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Many people begin to experiment with alcohol during adolescence, an important developmental period during which sex differences in the effects of ethanol appear. In the present study we evaluated the effect of ethanol (0, 0.625, 1.25 or 2.5 g/kg) on the acquisition of a conditioned place preference (CPP) in early and late adolescent male and female mice. In addition, we assessed the capacity of ethanol to induce reinstatement of the CPP after its extinction. CPP was induced in early and late adolescent females with 2.5 g/kg, and in early adolescent males with 1.25 or 2.5 g/kg of ethanol. No CPP was observed in late adolescent males. Priming with ethanol reinstated the CPP induced by the highest dose in early adolescent male and early and late adolescent female mice. Our data suggest that early adolescents of both sex and late adolescent females are particularly vulnerable to the effects of ethanol., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Studies reviewed show that lentiviral gene therapy directed either at inhibiting the synthesis of brain acetaldehyde generated from ethanol or at degrading brain acetaldehyde fully prevent ethanol intake by rats bred for their high alcohol preference. However, after animals have chronically consumed alcohol, the above gene therapy did not inhibit alcohol intake, indicating that in the chronic ethanol intake condition brain acetaldehyde is no longer the compound that generates the continued alcohol reinforcement. Oxidative stress and neuroinflammation generated by chronic ethanol intake are strongly associated with the perpetuation of alcohol consumption and alcohol relapse "binge drinking". Mesenchymal stem cells, referred to as guardians of inflammation, release anti-inflammatory cytokines and antioxidant products. The intravenous delivery of human mesenchymal stem cells or the intranasal administration of mesenchymal stem cell-generated exosomes reverses both (i) alcohol-induced neuro-inflammation and (ii) oxidative stress, and greatly (iii) inhibits (80-90%) chronic alcohol intake and relapse binge-drinking. The therapeutic effect of mesenchymal stem cells is mediated by increased levels of the brain GLT-1 glutamate transporter, indicating that glutamate signaling is pivotal for alcohol relapse. Human mesenchymal stem cells and the products released by these cells may have translational value in the treatment of alcohol-use disorders.

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]

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]

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]

Background Environmental lead ( Pb) exposure and alcohol abuse pose significant public health problems for our society. One of the proposed mechanisms of action of the developmental neurotoxicant Pb is related to its ability to affect antioxidant enzymes, including catalase ( CAT). Ethanol's ( Et OH) motivational effects are postulated to be mediated by the CAT-dependent acetaldehyde generated in the brain. The current study sought to investigate the role of this enzyme in the elevated EtOH intake previously reported in perinatally Pb-exposed rats. Methods Thirty-five-day-old male Wistar rats exposed to 220 ppm Pb during gestation and lactation were offered escalating Et OH solutions (2 to 10%) or water, 2 h/d for 28 days. Once baseline 10% Et OH intake was achieved, they were injected with (i) saline ( SAL), (ii) 3-amino 1,2,4 triazole (aminotriazole [AT], a CAT inhibitor, 250 mg/kg intraperitoneally [i.p.], 5 hours before the last 8 Et OH intake sessions), or (iii) 3-nitropropionic acid (3 NPA; a CAT activator, 20 mg/kg subcutaneously [s.c.], 45 minutes before the last 4 Et OH intake sessions). Rats were then sacrificed, blood collected, and brain regions harvested for CAT activity determination. Additional studies evaluated Et OH intake and CAT activity in response to 10 and 30 mg/kg 3 NPA. Both 3 NPA and AT were evaluated for striatal cytotoxicity. Results We observed that AT pretreatment blunted the increased Et OH intake, as well as the elevated CAT activity in blood, cerebellum, and hippocampus evidenced in the developmentally Pb-exposed rats that have consumed Et OH. Conversely, 20 mg/kg 3 NPA further increased voluntary Et OH intake in these animals as compared with controls, concomitantly with a slight elevation in CAT activity both in blood and in the striatum, associated with no changes in striatal cytotoxicity. Conclusions These results suggest a participation of CAT, and possibly acetaldehyde, in Pb-induced high Et OH intake, and open up new avenues to elucidate the mechanism that underlies the Pb and Et OH interaction. [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]

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: 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]

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]

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]

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]

Ethanol is an important risk factor for the occurrence of several brain disorders that depend on the amount, period and frequency of its consumption. Chronic use of ethanol often leads to the development of neurodegenerative syndromes, which cause morphological and functional impairments such as foetal alcohol syndrome in newborns exposed to ethanol during pregnancy, Wernicke-Korsakoff Syndrome and, more rarely, Marchiafava-Bignami disease (MBD). MBD is characterized by primary degeneration of the corpus callosum, without inflammation and is associated with oxidative stress and hypovitaminosis, as well as altered mental status, to mention dementia, seizures, depression and so on. This review discusses MBD and poor nutrition as a risk factor for the development of such alcoholic syndrome, with focus on diagnosis, pathogenic aspects, signs and symptoms, as well as therapeutic perspectives. On the basis of the inclusion/exclusion criteria adopted, the performed search in scientific databases (Pubmed, Scielo and Google Scholar) resulted in 100 studies that are being presented and discussed in the present work. Review, case-control and cohort studies on alcoholism-associated hypovitaminosis, oxidative stress, MBD and ethanol metabolism pathways were admitted as relevant. We highlight that MBD is a poorly described, diagnosed, insidious and progressive condition, for which evidence suggests a synergism between ethanol-induced neurotoxic effects and hypovitaminosis B. Present treatment consists of vitamin B1(thiamine) supplementation. Nonetheless, other strategies such as the inclusion of antidepressants or steroidal anti-inflammatories as add-on therapies have been employed as an attempt to improve the damage. Indeed, both the diagnosis and treatment are difficult, and death occurs within few years. [ABSTRACT FROM AUTHOR]

Background Molecular and behavioral studies support a role for innate immune proinflammatory pathways in mediating the effects of alcohol. Increased levels of Toll-like receptors (TLRs) have been observed in animal models of alcohol consumption and in human alcoholics, and many of these TLRs signal via the MyD88-dependent pathway. We hypothesized that this pathway is involved in alcohol drinking and examined some of its key signaling components. Methods Different ethanol (EtOH)-drinking paradigms were studied in male and female control C57BL/6J mice versus mice lacking CD14, TLR2, TLR4 (C57BL/10ScN), or MyD88. We studied continuous and intermittent access 2-bottle choice (2BC) and 1-bottle and 2BC drinking-in-the-dark (DID) tests as well as preference for saccharin, quinine, and NaCl. Results In the 2BC continuous access test, EtOH intake decreased in male TLR2 knockout (KO) mice, and we previously reported reduced 2BC drinking in male and female CD14 KO mice. In the intermittent access 2BC test, EtOH intake decreased in CD14 KO male and female mice, whereas drinking increased in MyD88 KO male mice. In the 2BC-DID test, EtOH drinking decreased in male and female mice lacking TLR2, whereas drinking increased in MyD88 KO male mice. In the 1-bottle DID test, EtOH intake decreased in female TLR2 KO mice. TLR2 KO and CD14 KO mice did not differ in saccharin preference but showed reduced preference for NaCl. MyD88 KO mice showed a slight reduction in preference for saccharin. Conclusions Deletion of key components of the MyD88-dependent pathway produced differential effects on EtOH intake by decreasing (TLR2 KO and CD14 KO) or increasing (MyD88 KO) drinking, while deletion of TLR4 had no effect. Some of the drinking effects depended on the sex of the mice and/or the EtOH-drinking model. [ABSTRACT FROM AUTHOR]

The innate immune response in the central nervous system ( CNS) participates in both synaptic plasticity and neural damage. Emerging evidence from human and animal studies supports the role of the neuroimmune system response in many actions of ethanol (EtOH) on the CNS. Research studies have shown that alcohol stimulates brain immune cells, microglia, and astrocytes, by activating innate immune receptors Toll-like receptors (TLRs) and NOD-like receptors (inflammasome NLRs) triggering signaling pathways, which culminate in the production of pro-inflammatory cytokines and chemokines that lead to neuroinflammation. This review focuses on evidence that indicates the participation of TLRs and the inflammasome NLRs signaling response in many effects of EtOH on the CNS, such as neuroinflammation associated with brain damage, cognitive and behavioral dysfunction, and adolescent brain development alterations. It also reviews findings that indicate the role of TLR4-dependent signaling immune molecules in alcohol consumption, reward, and addiction. The research data suggest that overactivation of TLR4 or NLRs increases pro-inflammatory cytokines and mediators to cause neural damage in the cerebral cortex and hippocampus, while modest TLR4 activation, along with the generation of certain cytokines and chemokines in specific brain areas (e.g., amygdala, ventral tegmental area), modulate neurotransmission, alcohol drinking, and alcohol rewards. Elimination of TLR4 and NLRP3 abolishes many neuroimmune effects of EtOH. Despite much progress being made in this area, there are some research gaps and unanswered questions that this review discusses. Finally, potential therapies that target neuroimmune pathways to treat neuropathological and behavioral consequences of alcohol abuse are also evaluated. [ABSTRACT FROM AUTHOR]

A prime mechanism that contributes to the development and maintenance of alcoholism is the dysregulation of the hypothalamic–pituitary–adrenal axis activity and the release of glucocorticoids (cortisol in humans and primates, corticosterone in rodents) from the adrenal glands. In the brain, sustained, local elevation of glucocorticoid concentration even long after cessation of chronic alcohol consumption compromises functional integrity of a circuit, including the prefrontal cortex (PFC), the hippocampus (HPC), and the amygdala (AMG). These structures are implicated in learning and memory processes as well as in orchestrating neuroadaptive responses to stress and anxiety responses. Thus, potentiation of anxiety-related neuroadaptation by alcohol is characterized by an abnormally AMG hyperactivity coupled with a hypofunction of the PFC and the HPC. This review describes research on molecular and epigenetic mechanisms by which alcohol causes distinct region-specific adaptive changes in gene expression patterns and ultimately leads to a variety of cognitive and behavioral impairments on prefrontal- and hippocampal-based tasks. Alcoholinduced neuroadaptations involve the dysregulation of numerous signaling cascades, leading to long-term changes in transcriptional profiles of genes, through the actions of transcription factors such as [cAMP response element-binding protein (CREB)] and chromatin remodeling due to posttranslational modifications of histone proteins. We describe the role of prefrontal–HPC–AMG circuit in mediating the effects of acute and chronic alcohol on learning and memory, and region-specific molecular and epigenetic mechanisms involved in this process. This review first discusses the importance of brain region-specific dysregulation of glucocorticoid concentration in the development of alcohol dependence and describes how persistently increased glucocorticoid levels in PFC may be involved in mediating working memory impairments and neuroadaptive changes during withdrawal from chronic alcohol intake. It then highlights the role of cAMP–PKA–CREB signaling cascade and histone acetylation within the PFC and limbic structures in alcohol-induced anxiety and behavioral impairments, and how an understanding of functional alterations of these pathways might lead to better treatments for neuropsychiatric disorders. [ABSTRACT FROM AUTHOR]

Background There is controversy regarding the active agent responsible for alcohol addiction. The theory that ethanol (EtOH) itself was the agent in alcohol drinking behavior was widely accepted until acetaldehyde (AcH) was found in the brain. The importance of AcH formation in the brain is still subject to speculation due to the lack of a method to accurately assay the AcH levels directly. A highly sensitive gas chromatography mass spectrometry (GC-MS) method to reliably determine AcH concentration with certainty is needed to address whether neural AcH is indeed responsible for increased alcohol consumption. Methods A headspace gas chromatograph coupled to selected-ion monitoring MS was utilized to develop a quantitative assay for AcH and EtOH. Our GC- MS approach was carried out using a Bruker Scion 436- GC SQ MS. Results Our approach yields limits of detection of AcH in the nanomolar range and limits of quantification in the low micromolar range. Our linear calibration includes 5 concentrations with a least-square regression greater than 0.99 for both AcH and EtOH. Tissue analyses using this method revealed the capacity to quantify EtOH and AcH in blood, brain, and liver tissue from mice. Conclusions By allowing quantification of very low concentrations, this method may be used to examine the formation of EtOH metabolites, specifically AcH, in murine brain tissue in alcohol research. [ABSTRACT FROM AUTHOR]

Background A number of studies have shown that acetaldehyde synthesized in the brain is necessary to induce ethanol (EtOH) reinforcement in naïve animals ( acquisition phase). However, after chronic intake is achieved ( maintenance phase), EtOH intake becomes independent of acetaldehyde generation or its levels. Glutamate has been reported to be associated with the maintenance of chronic EtOH intake. The levels of brain extracellular glutamate are modulated by 2 glial processes: glutamate reabsorption via an Na+-glutamate transporter ( GLT1) and a cystine-glutamate exchanger. Chronic EtOH intake lowers GLT1 levels and increases extracellular glutamate. The administration of N-acetyl cysteine ( NAC), a precursor of cystine, has been shown to reduce the relapse of several drugs of abuse, while NAC has not been tested on chronic EtOH intake or on EtOH's influence on the motivation for another drug. These were investigated in the present study. Methods (i) Rats bred for their high EtOH intake were allowed access to 10% EtOH and water up to 87 days. NAC was administered (30 and 60 mg/kg daily, intraperitoneally) for 14 consecutive days, either during the acquisition phase or the maintenance phase of EtOH drinking. (ii) In additional experiments, rats were allowed EtOH (10%) and water access for 61 days, after which EtOH was replaced by saccharin (0.3%) to determine both if chronic EtOH consumption influences saccharin intake and whether NAC modifies the post chronic EtOH saccharin intake. Results NAC did not influence the acquisition ('first hit') of chronic EtOH intake, but greatly inhibited (60 to 70%; p < 0.0001) EtOH intake when NAC was administered to animals that were consuming EtOH chronically. NAC did not influence saccharin intake in naïve animals. In animals that had consumed EtOH chronically and were thereafter offered a saccharin solution (0.3%), saccharin intake increased over 100% versus that of EtOH-untreated animals, an effect that was fully suppressed by NAC. Conclusions N-acetyl cysteine, a drug approved for use in humans, markedly reduces chronic EtOH intake and abolishes the increased intake of saccharin stimulated by chronic EtOH drinking. [ABSTRACT FROM AUTHOR]

An interaction exists between stress and alcohol in the etiology and chronicity of alcohol use disorders, yet a knowledge gap exists regarding the neurobiological underpinnings of this interaction. In this regard, we employed an 11-day unpredictable, chronic, mild stress (UCMS) procedure to examine for stress-alcohol cross-sensitization of motor activity as well as alcohol consumption/preference and intoxication. We also employed immunoblotting to relate the expression of glutamate receptor-related proteins within subregions of the nucleus accumbens (NAC) to the manifestation of behavioral cross-sensitization. UCMS mice exhibited a greater locomotor response to an acute injection of 2 g/kg alcohol than unstressed controls and this cross-sensitization extended to alcohol intake (0-20 percent), as well as to the intoxicating and sedative properties of 3 and 5 g/kg alcohol, respectively. Regardless of prior alcohol injection (2 g/kg), UCMS mice exhibited elevated NAC shell levels of mGlu1α, GluN2b and Homer2, as well as lower phospholipase Cβ within this subregion. GluN2b levels were also lower within the NAC core of UCMS mice. The expression of stress-alcohol locomotor cross-sensitization was associated with lower mGlu1α within the NAC core and lower extracellular signal-regulated kinase activity within both NAC subregions. As Homer2 regulates alcohol sensitization, we assayed also for locomotor cross-sensitization in Homer2 wild-type (WT) and knock-out (KO) mice. WT mice exhibited a very robust cross-sensitization that was absent in KO animals. These results indicate that a history of mild stress renders an animal more sensitive to the psychomotor and rewarding properties of alcohol, which may depend on neuroplasticity within NAC glutamate transmission. [ABSTRACT FROM AUTHOR]

Background: Alcohol addiction is a social problem leading to both loss of health and economic prosperity among addicted individuals. Common properties of anti-addictive compounds include anti-anxiety, anticonvulsants, anti-depressant, and nootropic actions primarily through modulation of gamma-aminobutyric acid (GABA) and serotonergic systems. Objective: Here, we screen ashwagandha and shilajit known ethnopharmacologically as nervine tonic and adaptogenic herbs for possible anti-addictive potential. Materials and Methods: Effect of ashwagandha churna and shilajit was measured on ethanol withdrawal anxiety using elevated plus maze. Role of ashwagandha and shilajit on chronic ethanol consumption (21 days) was measured using two bottle choice protocol of voluntary drinking. We also measured the effect of the above herbs on corticohippocampal GABA, dopamine, and serotonin levels. Results: Both ashwagandha and shilajit were found to reduce alcohol withdrawal anxiety in a dose-dependent manner. These herbs alone or in combination also decreased ethanol intake and increased water intake significantly after 21 days of chronic administration. Chronic administration of ashwagandha was found to significantly increase GABA and serotonin levels whereas shilajit altered cortico-hippocampal dopamine in mice. Conclusion: These central nervous system active herbs alone or in combination reduced both alcohol dependence and withdrawal thus showing promising anti-addictive potential. [ABSTRACT FROM AUTHOR]

This review analyzes literature that describes the behavioral effects of 2 metabolites of ethanol (EtOH): acetaldehyde and salsolinol (a condensation product of acetaldehyde and dopamine) generated in the brain. These metabolites are self-administered into specific brain areas by animals, showing strong reinforcing effects. A wealth of evidence shows that EtOH, a drug consumed to attain millimolar concentrations, generates brain metabolites that are reinforcing at micromolar and nanomolar concentrations. Salsolinol administration leads to marked increases in voluntary EtOH intake, an effect inhibited by mu-opioid receptor blockers. In animals that have ingested EtOH chronically, the maintenance of alcohol intake is no longer influenced by EtOH metabolites, as intake is taken over by other brain systems. However, after EtOH withdrawal brain acetaldehyde has a major role in promoting binge-like drinking in the condition known as the 'alcohol deprivation effect'; a condition seen in animals that have ingested alcohol chronically, are deprived of EtOH for extended periods, and are allowed EtOH re-access. The review also analyzes the behavioral effects of acetate, a metabolite that enters the brain and is responsible for motor incoordination at low doses of EtOH. Also discussed are the paradoxical effects of systemic acetaldehyde. Overall, evidence strongly suggests that brain-generated EtOH metabolites play a major role in the early ('first-hit') development of alcohol reinforcement and in the generation of relapse-like drinking. [ABSTRACT FROM AUTHOR]

Ethanol ( EtOH)-induced behavioral sensitization ( EIBS) is proposed to play a role in early and recurring steps of alcohol dependence, but its impact on alcohol abuse is not clear. EIBS development is dependent upon animal species, strain and also individual factors. We proposed here to decipher the co-expression of EIBS and EtOH intake in individual animals among outbred Swiss mice, which exhibit heterogeneity that parallels what may occur in humans. To do so, mice were exposed to a two-bottle choice with free access to water or 10% EtOH for 6 days just before and immediately after chronic intraperitoneal 2.5 g/kg ethanol injections once a day for 10 consecutive days. Based on their sensitization scores, mice were split into resistant and sensitized animals. First, we showed that individual susceptibility to EIBS is inversely correlated with voluntary EtOH consumption. Exposure to repeated EtOH during EIBS development increased subsequent EtOH intake among the entire population. Very interestingly, subsequent analyses suggested that the less the mice are sensitized the more they increase their EtOH intake; however, resistant mice were sensitive to EtOH adulteration with quinine, whereas sensitized ones maintained their EtOH intake levels, therefore exhibiting a compulsive-like drinking pattern. In addition, we showed that resistant mice do not exhibit a weaker sensitivity to the aversive properties of EtOH that may contribute to their higher level of EtOH intake compared to sensitized mice. This study confirms and extends previous data showing a deep relationship between propensity for EtOH consumption and susceptibility to EIBS in Swiss mice. [ABSTRACT FROM AUTHOR]

Rationale: Nowadays, very few approved anti-relapse treatments for alcoholism exist, and their overall efficacy can be considered moderate. An exciting rationale drug development opportunity for the treatment of chronic alcoholism is the use of acetaldehyde sequestering agents. Although these compounds are able to attenuate or prevent most of the behavioral and neurochemical effects of ethanol, the efficacy of acetaldehyde sequestration, by using agents such as d-penicillamine (DP), in relapse prevention has not been studied yet. Objectives: The aim of this study was to analyze the effects of DP treatment on the alcohol deprivation effect (ADE) in long-term ethanol-experienced rats as a model of relapse behavior and measure drug plasma and brain levels during treatment. Methods: Rats were subcutaneously implanted with mini-osmotic pumps delivering 0, 0.25, or 1 mg/h of DP during 1 week. The efficacy to prevent ADE was determined. DP plasma and brain levels achieved during its subcutaneous administration were measured. In a second experiment, animals received bilateral infusions of 0 or 1.5 μg/h of DP directly into pVTA, and the appearance of ADE was evaluated. Results: One milligram per hour, but not 0.25 mg/h, DP infusion prevented ADE and reduced the total ethanol preference in animals. DP plasma concentrations associated with ADE suppression were around 3-4 μg/ml, and brain DP levels in these conditions were about 2-3 % of those found in plasma. Intra-pVTA DP administration also suppressed ADE. Conclusion: DP is able to prevent alcohol-relapse-like drinking in rats suggesting that this drug may be a useful new tool in the management of relapse in alcohol-dependent patients. [ABSTRACT FROM AUTHOR]

Background Animals that have chronically consumed alcohol and are subsequently deprived of it markedly increase their intake above basal levels when access to alcohol is reinstated. Such an effect, termed the alcohol deprivation effect ( ADE), has been proposed to reflect (i) an obsessive-compulsive behavior, (ii) craving, or (iii) an increased reinforcing value of ethanol ( Et OH). It has been reported that acetaldehyde, a highly reinforcing metabolite of Et OH, is generated in the brain by the action of catalase. Recent studies show that the administration of an anticatalase (sh RNA)-encoding lentiviral vector into the brain ventral tegmental area ( VTA) of naïve rats virtually abolishes (85 to 95%) their Et OH intake. It is hypothesized that the antireinforcing effect of the anticatalase vector will also inhibit the ADE. Methods Two-month-old Wistar-derived UCh B alcohol drinker rats were offered free access to water and 10 and 20% Et OH for 67 days. Thereafter, the animals were deprived of Et OH for 15 days and were subsequently offered access to the Et OH solutions. At the start of the deprivation period, animals were microinjected a single dose of an anticatalase (or control) vector into the VTA. Et OH intake was measured on the first hour of Et OH re-exposure as well as on a 24-hour basis for 7 days. Results A marked ADE was observed when Et OH intake was measured on the first hour or 24 hours following Et OH re-exposure, compared to the corresponding controls. The administration of the anticatalase vector reduced ADE by 60 to 80% ( p < 0.001) on the first hour and by 63 to 80% ( p < 0.001) on the initial 24 hours of Et OH re-exposure (first and second ADE, respectively) without changing the total fluid intake, indicating a specific effect on Et OH drinking. Conclusions Ethanol intake associated with ADE-a binge-like drinking behavior-is markedly inhibited by the administration of an anticatalase vector into the VTA, which blocks the conversion of Et OH into acetaldehyde, strongly suggesting that the marked increased Et OH intake that follows an alcohol deprivation period is mediated by acetaldehyde and its reinforcing metabolite. [ABSTRACT FROM AUTHOR]

Background: Striatopallidal medium spiny neurons have been viewed as a final common path for drug reward and the ventral pallidum as an essential convergent point for hedonic and motivational signaling in the brain. The medium spiny neurons are GABAergic, but they colocalize enkephalin. Purpose of this study was to investigate the role of the opioidergic mechanisms of the ventral pallidum in ethanol self-administration behavior. Methods: Effects of bilateral microinjections of μ-, δ-, and κ-opioid receptor agonists and antagonists into the ventral pallidum on voluntary ethanol consumption were monitored in alcohol-preferring Alko Alcohol (AA) rats using the 90-minute limited access paradigm. Results: Stimulation of μ-opioid receptors with DAMGO (0.01 to 0.1 μg) or morphine (1 to 10 μg) in the ventral pallidum decreased ethanol intake dose-dependently. Conversely, blocking μ-receptors with CTOP (0.3 to 3 μg) increased ethanol intake significantly. Unlike CTOP, DAMGO also increased locomotor activity. Consumption of ethanol was not modified significantly by a broad-spectrum opioid receptor antagonist naltrexone, by δ-opioid receptor agonist DPDPE or antagonist naltrindole, or by a κ-opioid receptor agonist U50,488H or antagonist nor-BNI. Conclusions: The study provides evidence for μ- but not δ- or κ-opioid receptors in the ventral pallidum playing a role in the regulation of voluntary ethanol consumption. Furthermore, present findings give support to earlier work, suggesting an essential role of pallidal opioidergic transmission in drug reward. [ABSTRACT FROM AUTHOR]

While the molecular entity responsible for the rewarding effects of virtually all drugs of abuse is known, that for ethanol remains uncertain. Some lines of evidence suggest that the rewarding effects of alcohol are mediated not by ethanol per se but by acetaldehyde generated by catalase in the brain. However, the lack of specific inhibitors of catalase has not allowed strong conclusions to be drawn about its role on the rewarding properties of ethanol. The present studies determined the effect on voluntary alcohol consumption of two gene vectors, one designed to inhibit catalase synthesis and one designed to synthesize alcohol dehydrogenase (ADH), to respectively inhibit or increase brain acetaldehyde synthesis. The lentiviral vectors, which incorporate the genes they carry into the cell genome, were (i) one encoding a shRNA anticatalase synthesis and (ii) one encoding alcohol dehydrogenase (rADH1). These were stereotaxically microinjected into the brain ventral tegmental area (VTA) of Wistar-derived rats bred for generations for their high alcohol preference (UChB), which were allowed access to an ethanol solution and water. Microinjection into the VTA of the lentiviral vector encoding the anticatalase shRNA virtually abolished (−94% p < 0.001) the voluntary consumption of alcohol by the rats. Conversely, injection into the VTA of the lentiviral vector coding for ADH greatly stimulated (2 to 3 fold p < 0.001) their voluntary ethanol consumption. The study strongly suggests that to generate reward and reinforcement, ethanol must be metabolized into acetaldehyde in the brain. Data suggest novel targets for interventions aimed at reducing chronic alcohol intake. [ABSTRACT FROM AUTHOR]

The brain is one of the major target organs of alcohol actions. Alcohol abuse can lead to alterations in brain structure and functions and, in some cases, to neurodegeneration. Cognitive deficits and alcohol dependence are highly damaging consequences of alcohol abuse. Clinical and experimental studies have demonstrated that the developing brain is particularly vulnerable to alcohol, and that drinking during gestation can lead to a range of physical, learning and behavioral defects (fetal alcohol spectrum disorders), with the most dramatic presentation corresponding to fetal alcohol syndrome. Recent findings also indicate that adolescence is a stage of brain maturation and that heavy drinking at this stage can have a negative impact on brain structure and functions causing important short- and long-term cognitive and behavioral consequences. The effects of alcohol on the brain are not uniform; some brain areas or cell populations are more vulnerable than others. The prefrontal cortex, the hippocampus, the cerebellum, the white matter and glial cells are particularly susceptible to the effects of ethanol. The molecular actions of alcohol on the brain are complex and involve numerous mechanisms and signaling pathways. Some of the mechanisms involved are common for the adult brain and for the developing brain, while others depend on the developmental stage. During brain ontogeny, alcohol causes irreversible alterations to the brain structure. It also impairs several molecular, neurochemical and cellular events taking place during normal brain development, including alterations in both gene expression regulation and the molecules involved in cell--cell interactions, interference with the mitogenic and growth factor response, enhancement of free radical formation and derangements of glial cell functions. However, in both adult and adolescent brains, alcohol damages specific brain areas through mechanisms involving excitotoxicity, free radical formation and neuroinflammatory damage resulting from activation of the innate immune system mediated by TLR4 receptors. Alcohol also acts on specific membrane proteins, such as neurotransmitter receptors ( e.g. NMDA, GABA-A), ion channels ( e.g. L-type Ca2++ channels, GIRKs), and signaling pathways ( e.g. PKA and PKC signaling). These effects might underlie the wide variety of behavioral effects induced by ethanol drinking. The neuroadaptive changes affecting neurotransmission systems which are more sensitive to the acute effects of alcohol occur after long-term alcohol consumption. Alcohol-induced maladaptations in the dopaminergic mesolimbic system, abnormal plastic changes in the reward-related brain areas and genetic and epigenetic factors may all contribute to alcohol reinforcement and alcohol addiction. This manuscript reviews the mechanisms by which ethanol impacts the adult and the developing brain, and causes both neural impairments and cognitive and behavioral dysfunctions. The identification and the understanding of the cellular and molecular mechanisms involved in ethanol toxicity might contribute to the development of treatments and/or therapeutic agents that could reduce or eliminate the deleterious effects of alcohol on the brain. [ABSTRACT FROM AUTHOR]

The article discusses the systems approach of alcoholism to addictive behavior. It states that alcoholism has acute and chronic effects in the body's system for it targets the brain due to its ethanol content, and alters gene expression that is important for the brain's adaptations. It also notes that addictive use of alcoholism affects neuronal network activity and opioid systems.

Background: Muscarinic acetylcholine receptors (mAChRs) are well positioned to mediate ethanol’s stimulant effects. To investigate this possibility, we examined the effects of scopolamine, a receptor subtype nonselective mAChR antagonist, on ethanol-induced stimulation in genotypes highly sensitive to this effect of ethanol. We also investigated whether the dopamine D1-like receptor antagonist, SCH-23390 or the dopamine D2-like receptor antagonist, haloperidol, could block the extreme stimulant response found following co-administration of scopolamine and ethanol. Methods: Scopolamine (0, 0.0625, 0.125, 0.25, or 0.5 mg/kg) was given 10 minutes prior to saline or ethanol (0.75 to 2 g/kg) to female FAST (Experiment I) or DBA/2J (Experiment II) mice that were then tested for locomotion for 30 minutes. In Experiments III and IV, respectively, SCH-23390 (0, 0.015, or 0.03 mg/kg) was given 10 minutes prior, and haloperidol (0, 0.08, or 0.16 mg/kg) was given 2 minutes prior, to scopolamine (0 or 0.5 mg/kg), followed 10 minutes later by saline or ethanol (1.5 g/kg) and female DBA/2J mice were tested for locomotion for 30 minutes. Results: FAST and DBA/2J mice displayed a robust enhancement of the locomotor effects of ethanol following pretreatment with scopolamine that was suggestive of synergism. SCH-23390 had no effect on the response to the scopolamine + ethanol drug combination, nor did it attenuate ethanol- or scopolamine-induced locomotor activity. Haloperidol, while attenuating the effects of ethanol, was not able to block the effects of scopolamine or the robust response to the scopolamine-ethanol drug combination. Conclusions: These results suggest that while muscarinic receptor antagonism robustly enhances acute locomotor stimulation to ethanol, dopamine receptors are not involved in the super-additive interaction of scopolamine and ethanol treatment. They also suggest that in addition to cautions regarding the use of alcohol when scopolamine is clinically prescribed due to enhanced sedative effects, enhanced stimulation may also be a concern. [ABSTRACT FROM AUTHOR]

Background: Experimental evidences suggest that acetaldehyde (ACD) contributes to the positive motivational properties of ethanol (EtOH) as assessed by the place conditioning paradigm; indeed, we found that by reducing ACD production and/or by using ACD-sequestrating agents, EtOH is deprived from its motivational properties. Thiol products, such as the amino acid cysteine, are known to be effective ACD-sequestering agents. Cysteine is able to covalently bind ACD thereby forming a stable, nontoxic 2-methyl-thiazolidine-4-carboxylic acid compound. Thus, we treated rats withl-cysteine before intragastric administration of EtOH or ACD. Methods: Male Wistar rats were pretreated intraperitoneally with saline orl-cysteine (10, 20, or 30 mg/kg), before intragastric administration of saline, EtOH (1 g/kg), or ACD (20 mg/kg). The specificity ofl-cysteine effect was addressed using morphine-induced conditioned place preference (cpp) (2.5 mg/kg, i.p.). Results: l-cysteine dose-dependently prevented both EtOH and ACD-induced cpp but did not interfere with morphine-induced cpp, suggesting thatl-cysteine specifically modulates the motivational properties of EtOH. Conclusion: The present results further underscore the role of EtOH-derived ACD in EtOH-induced motivational properties.l-cysteine, by binding EtOH-derived ACD, would deprive it of its rewarding properties and reduce its abuse liability. [ABSTRACT FROM AUTHOR]

Background: Disulfiram, an inhibitor of aldehyde dehydrogenase used in the treatment of alcoholism, is an effective medication when its intake is supervised by a third person. However, its therapeutic efficacy varies widely, in part due to the fact that disulfiram is a pro-drug that requires its transformation into an active form and because it shows a wide range of secondary effects which often prevent the use of doses that ensure full therapeutic effectiveness. In this preclinical study in rats we report the development of tolerance to disulfiram induced by the chronic ingestion of ethanol, an additional source of variation for the actions of disulfiram with possible therapeutic significance, We also addresses the likely mechanism of this effect. Methods: Wistar-derived rats bred for generations as high ethanol drinkers (UChB) were trained for either 3 days (Group A) or 30 days (Group B) to choose between ethanol (10% v/v) or water, which were freely available from 2 bottles on a 24-hour basis. Subsequently, animals in both groups were administered disulfiram or cyanamide (another inhibitor of aldehyde dehydrogenase) and ethanol intake in this free choice paradigm was determined. Animals were also administered a standard dose of 1 g ethanol/kg (i.p) and arterial blood acetaldehyde was measured. Results: Disulfiram (12.5 and 25 mg/kg) and cyanamide (10 mg/kg) markedly inhibited ethanol intake (up to 60 to 70%) in animals that had ethanol access for only 3 days (Group A). However both drugs were inactive in inhibiting ethanol intake in animals that had consumed ethanol for 30 days (Group B). Following the injection of 1 g ethanol/kg, arterial blood acetaldehyde levels reached levels of 150 and 300 μM for disulfiram and cyanamide respectively, values which were virtually identical regardless of the length of prior ethanol intake of the animals. Conclusions: Chronic ethanol intake in high-drinker rats leads to marked tolerance to the aversive effects of disulfiram and cyanamide on ethanol intake despite the presence of consistently high levels of blood acetaldehyde. These findings may have implications for the use of disulfiram for the treatment of alcoholism in humans. [ABSTRACT FROM AUTHOR]

Despite the generally held view that alcohol is an unspecific pharmacological agent, recent molecular pharmacology studies demonstrated that alcohol has only a few known primary targets. These are the NMDA, GABA(A), glycine, 5-hydroxytryptamine 3 (serotonin) and nicotinic ACh receptors as well as L-type Ca(2+) channels and G-protein-activated inwardly rectifying K(+) channels. Following this first hit of alcohol on specific targets in the brain, a second wave of indirect effects on a variety of neurotransmitter/neuropeptide systems is initiated that leads subsequently to the typical acute behavioural effects of alcohol, ranging from disinhibition to sedation and even hypnosis, with increasing concentrations of alcohol. Besides these acute pharmacodynamic aspects of alcohol, we discuss the neurochemical substrates that are involved in the initiation and maintenance phase of an alcohol drinking behaviour. Finally, addictive behaviour towards alcohol as measured by alcohol-seeking and relapse behaviour is reviewed in the context of specific neurotransmitter/neuropeptide systems and their signalling pathways. The activity of the mesolimbic dopaminergic system plays a crucial role during the initiation phase of alcohol consumption. Following long-term, chronic alcohol consumption virtually all brain neurotransmission seems to be affected, making it difficult to define which of the systems contributes the most to the transition from controlled to compulsive alcohol use. However, compulsive alcohol drinking is characterized by a decrease in the function of the reward neurocircuitry and a recruitment of antireward/stress mechanisms comes into place, with a hypertrophic corticotropin-releasing factor system and a hyperfunctional glutamatergic system being the most important ones. [ABSTRACT FROM AUTHOR]

The mammalian adolescent period is characterized by enhanced vulnerability to drug-induced neuroadaptations. Epidemiological evidence indicates that individuals who start drinking alcohol during adolescence are four times more likely to develop alcohol dependence in adulthood, but little is known about the adaptive mechanism(s) that may underlie this observation. Behavioral sensitization in rodents is a model of neurobehavioral plasticity that occurs following repeated drug exposure and may underlie components of addiction. The goal of this study was to determine if adolescent mice are differentially sensitive to ethanol-induced locomotor sensitization as compared to adults. Adolescent and adult DBA/2J mice were treated with saline or ethanol (1.0, 1.5, 2.0, 2.5 g/kg) for 7, 11, or 15 days and tested for acute and sensitized locomotor activity. Blood ethanol clearance (BEC) was also assessed 10, 60, and 180 min following treatment with ethanol 2 g/kg. Adolescent mice were more sensitive than adult mice to the acute locomotor activating effects of ethanol. However, adolescent mice were less sensitive than adult mice to locomotor sensitization, as only the highest dose of ethanol (2.5 g/kg) induced sensitization in the adolescent mice, while lower doses of ethanol elicited sensitization in the adult mice. The differential response to ethanol sensitization was not related to duration of treatment or differential BEC . These results indicate that adolescent mice are less sensitive to ethanol sensitization, and this blunted behavioral response in adolescents might reflect differential ethanol-induced neurobehavioral adaptations. [ABSTRACT FROM AUTHOR]

Background: Acetaldehyde (ACD), the first metabolite of ethanol (EtOH), is produced peripherally by gastric and hepatic alcohol dehydrogenase (ADH) and centrally by brain catalase. In spite of the aversive properties classically ascribed to ACD, it has recently been suggested that ACD might mediate some of the motivational effects of EtOH. Accordingly, the relative role of ACD in the positive motivational properties of EtOH ingested is increasingly becoming the matter of debate. Thus, we studied the ability of intragastrically administered EtOH, ACD and EtOH-derived ACD to induce conditioned place preference (cpp) in rats. Methods: Wistar rats were pretreated intraperitoneally with saline, the peripheral competitive inhibitor of ADH, 4-methylpyrazole (4-MP, 22.5, 45 or 67.5 mg/kg) or with the selective ACD-sequestrating agent,d-penicillamine (DP, 25 or 50 mg/kg), before the intragastric administration of saline, EtOH (0.5, 1 or 2 g/kg) or ACD (10, 20, or 40 mg/kg). The specificity of 4-MP and DP effects was addressed using morphine-induced cpp (2.5 mg/kg). Results: Both, EtOH and ACD dose-dependently induced cpp; further, while EtOH-induced cpp was prevented by the administration of 4-MP and by DP, ACD-induced cpp was unaltered by 4-MP administration and prevented by DP. Both pretreatments did not interfere with morphine-induced cpp indicating that 4-MP and DP specifically modulate the motivational properties of EtOH and ACD. Conclusion: The ability of 4-MP and DP to decrease EtOH-induced cpp suggests that a reduction of ACD levels is crucial in depriving EtOH from its motivational properties as indexed by the cpp procedure. In addition, this conclusion is supported by the inefficacy of 4-MP in preventing ACD-induced cpp, and by its blockade observed after administration of the selective ACD sequestrating agent DP. The present results underscore the role of EtOH-derived ACD in EtOH-induced motivational properties as well as its abuse liability. [ABSTRACT FROM AUTHOR]

Background: Pharmacological studies have implicated the endogenous opioid system in mediating alcohol intake. Other evidence has shown that alcohol administration can influence endorphinergic and enkephalinergic activity, while very few studies have examined its effect on dynorphinergic systems. The aim of the present study was to investigate the effect of alcohol administration or a mechanical stressor on extracellular levels of dynorphin A1–8 in the rat nucleus accumbens—a brain region that plays a significant role in the processes underlying reinforcement and stress. Methods: Male Sprague–Dawley rats were implanted with a microdialysis probe aimed at the shell region of the nucleus accumbens. Artificial cerebrospinal fluid was pumped at a rate of 1.5 μL/min in awake and freely moving animals and the dialysate was collected at 30-minute intervals. In one experiment, following a baseline period, rats were injected intraperitoneally with either physiological saline or 1 of 3 doses of alcohol, 0.8, 1.6, or 3.2 g ethanol/kg body weight. In a second experiment, following a baseline period, rats were applied a clothespin to the base of their tail for 20 minutes. The levels of dynorphin A1–8 in the dialysate were analyzed with solid-phase radioimmunoassay. Results: Relative to saline-treated controls, an alcohol dose of 1.6 and 3.2 g/kg caused a transient increase in the extracellular levels of dynorphin A1–8 in the first 30 minutes of alcohol administration. However, the effect resulting from the high 3.2 g/kg dose was far more pronounced and more significant than with the moderate dose. There was no effect of tail pinch on dynorphin A1–8 levels in the nucleus accumbens. Conclusions: In this experiment, a very high dose of alcohol was especially capable of stimulating dynorphin A1–8 release in the nucleus accumbens. Dynorphin release in the accumbens has been previously associated with aversive stimuli and may thus reflect a system underlying the aversive properties of high-dose alcohol administration. However, the lack of effect of tail-pinch stress in the present study suggests that dynorphin A1–8 is not released in response to all forms of stressful/aversive stimuli. [ABSTRACT FROM AUTHOR]

Background: Alcohol-preferring alko alcohol (AA) rats are more susceptible to morphine-induced behavioral and neurochemical sensitization than alcohol nonpreferring alko nonalcohol (ANA) rats. Alko alcohol rats sensitized to morphine, however, do not show enhanced acquisition of ethanol drinking. The purpose of the present study was to clarify further interactions between morphine-induced behavioral sensitization and voluntary ethanol drinking in the AA rats. Methods: Alko alcohol rats drinking ethanol in a limited 6-hour access paradigm were sensitized to morphine with repeated injections of morphine (5–15 mg/kg). Injection days alternated with days of ethanol access. Controls had access only to water and/or were given injections of saline. After a 5-day washout period from ethanol and morphine, the rats were challenged with morphine or saline and subsequent ethanol drinking or locomotor activity was recorded. Results: Ethanol intake was suppressed during the repeated treatment with morphine, and the morphine-treated rats did not differ in ethanol intake from the controls when given access to ethanol after the washout. Intake of ethanol was, however, increased when the rats were challenged with morphine [1 or 10 mg/kg, subcutaneously (s.c.)], while in the controls an increase in ethanol intake was seen only after 1 mg/kg morphine. Sensitization to the locomotor stimulating effects of morphine was revealed in the morphine-treated rats after a challenge with morphine (3 or 10 mg/kg, s.c.). The controls that had been drinking ethanol also showed a sensitized response after morphine (3 mg/kg). Conclusions: Ethanol did not interfere with the development of sensitization to morphine. Furthermore, the neuroadaptations induced by repeated exposure to ethanol were sufficient to cause behavioral cross-sensitization to morphine. Sensitization to the behavioral effects of morphine alone, however, neither enhances the reinforcing properties of voluntarily consumed ethanol nor contributes to increase in its intake. The increase in ethanol intake found after an acute dose of morphine was augmented in rats withdrawn from repeated treatment with morphine. The data suggest that the neuronal mechanisms underlying behavioral sensitization to morphine probably are distinct from those mediating reinforcement from ethanol and that the morphine-induced neuroadaptations contribute to the enhancement of increase in ethanol intake by morphine. [ABSTRACT FROM AUTHOR]

Background: Well-known reports suggest that the use of energy drinks might reduce the intensity of the depressant effects of alcohol. However, there is little scientific evidence to support this hypothesis. Objective and Methods: The present study aimed at evaluating the effects of the simultaneous ingestion of an alcohol (vodka37.5%v/v) and an energy drink (Red Bull®—3.57 mL/kg), compared with those presented after the ingestion of an alcohol or an energy drink alone. Twenty-six young healthy volunteers were randomly assigned to 2 groups that received 0.6 or 1.0 g/kg alcohol, respectively. They all completed 3 experimental sessions in random order, 7 days apart: alcohol alone, energy drink alone, or alcohol plus energy drink. We evaluated the volunteers' breath alcohol concentration, subjective sensations of intoxication, objective effects on their motor coordination, and visual reaction time. Results: When compared with the ingestion of alcohol alone, the ingestion of alcohol plus energy drink significantly reduced subjects' perception of headache, weakness, dry mouth, and impairment of motor coordination. However, the ingestion of the energy drink did not significantly reduce the deficits caused by alcohol on objective motor coordination and visual reaction time. The ingestion of the energy drink did not alter the breath alcohol concentration in either group. Conclusions: Even though the subjective perceptions of some symptoms of alcohol intoxication were less intense after the combined ingestion of the alcohol plus energy drink, these effects were not detected in objective measures of motor coordination and visual reaction time, as well as on the breath alcohol concentration. [ABSTRACT FROM AUTHOR]

Evaluating medications in animal laboratory paradigms can reveal whether the compound is effective in an established alcoholism model, at clinically relevant doses and exposure conditions, when administered orally (or transdermally) and without serious limiting side effects. Positive outcomes constitute a possible discovery for relevance to alcoholism and, under favorable marketing conditions, encourage further development. Medication testing using animal models of alcoholism might also guide clinical testing by discriminating clinically effective from clinically ineffective compounds. This ability rests on whether there are tests or, more reasonably, batteries of tests having this discriminative ability. The present paper examines this possibility. Effects of naltrexone and acamprosate in animal paradigms which model behavioral aspects of alcoholism are reviewed and compared with the effects of compounds which have limited effects in alcoholics. It is not clear at present whether any single paradigm or combination of paradigms differentiates clinically effective from clinically limited compounds. Steps are suggested to improve the use of preclinical laboratory tests to predict which compounds are likely to be effective medications for reducing drinking and sustaining abstinence in human alcoholics. [ABSTRACT FROM AUTHOR]

Acetaldehyde is the first and principal metabolite of ethanol administered systemically. To its rise in blood, after administration of disulfiram, is ascribed the aversive reaction that should discourage alcoholics from drinking. In the present study, we sought to determine the effect of acetaldehyde on the electrophysiological properties of dopamine (DA)-containing neurons in the ventro tegmental area (VTA) of rats in vivo. Intravenous (i.v.) administration of acetaldehyde (5-40 mg/kg) readily and dose-dependently increased the firing rate, spikes/burst, and burst firing of VTA neurons. Ethanol (250-1000 mg/kg/i.v.) administration produced similar increments in electrophysiological parameters. In addition, a second group of rats was pretreated with the alcohol-dehydrogenase inhibitor 4-methylpyrazole (90 mg/kg) intraperitoneally (i.p.), and ethanol and acetaldehyde were administered i.v. at the same doses, 48 h later. In this group, ethanol effects were drastically reduced and the firing rate, spikes/burst, and burst firing were not significantly altered. In contrast, acetaldehyde fully retained its capacity to stimulate electrophysiological indices. The results indicate that acetaldehyde produces electrophysiological actions on VTA neurons in vivo, similar to those produced by ethanol, and significantly participate in ethanol-induced increment in DA neuronal activity. These results also suggest that acetaldehyde, by increasing DA neuronal activity in the VTA, may significantly contribute to the centrally mediated positive motivational properties of ethanol, which would oppose the well-known peripherally originating aversive properties. [ABSTRACT FROM AUTHOR]