechanism(s) of action of ethanol in this area and contribute to an exciting research avenue prosperous of theoretical and practical consequences. [ABSTRACT FROM AUTHOR]

Alcohol exposure during pregnancy is harmful to the fetus and causes a wide range of long-lasting physiological and neurocognitive impairments, collectively referred to as fetal alcohol spectrum disorders (FASD). The neurobehavioral deficits observed in FASD result from structural and functional damages in the brain, with neurodegeneration being the most destructive consequence. Currently, there are no therapies for FASD. It is exigent to delineate the underlying mechanisms of alcohol neurotoxicity and develop an effective strategy of treatment. ER stress, caused by the accumulation of unfolded/misfolded proteins in the ER, is the hallmark of many neurodegenerative diseases, including alcohol-induced neurodegeneration. Mesencephalic astrocyte-derived neurotrophic factor (MANF) is a newly discovered endoplasmic reticulum (ER) stress responsive neurotrophic factor that regulates diverse neuronal functions. This review summarizes the recent findings revealing the effects of MANF on the CNS and its protective role against neurodegeneration. Particularly, we focus the role of MANF on alcohol-induced ER stress and neurodegeneration and discuss the therapeutic potential of MANF in treating alcohol neurotoxicity such as FASD. [ABSTRACT FROM AUTHOR]

An implicit tenet of the alcohol use disorder (AUD) research field is that knowledge of how alcohol interacts with the brain is critical to the development of an understanding of vulnerability to AUD and treatment approaches. Gaining this understanding requires the mapping of brain function critical to specific components of this heterogeneous disorder. Early approaches in humans and animal models focused on the determination of specific brain regions sensitive to alcohol action and their participation in AUD-relevant behaviors. Broadly speaking, this research has focused on three domains, Binge/Intoxication, Negative Affect/Withdrawal, and Preoccupation/Anticipation, with a number of regions identified as participating in each. With the generational advances in technologies that the field of neuroscience has undergone over the last two decades, this focus has shifted to a circuit-based analysis. A wealth of new data has sharpened the field's focus on the specific roles of the interconnectivity of multiple brain regions in AUD and AUD-relevant behaviors, as well as demonstrating that the three major domains described above have much fuzzier edges than originally thought.In this chapter, we very briefly review brain regions previously implicated in aspects of AUD-relevant behavior from animal model research. Next, we move to a more in-depth overview of circuit-based approaches, and the utilization of these approaches in current AUD research., (© 2023. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Background: Clinical and experimental studies support the therapeutic potential of Withania somnifera (WS) (L.) Dunal on anxiety disorders. This potential is attributable to components present in different plant extracts; however, the individual compound(s) endowed with specific anxiolytic effects and potential modulatory activity of the GABAA receptor complex (GABAAR) have remained unidentified until the recent isolation from a WS methanolic root extract of some GABAAR-active compounds, including the long alkyl-chain ferulic acid ester, docosanyl ferulate (DF). Aims: This study was designed to assess whether DF (0.05, 0.25 and 2 mg/kg), similarly to diazepam (2 mg/kg), may exert anxiolytic effects, whether these effects may be significantly blocked by the benzodiazepine antagonist flumazenil (10 mg/kg) and whether DF may lack some of the benzodiazepines' typical motor, cognitive and motivational side effects. Methods: The behavioural paradigms Elevated Plus Maze, Static Rods, Novel Object Recognition, Place Conditioning and potentiation of ethanol-induced Loss of Righting Reflex were applied on male CD-1 mice. Results: Similarly to diazepam, DF exerts anxiolytic effects that are blocked by flumazenil. Moreover, at the full anxiolytic dose of 2 mg/kg, DF lacks typical benzodiazepine-like side effects on motor and cognitive performances and on place conditioning. Moreover, DF fails to potentiate ethanol's (3 g/kg) depressant activity at the ethanol-induced Loss of Righting Reflex paradigm. Conclusions: These data point to DF as an effective benzodiazepine-like anxiolytic compound that, in light of its lack of motor, mnemonic and motivational side effects, could be a suitable candidate for the treatment of anxiety disorders. [ABSTRACT FROM AUTHOR]

Acetaldehyde (ACD), the first metabolite of ethanol, is implicated in several of ethanol's actions, including the reinforcing and aversive effects. The neuronal mechanisms underlying ACD's aversive effect, however, are poorly understood. The lateral habenula (LHb), a regulator of midbrain monoaminergic centers, is activated by negative valence events. Although the LHb has been linked to the aversive responses of several abused drugs, including ethanol, little is known about ACD. We, therefore, assessed ACD's action on LHb neurons in rats. The results showed that intraperitoneal injection of ACD increased cFos protein expression within the LHb and that intra-LHb infusion of ACD induced conditioned place aversion in male rats. Furthermore, electrophysiological recording in brain slices of male and female rats showed that bath application of ACD facilitated spontaneous firing and glutamatergic transmission. This effect of ACD was potentiated by an aldehyde dehydrogenase (ALDH) inhibitor, disulfiram (DS), but attenuated by the antagonists of dopamine (DA) receptor (DAR) subtype 1 (SCH23390) and subtype 2 (raclopride), and partly abolished by the pretreatment of DA or DA reuptake blocker (GBR12935; GBR). Moreover, application of ACD initiated a depolarizing inward current (IACD) and enhanced the hyperpolarizing-activated currents in LHb neurons. Bath application of Rp-cAMPs, a selective cAMP-PKA inhibitor, attenuated ACD-induced potentiation of EPSCs and IACD. Finally, bath application of ZD7288, a selective blocker of hyperpolarization-activated cyclic nucleotide-gated channels, attenuated ACD-induced potentiation of firing, EPSCs, and IACD. These results show that ACD exerts its aversive property by exciting LHb neurons via multiple cellular mechanisms, and new treatments targeting the LHb may be beneficial for alcoholism. [ABSTRACT FROM AUTHOR]

Aim: Despite animal evidence of a role of calcium in the pathogenesis of spinal cord injury, several studies conducted in the past found calcium blockade ineffective. However, those studies involved oral or parenteral administration of Ca++ antagonists. We hypothesized that Ca++ blockade might be effective with local/immediate application (LIA) at the time of neural injury. Methods: In this study, we assessed the effects of LIA of BAPTA (1,2‐bis (o‐aminophenoxy) ethane‐N, N, N′, N'‐tetraacetic acid), a cell‐permeable highly selective Ca++ chelator, after spinal cord transection (SCT) in mice over 4 weeks. Effects of BAPTA were assessed behaviorally and with immunohistochemistry. Concurrently, BAPTA was submitted for the first time to multimodality assessment in an in vitro model of neural damage as a possible spinal neuroprotectant. Results: We demonstrate that BAPTA alleviates neuronal apoptosis caused by physical damage by inhibition of neuronal apoptosis and reactive oxygen species (ROS) generation. This translates to enhanced preservation of electrophysiological function and superior behavioral recovery. Conclusion: This study shows for the first time that local/immediate application of Ca++ chelator BAPTA is strongly neuroprotective after severe spinal cord injury. [ABSTRACT FROM AUTHOR]

Rationale: Opioid receptor antagonists reliably alter the expression or extinction of ethanol's conditioned motivational effects as indexed by the place conditioning procedure, suggesting endogenous opioids are normally involved. These studies examined how exogenous stimulation of opioid receptors alters ethanol's conditioned rewarding and aversive effects. Objectives: Drugs that either directly (morphine) or indirectly (ethanol) stimulate opioid receptors were tested for their effects on the expression and extinction of ethanol-induced conditioned place preference (CPP) and conditioned place aversion (CPA). Methods: Male DBA/2J mice were exposed to unbiased ethanol (2 g/kg) conditioning procedures that produced either CPP (experiments 1–2) or CPA (experiments 3–4). Morphine (0, 2.5, 5, or 10 mg/kg) was injected before three post-conditioning tests in experiments 1 and 3, whereas ethanol (0, 1, 2, or 3 g/kg) was injected before tests in experiments 2 and 4. All groups received vehicle on test 4 to determine whether the drug pretreatments altered the course of extinction. Results: Morphine dose-dependently enhanced CPP expression (experiment 1), but ethanol dose-dependently reduced CPP expression (experiment 2). Test 4 showed no differences between drug-treated mice and mice given vehicle on all tests. Morphine had no effect on expression or extinction of ethanol-induced CPA (experiment 3). The highest ethanol dose (3 g/kg) interfered with CPA expression, but not extinction (experiment 4). Conclusions: Pretreatment drug effects on ethanol CPP and CPA expression were most likely a byproduct of their activity altering effects rather than opioid-receptor mediated modulation of ethanol's conditioned motivational effects. Neither drug affected the course of extinction. [ABSTRACT FROM AUTHOR]

Copper storage disease occurs in multiple dog breeds and is one of the most common causes of chronic hepatitis in this species. The disease is caused by hereditary defects in copper metabolism in conjunction with high dietary copper levels. The progressive copper accumulation leads to hepatitis, cirrhosis, and eventually death if left untreated. Copper chelators are critical in modulating the effects of this disease. It is therefore of significant practicality to understand the pharmacokinetic (PK) parameters of chelating agents, particularly since they are oftentimes quite expensive. A liquid chromatography-tandem mass spectrometric (LC/MS/MS) method was developed to measure plasma levels of one of the most common chelators, d-penicillamine. The compound was discovered to exist in two forms, monomeric and dimeric, and various chemical derivatizations were tried to force the compound into one form or the other. Eventually, the simplest approach was individual determination of penicillamine and its dimer, with summation of the two quantities. This enabled determination of canine PK parameters for penicillamine based on comparison of oral and intravenous administration of the drug, including time to maximum drug level (Tmax), concentration at maximum (Cmax), clearance (Cls) and volume of distribution (Vdss). The drug was found to exist predominantly in the dimeric form in plasma, which is incapable of chelating copper owing to lack of free sulfhydryl groups and must therefore provide a storage form of the drug in equilibrium with its monomeric form in vivo. Mechanisms are discussed for the electrospray-induced fragmentation of penicillamine as well as of its dimer. [ABSTRACT FROM AUTHOR]

This review concerns the current knowledge of melatonin and alcohol-related disorders. Chronobiological effects of ethanol are related to melatonin suppression and in relation to inflammation, stress, free radical scavenging, autophagy and cancer risk. It is postulated that both alcohol- and inflammation-induced production of reactive oxygen species (ROS) alters cell membrane properties leading to tissue dysfunction and, subsequent further ROS production. Lysosomal enzymes are often used to assess the relationships between intensified inflammation states caused by alcohol abuse and oxidative stress as well as level of tissue damage estimated by the increased release of cellular enzymes into the extracellular space. Studies have established a link between alcoholism and desynchronosis (circadian disruption). Desynchronosis results from the disorganization of the body's circadian time structure and is an aspect of the pathology of chronic alcohol intoxication. The inflammatory conditions and the activity of lysosomal enzymes in acute alcohol poisoning or chronic alcohol-dependent diseases are in most cases interrelated. Inflammation can increase the activity of lysosomal enzymes, which can be regarded as a marker of lysosomal dysfunction and abnormal cellular integrity. Studies show alcohol toxicity is modulated by the melatonin (Mel) circadian rhythm. This hormone, produced by the pineal gland, is the main regulator of 24 h (sleep-wake cycle) and seasonal biorhythms. Mel exhibits antioxidant properties and may be useful in the prevention of oxidative stress reactions known to be responsible for alcohol-related diseases. Naturally produced Mel and exogenous sources in food can act in free radical reactions and activate the endogenous defense system. Mel plays an important role in the normalization of the post-stress state by its influence on neurotransmitter systems and the synchronization of circadian rhythms. Acting simultaneously on the neuroendocrine and immune systems, Mel optimizes homeostasis and provides protection against stress. Abbreviations: ROS, reactive oxygen species; Mel, melatonin; SRV, resveratrol; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; ANT, arylalkylamine-N-acetyltransferase; EC cells, gastrointestinal enterochromaffin cells; MT1, melatonin high-affinity nanomolecular receptor site; MT2, melatonin low-affinity nanomolecular receptor site; ROR/RZR, orphan nuclear retinoid receptors; SOD, superoxide dismutase; CAT, catalase; GPx, glutathione peroxidase; GR, glutathione reductase; GSH, reduced form of glutathione; GSSG, oxidized form of glutathione; TAC, total antioxidant capacity; ONOO∙–, peroxynitrite radical; NCAM, neural cell adhesion molecules; LPO, lipid peroxidation; α-KG, α-ketoglutarate, HIF-1α, Hypoxia-inducible factor 1-α, IL-2, interleukin-2; HPA axis, hypothalamic-pituitary-adrenal axis; Tph1, tryptophan hydroxylase 1; AA-NAT, arylalkylamine-N-acetyltransferase; AS-MT, acetylserotonin O-methyltransferase; NAG, N-acetyl-beta-D-glucosaminidase; HBA1c glycated hemoglobin; LPS, lipopolysaccharide; AAP, alanyl-aminopeptidase; β-GR, β-glucuronidase; β-GD, β-galactosidase; LAP, leucine aminopeptidase. [ABSTRACT FROM AUTHOR]

Nowadays, dietary proteins play a very crucial role against oxidation, which is a fundamental process in the occurrence of many diseases. The aim of this study was to hydrolyze globulin fractions from C. moschata (CMH), C. lanatus (CLH) and L. siceraria (LSH), and to evaluate their in vivo antioxidant potential. The in vivo antioxidant potential was conducted using in vivo catalase and lipid peroxidation (LPO) assay methods. The total protein content was also estimated using Bio-Rad protein assay and bovine serum albumin methods. For in vivo study, ethanol was induced into test animals for toxicity and oxidative damage for 15 days. The catalase and LOP of serum / liver homogenate were determined. The results showed that globulin hydrolysates decrease the MDA level and increase the catalase level in normal mice. Based on these findings, this study provides information about in vivo antioxidant activities of C. moschata, C. lanatus and L. siceraria hydrolysates. Globulin hydrolysates of L. siceraria showed effective antioxidant properties in vivo models, whereas globulin hydrolysates of C. moschata and C. lanatus exhibited remarkable antioxidant properties, as well. Thus, the results suggest that globulin hydrolysates might be used as a novel source in reducing the risk of oxidative stressed diseases and development of functional foods. [ABSTRACT FROM AUTHOR]

For many years, research from around the world has suggested that the neuroactive steroid (3α,5α)‐3‐hydroxypregnan‐20‐one (allopregnanolone or 3α,5α‐THP) may have therapeutic potential for treatment of various symptoms of alcohol use disorders (AUDs). In this critical review, we systematically address all the evidence that supports such a suggestion, delineate the etiologies of AUDs that are addressed by treatment with allopregnanolone or its precursor pregnenolone, and the rationale for treatment of various components of the disease based on basic science and clinical evidence. This review presents a theoretical framework for understanding how endogenous steroids that regulate the effects of stress, alcohol, and the innate immune system could play a key role in both the prevention and the treatment of AUDs. We further discuss cautions and limitations of allopregnanolone or pregnenolone therapy with suggestions regarding the management of risk and the potential for helping millions who suffer from AUDs. [ABSTRACT FROM AUTHOR]

Background: Binge alcohol drinking has been characterized as a key feature of alcoholism. The drinking‐in‐the‐dark (DID) preclinical model, a procedure that promotes high levels of ethanol (EtOH) intake in short periods of time, has been extensively used to investigate neuropharmacological and genetic determinants of binge‐like EtOH consumption. Using DID methodology, alcohol‐preferring strains of mice such as C57BL/6J (B6) mice consume enough EtOH to achieve blood concentrations (≥1.0 mg/ml) associated with behavioral intoxication (i.e., motor incoordination). DID procedures typically involve the use of socially isolated animals (single‐housed prior to and during the experiment). Previous research indicates that stress associated with social isolation can induce anxiety‐like behavior and promote increases in EtOH intake. The present study investigates the role of housing conditions in anxiety‐like behavior and binge‐like EtOH intake using a DID procedure. Methods: Male and female B6 mice were isolated or pair‐housed for a period of 6 weeks prior to evaluation of anxiety‐like (elevated plus maze, light and dark box, open field) and drinking (water, 10% sucrose, 10 to 30% EtOH) behavior. In order to measure intake, a variation of the standard DID procedure using a removable, transparent, and perforated plastic barrier strip (designed to temporarily divide the cage in 2) was introduced. This allowed for individual intake records (2‐hour test) of isolated and socially housed animals. Results: Increased anxiety‐like behavior and reduced sucrose consumption were found in isolated mice. The effects of housing conditions on EtOH intake were sex‐ and concentration‐dependent. In male mice, isolation increased 20 and 30% EtOH intake. In females, however, an increased intake of EtOH (30%) was found in socialized animals. No effects of housing or sex were found at EtOH 10%. Conclusions: Together with previous literature, the present study suggests that social isolation can promote anxiety‐associated behavior and produce sex‐dependent changes in binge‐like EtOH consumption. [ABSTRACT FROM AUTHOR]

Background: Adolescence is a critical period for neural development, and alcohol exposure during adolescence can lead to an elevated risk for health consequences as well as alcohol use disorders. Clinical and experimental data suggest that chronic alcohol exposure may produce immunomodulatory effects that can lead to the activation of pro‐inflammatory cytokine pathways as well as microglial markers. The present study evaluated, in brain and blood, the effects of adolescent alcohol exposure and withdrawal on microglia and on the most representative pro‐ and anti‐inflammatory cytokines and major chemokines that can contribute to the establishing of a neuroinflammatory environment. Methods: Wistar rats (males, n = 96) were exposed to ethanol (EtOH) vapors, or air control, for 5 weeks over adolescence (PD22‐PD58). Brains and blood samples were collected at 3 time points: (i) after 35 days of vapor/air exposure (PD58); (ii) after 1 day of withdrawal (PD59), and (iii) 28 days after withdrawal (PD86). The ionized calcium‐binding adapter molecule 1 (Iba‐1) was used to index microglial activation, and cytokine/chemokine responses were analyzed using magnetic bead panels. Results: After 35 days of adolescent vapor exposure, a significant increase in Iba‐1 immunoreactivity was seen in amygdala, frontal cortex, hippocampus, and substantia nigra. However, Iba‐1 density returned to control levels at both 1 day and 28 days of withdrawal except in the hippocampus where Iba‐1 density was significantly lower than controls. In serum, adolescent EtOH exposure induced a reduction in IL‐13 and an increase in fractalkine at day 35. After 1 day of withdrawal, IL‐18 was reduced, and IP‐10 was elevated, whereas both IP‐10 and IL‐10 were elevated at 28 days following withdrawal. In the frontal cortex, adolescent EtOH exposure induced an increase in IL‐1β at day 35, and 28 days of withdrawal, and IL‐10 was increased after 28 days of withdrawal. Conclusion: These data demonstrate that EtOH exposure during adolescence produces significant microglial activation; however, inflammatory markers seen in the blood appear to differ from those observed in the brain. [ABSTRACT FROM AUTHOR]

Background and Purpose: Toll-like receptors (TLRs) are a family of innate immune system receptors that respond to pathogen-derived and tissue damage-related ligands and are increasingly recognized for their impact on homeostasis and its dysregulation in the nervous system. TLR signaling participates in brain injury and addiction, but its role in the alcohol-seeking behavior, which initiates alcohol drinking, is still poorly understood. In this review, we discuss our findings designed to elucidate the potential contribution of the activated TLR4 signal located in neurons, on impulsivity and the predisposition to initiate alcohol drinking (binge drinking). Results: Our findings indicate that the TLR4 signal is innately activated in neurons from alcohol-preferring subjects, identifying a genetic contribution to the regulation of impulsivity and the alcohol-seeking propensity. Signal activation is through the non-canonical, previously unknown, binding of TLR4 to the α2 subunit of the γ-aminobutyric 2 acid A receptor (GABAAR α2). Activation is sustained by the stress hormone corticotrophin-releasing factor (CRF) and additional still poorly recognized ligand/scaffold proteins. Focus is on the effect of TLR4 signal activation on the balance between pro- and anti-inflammatory chemokines [chemokine (C-C motif) ligand 2 (CCL2)/chemokine (C-X3-C motif) ligand 1 (CX3CL1)] and its effect on binge drinking. Conclusion: The results are discussed within the context of current findings on the distinct activation and functions of TLR signals located in neurons, as opposed to immune cells. They indicate that the balance between pro- and anti-inflammatory TLR4 signaling plays a major role in binge drinking. These findings have major impact on future basic and translational research, including the development of potential therapeutic and preventative strategies. [ABSTRACT FROM AUTHOR]

Rationale: Alcohol use disorder (AUD) involves dysregulation of innate immune signaling in brain. Toll-like receptor 3 (TLR3), an innate immune receptor that is upregulated in post-mortem human alcoholics, leads to induction of interferon (IFN) signaling. IFNs have been linked to depressive-like symptoms and therefore may play a role in addiction pathology. Astrocyte-neuronal signaling may contribute to maladaptation of neuronal circuits. Objectives: In this manuscript, we examine ethanol (EtOH) induction of IFN signaling in neuronal, astrocyte, and microglial cell lines and assess astrocyte-neuronal interactions. Methods: U373 astrocytes, SH-SY5Y neurons, and BV2 microglia were treated with EtOH and analyzed for autocrine/paracrine IFN signaling. Results: EtOH induced TLR3, IFNβ, and IFNγ in SH-SY5Y neurons and U373 astrocytes, but not in BV2 microglia. The IFN response gene TRAIL was also strongly upregulated by TLR3 agonist Poly(I:C) and EtOH in U373 astrocytes. TRAIL blockage via neutralizing antibody prevented induction of IFNs in SH-SY5Y neurons but not in U373 astrocytes. Blocking TRAIL in conditioned media from EtOH-treated astrocytes prevented induction of IFNs in SH-SY5Y neurons. Finally, an in vivo model of chronic 10-day binge EtOH exposure in C57BL6/J mice, as well as single acute treatment with Poly(I:C), showed increased TRAIL +IR cells in both orbitofrontal and entorhinal cortex. Conclusions: This study establishes a role of astrocyte to neuron TRAIL release in EtOH-induced IFN responses. This may contribute to alcohol associated negative affect and suggest potential therapeutic benefit of TRAIL inhibition in AUD. [ABSTRACT FROM AUTHOR]

An unsafe level of manganese (Mn) was detected in the drinking water in some arsenic (As)-contaminated areas in Bangladesh. Mn is an essential trace element; however, the intake of a higher level of Mn through the drinking water is associated with the development of toxicity in humans. This study was designed to evaluate the effects of As and Mn co-exposure on neurobehavioral and biochemical alterations in a mouse model. Sodium arsenite (10 mg/kg body weight) and manganese chloride tetrahydrate (10 mg/kg body weight) were given to mice individually and in combination with drinking water for 90 days. Results showed that individual As and Mn exposure as well as co-exposure of As and Mn significantly (p < 0.05) reduced the percent of time spent in the open arms when compared with that of control mice. In addition, percent of time spent in open arms significantly (p < 0.05) increased in co-exposed mice compared with As exposure in elevated plus maze (42.05 ± 1.10 versus 38.94 ± 0.66). In the Morris water maze test, the mean time latency to find the platform was longer in metal-treated mice in comparison to that of control mice (p < 0.05). Importantly, the co-exposed group had shorter time when compared with the As-exposed group during the training periods (p < 0.05). Moreover, co-exposed mice stayed significantly (p < 0.05) more time in the target quadrant in the probe trial in comparison with that of As-exposed mice (27.25 ± 1.21 versus 23.83 ± 0.87 s) but less time than control mice (27.25 ± 1.21 versus 43.17 ± 1.49 s). In addition, a significant (p < 0.05) alteration of biochemical parameters such as ALT, AST, ALP, BChE, and SOD as well as urea and creatinine levels were noted in the As-exposed group compared with the control group and Mn significantly (p < 0.05) attenuated the effects of As in co-exposed mice. Therefore, the results of this study suggest that As and Mn may have some antagonistic effect and Mn could attenuate the As-induced neurobehavioral and biochemical alterations in co-exposed mice. [ABSTRACT FROM AUTHOR]

Acetaldehyde is a metabolite of ethanol, an important constituent of tobacco pyrolysis and the aldehydic product of lipid peroxidation. Acetaldehyde induced toxicity is mainly due to its binding to cellular macromolecules resulting in the formation of stable adducts accompanied by oxidative stress. The aim of this study was to characterize structural and immunological alterations in human immunoglobulin G (IgG) modified with acetaldehyde in the presence of sodium borohydride, a reducing agent. The IgG modifications were studied by various physicochemical techniques such as fluorescence and CD spectroscopy, free amino group estimation, 2,2‐azobis 2‐amidinopropane (AAPH) induced red blood cell hemolysis as well as transmission electron microscopy. Molecular docking was also employed to predict the preferential binding of acetaldehyde to IgG. The immunogenicity of native and acetaldehyde‐modified IgG was investigated by immunizing female New Zealand white rabbits using native and modified IgG as antigens. Binding specificity and cross reactivity of rabbit antibodies was screened by competitive inhibition ELISA and band shift assays. The modification of human IgG with acetaldehyde results in quenching of the fluorescence of tyrosine residues, decrease in free amino group content, a change in the antioxidant property as well as formation of cross‐linked structures in human IgG. Molecular docking reveals strong binding of IgG to acetaldehyde. Moreover, acetaldehyde modified IgG induced high titer antibodies (>1:12800) in the experimental animals. The antibodies exhibited high specificity in competitive binding assay toward acetaldehyde modified human IgG. The results indicate that acetaldehyde induces alterations in secondary and tertiary structure of IgG molecule that leads to formation of neo‐epitopes on IgG that enhances its immunogenicity. [ABSTRACT FROM AUTHOR]

Alcohol use disorder is a chronic relapsing disease. Maintaining abstinence represents a major challenge for alcohol-dependent patients. Yet the molecular underpinnings of alcohol relapse remain poorly understood. In the present study, we investigated the potential role of the mammalian target of rapamycin complex 1 (mTORC1) in relapse to alcohol-seeking behavior by using the reinstatement of a previously extinguished alcohol conditioned place preference (CPP) response as a surrogate relapse paradigm. We found that mTORC1 is activated in the nucleus accumbens shell following alcohol priming-induced reinstatement of alcohol place preference. We further report that the selective mTORC1 inhibitor, rapamycin, abolishes reinstatement of alcohol place preference. Activation of mTORC1 initiates the translation of synaptic proteins, and we observed that reinstatement of alcohol CPP is associated with increased protein levels of one of mTORC1's downstream targets, collapsin response mediator protein-2 (CRMP2), in the nucleus accumbens. Importantly, the level of mTORC1 activation and CRMP2 expression positively correlate with the CPP score during reinstatement. Finally, we found that systemic administration of the CRMP2 inhibitor, lacosamide, attenuates alcohol priming-induced reinstatement of CPP. Together, our results reveal that mTORC1 and its downstream target, CRMP2, contribute to mechanisms underlying reinstatement of alcohol reward seeking. Our results could have important implications for the treatment of relapse to alcohol use and position the Food and Drug Administration approved drugs, rapamycin and lacosamide, for the treatment of alcohol use disorder. [ABSTRACT FROM AUTHOR]

Background: Ethanol (EtOH), one of the most widely consumed substances of abuse, can induce brain damage and neurodegeneration. EtOH is centrally metabolized into acetaldehyde, which has been shown to be responsible for some of the neurophysiological and cellular effects of EtOH. Although some of the consequences of chronic EtOH administration on cell oxidative status have been described, the mechanisms by which acute EtOH administration affects the brain's cellular oxidative status and the role of acetaldehyde remain to be elucidated in detail. Methods: Swiss CD‐I mice were pretreated with the acetaldehyde‐sequestering agent d‐penicillamine (DP; 75 mg/kg, i.p.) or the antioxidant lipoic acid (LA; 50 mg/kg, i.p.) 30 minutes before EtOH (2.5 g/kg, i.p.) administration. Animals were sacrificed 30 minutes after EtOH injection. Glutathione peroxidase (GPx) mRNA levels; GPx and glutathione reductase (GR) enzymatic activities; reduced glutathione (GSH), glutathione disulfide (GSSG), glutamate, g‐L‐glutamyl‐L‐cysteine (Glut‐Cys), and malondialdehyde (MDA) concentrations; and protein carbonyl group (CG) content were determined in whole‐brain samples. Results: Acute EtOH administration enhanced GPx activity and the GSH/GSSG ratio, while it decreased GR activity and GSSG concentration. Pretreatment with DP or LA only prevented GPx activity changes induced by EtOH. Conclusions: Altogether, these results show the capacity of a single dose of EtOH to unbalance cellular oxidative homeostasis. [ABSTRACT FROM AUTHOR]

Objective: The present study aimed to evaluate the ameliorative effect of low-dose ethanol (Eth) on amnesia induced by a brief seizure model and the role of N-methyl D-aspartate (NMDA) signaling in this event. Materials and Methods: Four groups of rats (total number = 36; n = 9, each group) were used: control, Eth (0.5 g/kg/i.p.), pentylenetetrazole (PTZ) (60 mg/kg/i.p.), and Eth+PTZ. Eth was administered for 6 days before the single injection of PTZ, at minute dose that cannot induce memory impairment. The consequences of Eth pretreatment, coadministered with PTZ, were studied in an inhibitory avoidance (IA) memory model. The PTZ was injected 30 min prior to the IA memory test. Thereafter, locomotion, liver enzymes, and the Real-time PCR for NR1 subunit of NMDA receptor were studied. The statistical analyses were performed using the parametric/nonparametric ANOVA and the post-hoc tests. Results: Our findings revealed that Eth pretreatment significantly improved the IA memory impairment induced by PTZ (P < 0.001), and indicated no change in locomotion and serum ALT, but significantly differed for AST between the PTZ and PTZ groups (P = < 0.05). The Real-time PCR results indicate the decreased NR1 mRNA expression in Eth and PTZ groups and the increased NR1 mRNA expression in Eth+PTZ group, compared to the control group (P < 0.001); however, the NR1 mRNA expression was increased in the Eth+PTZ group, compared to PTZ group (P < 0.001). Conclusion: The present study provides evidence that the low-dose Eth can improve the amnesia induced by a brief seizure model presumably via NMDA signaling in a rat. [ABSTRACT FROM AUTHOR]

Chronic low-grade neuroinflammation is increasingly implicated in organ damage caused by alcohol abuse. Purinergic P2X7 receptors (P2X7Rs) play an important role in the generation of inflammatory responses during a number of CNS pathologies as evidenced from studies using pharmacological inhibition approach. P2X7Rs antagonism has not been tested during chronic alcohol abuse. In the present study, we tested the potential of P2X7R antagonist A804598 to reduce/abolish alcohol-induced neuroinflammation using chronic intragastric ethanol infusion and high-fat diet (Hybrid) in C57BL/6J mice. We have previously demonstrated an increase in neuroinflammatory response in 8 weeks of Hybrid paradigm. In the present study, we found neuroinflammatory response to 4 weeks of Hybrid exposure. A804598 treatment reversed the changes in microglia and astrocytes, reduced/abolished increases in mRNA levels of number of inflammatory markers, including IL-1β, iNOS, CXCR2, and components of inflammatory signaling pathways, such as TLR2, CASP1, NF-kB1 and CREB1, as well in the protein levels of pro-IL-1β and Nf-kB1. The P2X7R antagonist did not affect the increase in mRNA levels of fraktalkine (CX3CL1) and its receptor CX3CR1, an interaction that plays a neuroprotective role in neuron-glia communication. P2X7R antagonism also resulted in reduction of the inflammatory markers but did not alter steatosis in the liver. Taken together, these findings demonstrate how P2X7R antagonism suppresses inflammatory response in brain and liver but does not alter the neuroprotective response caused by Hybrid exposure. Overall, these findings support an important role of P2X7Rs in inflammation in brain and liver caused by combined chronic alcohol and high-fat diet. [ABSTRACT FROM AUTHOR]

Evidence suggests a predictive link between elevated basal activity within reward-related networks (e.g., cortico-basal ganglia-thalamic networks) and vulnerability for alcoholism. Both calcium channel function and cyclic adenosine monophosphate (cAMP)/protein kinase A-mediated signaling are critical modulators of reward neurocircuitry and reward-related behaviors. Calcium/calmodulin-stimulated adenylyl cyclases (AC) 1 and 8 are sensitive to activity-dependent increases in intracellular calcium and catalyze cAMP production. Therefore, we hypothesized AC1 and 8 regulate brain activity in reward regions of the cortico-basal ganglia-thalamic circuit and that this regulatory influence predicts voluntary ethanol drinking responses. This hypothesis was evaluated by manganese-enhanced magnetic resonance imaging and chronic, intermittent ethanol access procedures. Ethanol-naïve mice with genetic deletion of both AC1 and 8 (DKO mice) exhibited bilateral reductions in baseline activity within cortico-basal ganglia-thalamic regions associated with reward processing compared to wild-type controls (WT, C57BL/6 mice). Significant activity changes were not evident in regions either outside of the cortico-basal ganglia-thalamic network or within the network that are not associated with reward processing. Parallel studies demonstrated that reward network hypoactivity in DKO mice predicted a significant attenuation in consumption and preference levels to escalating ethanol concentrations (12, 20 and 30%) compared to WT mice, an effect that was maintained over extended access (14 sessions) to 20% ethanol. Summarizing, these data support a contribution of AC1 and 8 in cortico-basal ganglia-thalamic activity and the predictive value of this regulatory influence on ethanol drinking behavior, which merits the future evaluation of calcium-stimulated ACs in the neural processes that engender vulnerability to maladaptive alcohol drinking. [ABSTRACT FROM AUTHOR]

Groundwater particularly drinking water contamination with metals has created an environmental disaster in Bangladesh. Manganese (Mn), an essential trace element, plays a key role in the development and function of the brain. Excess Mn exposure is reported to be associated with complex neurological disorders. Here, we have found a notably large extent of Mn above the permissive limit in the tube-well water of Rajshahi and Naogaon districts in Bangladesh. Higher levels of Mn in hair and nail samples, and a decreasing level of butyrylcholinesterase (BChE) activity were detected in plasma samples of the human subjects recruited from Naogaon district. Mn concentrations in water, hair, and nails were negatively correlated with the plasma BChE levels in Mn-exposed populations. To compare and validate these human studies, an animal model was used to determine the in vivo effects of Mn on neurobehavioral changes and blood BChE levels. In elevated plus maze, the time spent was significantly reduced in open arms and increased in closed arms of Mn-exposed mice compared to control group. The mean latency time to find the platform was declined significantly in control mice compared to Mn-treated group during 7 days in Morris water maze test, and Mn-exposed group also spent significantly less time in the desired quadrant as compared to the control group in probe trial. BChE activity was significantly reduced in Mn-exposed mice compared to control mice. Taken together, these results suggest that plasma BChE levels may serve as reliable biomarker of Mn-induced neurotoxicity related to behavioral changes. [ABSTRACT FROM AUTHOR]

Alcohol consumption is considered a major risk factor for disease and mortality worldwide. In the absence of effective treatments in alcohol use disorders, it is important to find new biological targets that could modulate alcohol consumption. We tested the role of the N-terminal galanin fragment (1-15) [GAL(1-15)] in voluntary ethanol consumption in rats using the two-bottle choice paradigm as well as compare the effects of GAL(1-15) with the whole molecule of GAL. We describe for the first time that GAL(1-15), via central mechanisms, induces a strong reduction in preference and ethanol consumption in rats. These effects were significantly different than GAL. GAL receptor (GALR) 2 was involved in these effects, because the specific GALR2 antagonist M871 blocked GAL(1-15) mediated actions in preference and ethanol intake. Importantly, the mechanism of this action involves changes in GALR expression and also in immediate-early gene C-Fos and receptors-internalization-related gene Rab5 in the striatum. The relevance of the striatum as a target for GAL(1-15) was supported by the effect of GAL(1-15) on the locomotor activity of rats after ethanol administration. These results may give the basis for the development of novel therapeutics strategies using GAL(1-15) analogues for the treatment of alcohol use disorders in humans. [ABSTRACT FROM AUTHOR]

Background: Evidence supports a role for the circadian system in alcohol use disorders, but the impact of adolescent alcohol exposure on circadian timing later in life is unknown. Acute ethanol (EtOH) attenuates circadian photic phase‐resetting in adult, but not adolescent, rodents. However, nearly all studies have focused on males and it is unknown whether this adolescent‐typical insensitivity to EtOH persists into adulthood after adolescent drinking. Methods: Circadian activity was monitored in C57BL/6J mice receiving adolescent intermittent EtOH (AIE) exposure (15% EtOH and water every other day throughout adolescence) or water alone followed by 24 days wherein EtOH was not available (washout). Mice then received a challenge dose of EtOH (1.5 g/kg, intraperitoneal) or saline 15 minutes prior to a 30‐minute phase‐delaying light pulse and then were released into constant darkness (DD). To control for possible phase‐shifting by EtOH challenge alone, a separate group of mice underwent AIE exposure (or water‐only) and washout and then received an EtOH or saline injection, but did not receive a light pulse prior to DD. Results: Striking sex differences in nearly all measures of circadian photic entrainment were observed during adolescence but AIE effects were subtle and few. Only EtOH‐naïve adult male mice showed attenuated photic phase‐shifts with EtOH challenge, while all other groups showed normal phase‐resetting responses to light. AIE‐exposed females showed a persistent delay in activity offset. Conclusions: Adult male AIE‐exposed mice retained adolescent‐like insensitivity to EtOH‐induced suppression of photic phase‐resetting, suggesting AIE‐induced "lock‐in" of an adolescent behavioral phenotype. Adult AIE‐exposed females showed delayed initiation of the rest phase. Our results also indicate that intermittent EtOH drinking has subtle effects on circadian activity in mice during adolescence that differ from previously reported effects on adult males. The observed sex differences in circadian activity, EtOH consumption and preference, and responses to EtOH challenge merit future mechanistic study. Differential effects of adolescent drinking on circadian rhythms in adult mice. A) Adult female mice showed persistent delays in activity offset after exposure to adolescent intermittent ethanol (AIE), perhaps reflecting increased latency to sleep. B) Adult male mice with prior AIE exposure showed persistent insensitivity to acute ethanol‐induced attenuation of circadian phaseresetting to light. These data suggest that adolescent drinking affects circadian rhythms differently between the sexes, and may ultimately play a sex‐dependent role in motivation to drink in adulthood. [ABSTRACT FROM AUTHOR]

Chronic alcohol consumption induces damage to the brain that can cause various forms of dementia. An abundance of acetaldehyde is produced by excessive alcohol consumption and accumulates in the body to induce oxidative stress, apoptosis, and inflammation in neuronal cells, which results in learning and cognitive decline. In the present study, C57BL/N mice were orally administered alcohol (16%) and Carthamus tinctorius L. seed (CTS) (100 and 200 mg/kg/day). Behavioral experiments showed that memory and cognitive abilities were significantly higher in the CTS groups than the alcohol-treated control group in the T-maze test, novel object recognition test, and Morris water maze test. In addition, CTS inhibited alcohol-induced lipid peroxidation and nitric oxide production in the brain, kidney, and liver. Moreover, alcohol increased acetylcholinesterase activity in the brain, but this was significantly decreased by the administration of CTS. Therefore, CTS may play role in the prevention of alcohol-related dementia. [ABSTRACT FROM AUTHOR]

Background: Alcoholism is the most common form of addiction and a worldwide problem. Alcohol addiction primarily leads to alcohol dependence and on abstinence leads to withdrawal effects. Common pharmacological properties of compounds used against alcohol addiction include anti-anxiety, anticonvulsant, antidepressant, and nootropic actions. valeriana wallichii known ethnopharmacologically for its sleep-inducing effects have all the above-pharmacological properties. Aim: Here, we screen valeriana for possible anti-addictive potential. Materials and Methods: Effect of valeriana was measured on ethanol withdrawal anxiety using elevated plus maze. The role of valeriana on chronic ethanol consumption (21 days) was measured using two bottle choice method of voluntary drinking. We also measured the effect of the above herb on cortico-hippocampal gamma-aminobutyric acid (GABA) levels. Results: Valeriana was found to reduce ethanol withdrawal anxiety in a dose-dependent manner. The herb also decreased ethanol intake and increased water intake significantly (P < 0.001) after 4 days of administration. Both these effects were potentiated (P < 0.001) by GABAA agonist zolpidem, and not affected by N-Methyl D-aspartic acid antagonist memantine, suggesting the role of GABAA receptor. Chronic administration of valeriana (10 days) also significantly (P < 0.01) increased cortico-hippocampal GABA levels in mice. Conclusion: Thus, valeriana reduced both ethanol dependence and withdrawal in a GABAA-dependent manner showing promising anti-addictive potential. Abbreviations Used: GABA: Gamma-aminobutyric acid; CNS: Central nervous system; CPP: Conditioned place preference; EPM: Elevated plus maze; NMDA: N-Methyl D-aspartic acid; HIV: Human Immunodeficiency virus. [ABSTRACT FROM AUTHOR]

Alcohol binge drinking is a pattern of heavy alcohol consumption that is increasingly practiced by adolescents and young adults. Evidence indicates that alcohol binges induce peripheral inflammation and an exacerbated neuroimmune response that may participate in alcohol-induced cognitive/behavioral dysfunctions. Here, we recruited 20-year-old male and female university students who were identified as binge drinkers for at least 2 years. Compared with controls, young alcohol binge drinkers had elevated levels of blood endotoxin and upregulated markers of the toll-like receptor 4/NF-κB inflammatory pathway in peripheral blood mononuclear cells, together with pro-inflammatory cytokine/chemokine release, oxidative stress and lipid peroxidation. These changes positively correlate with the estimated blood alcohol levels achieved during alcohol binge intoxication and negatively correlate with the time elapsed from the last alcohol consumption. The immune/inflammatory changes were more prominent in female drinkers, who showed elevated levels of alcohol danger-associated molecules, such as high mobility group box 1, indicating that there are sex-related differences in the peripheral inflammatory response to alcohol. In contrast, cortisol levels were decreased in alcohol binge drinkers. Finally, higher levels of inflammatory markers, mainly monocyte chemoattractant protein-1, as well as LPS, high mobility group box 1, toll-like receptor 4, IL-6 and ciclooxygenase-2, correlated with worse scores on episodic memory and executive functioning tasks in female binge drinkers but not in male binge drinkers. These results emphasize possible risky consequences of alcohol use in binge episodes during young adulthood and call attention to sex-related differences in the alcohol-induced immune/inflammatory and neurocognitive responses. [ABSTRACT FROM AUTHOR]

The role of norepinephrine (NE) in the development of alcohol use disorder (AUD) has been studied over the past several decades. However, the NE system has been largely ignored for many years as a potential target for medication development for AUD. More recently, preclinical and clinical studies have demonstrated the potential value of targeting NE signaling for developing new pharmacological treatments for AUD. This review contributes to a special issue of Psychopharmacology focused on promising targets for alcohol addiction. Specifically, this review coalesces preclinical and clinical neuroscience that re-evaluate the noradrenergic system, and in particular the alpha-1 receptor, as a potential target for AUD. [ABSTRACT FROM AUTHOR]

In utero alcohol exposure is emerging as a major risk factor for lifelong aberrant neuroimmune function. Fetal alcohol spectrum disorder encompasses a range of behavioral and physiological sequelae that may occur throughout life and includes cognitive developmental disabilities as well as disease susceptibility related to aberrant immune and neuroimmune actions. Emerging data from clinical studies and findings from animal models support that very low to moderate levels of fetal alcohol exposure may reprogram the developing central nervous system leading to altered neuroimmune and neuroglial signaling during adulthood. In this review, we will focus on the consequences of low to moderate prenatal alcohol exposure (PAE) on neuroimmune interactions during early life and at different stages of adulthood. Data discussed here will include recent studies suggesting that while abnormal immune function is generally minimal under basal conditions, following pathogenic stimuli or trauma, significant alterations in the neuroimmune axis occur. Evidence from published reports will be discussed with a focus on observations that PAE may bias later-life peripheral immune responses toward a proinflammatory phenotype. The propensity for proinflammatory responses to challenges in adulthood may ultimately shape neuron-glial-immune processes suspected to underlie various neuropathological outcomes including chronic pain and cognitive impairment. [ABSTRACT FROM AUTHOR]

There is a marked comorbidity between alcohol abuse and eating disorders, especially in the young population. We have previously reported that bingeing on fat during adolescence increases the rewarding effects of ethanol (EtOH). The aim of the present work was to study if vulnerability to EtOH persists after cessation of binge eating. OF1 mice binged on fat (HFB: high-fat binge) during adolescence (PND 25–43) and were tested for 15 days after the last access to HFB (on PND 59) using the self-administration paradigm, the conditioned place preference (CPP) and locomotor sensitization to ethanol. Our results showed that after 15 days of cessation of fat ingestion, mice increased their consumption of ethanol and showed greater motivation to obtain ethanol. On the other hand, no effects were observed in the CPP, while an increased locomotor response to ethanol was detected. The present results confirm and extend our previous study demonstrating that the compulsive intake of fat induces long-lasting effects on the reward system that lead to an increased consumption of EtOH. [ABSTRACT FROM AUTHOR]

In the developed and developing world, opioid consumption in combination with alcohol has become one of the substances abused. In this experiment, we examined the effects of alcohol, morphine, and morphine+alcohol combination on cognitive functions and neuroinflammatory responses in the medial prefrontal cortex (mPFC) of juvenile male rats. Alcohol (1.0 ml of 15% v/v ethanol twice daily, subcutaneously, 7 hours apart), morphine (0.5 ml/kg of 0.4 mg/kg morphine chlorate twice daily, subcutaneously, 7 hours apart), morphine+alcohol co-treatment (0.5 ml/kg of 0.4 mg/kg morphine chlorate+1.0 ml of 15% v/v ethanol twice daily, subcutaneously, 7 hours apart) were administered for 21 days. Treatment with morphine+alcohol significantly impairs cognition functions in the Morris water maze, passive avoidance, and novel object recognition tests, furthermore, the treatment significantly increased the quantitative count of astrocytic cells and also conferred marked neuronal cell death in the mPFC, which were studied by glial fibrillary acidic protein immunochemistry for astrocytes and Cresyl violet for Nissl's substance distribution in neurons respectively. These results suggest that alcohol, morphine, and morphine+alcohol co-treatment may trigger cognitive deficits and neuroinflammatory responses in the brain. [ABSTRACT FROM AUTHOR]

The aim of the present study was to evaluate the effects of oregano essential oil (OEO) on the hippocampus and prefrontal cortex TLR 2/4 gene expression and depressive like behavior induced by chronic unpredictable stress (CUS). Sucrose preference and forced swim tests were adopted to examine the antidepressant effect. Control (CON), OEO, CUS, and CUS + OEO groups were used. The OEO and CUS + OEO groups received OEO (0.2 mL/kg, i.p.), CON and CUS received saline (0.2 mL/kg, i.p.), and the positive drug groups of CUS rats received fluoxetine (10 mg/kg) and diazepam (3 mg/kg) once daily for 14 days. The expression of TLR 2/4 was determined using real time quantitative polymerase chain reaction with the SYBR green reporter dye. The compositions of the OEO were determined by gas chromatography-mass spectroscopy. The main constituents were thymol (20.72%), gamma-terpinene (8.83%), borneol (8.72%), cymene (6.83%), carvacrol (6.274%), alfa-terpinene (5.26%), and sabinene (4.92%). Administration of OEO significantly alleviated the depressive symptoms of CUS. A higher level of TLR2/4 mRNA was seen in the brain of CUS group (P < 0.05). The CUS-induced increases in the TLR2/4 levels were not reversed by OEO. According to the present study OEO may have the antidepressant-like activity but have no effect on the stress-induced TLR-2/4 upregulation. [ABSTRACT FROM AUTHOR]