Preclinical evidence implicating corticotropin‐releasing factor signaling in ethanol consumption and neuroadaptation

The results of many studies support the influence of the corticotropin‐releasing factor (CRF) system on ethanol (EtOH) consumption and EtOH‐induced neuroadaptations that are critical in the addiction process. This review summarizes the preclinical data in this area after first providing an overview of the components of the CRF system. This complex system involves hypothalamic and extra‐hypothalamic mechanisms that play a role in the central and peripheral consequences of stressors, including EtOH and other drugs of abuse. In addition, several endogenous ligands and targets make up this system and show differences in their involvement in EtOH drinking and in the effects of chronic or repeated EtOH treatment. In general, genetic and pharmacological approaches paint a consistent picture of the importance of CRF signaling via type 1 CRF receptors (CRF₁) in EtOH‐induced neuroadaptations that result in higher levels of intake, encourage alcohol seeking during abstinence and alter EtOH sensitivity. Furthermore, genetic findings in rodents, non‐human primates and humans have provided some evidence of associations of genetic polymorphisms in CRF‐related genes with EtOH drinking, although additional data are needed. These results suggest that CRF₁ antagonists have potential as pharmacotherapeutics for alcohol use disorders. However, given the broad and important role of these receptors in adaptation to environmental and other challenges, full antagonist effects may be too profound and consideration should be given to treatments with modulatory effects.     

Function and Mechanism of Myelin Regulation in Alcohol Abuse and Alcoholism

Excessive alcohol use has adverse effects on the central nervous system (CNS) and can lead to alcohol use disorders (AUDs). Recent studies have suggested that myelin reductions may directly contribute to CNS dysfunctions associated with AUDs. Myelin consists of compact lipid membranes wrapped around axons to provide electrical insulation and trophic support. Regulation of myelin is considered as a new form of neural plasticity due to its profound impacts on the computation of neural networks. In this review, the authors first discuss experimental evidence showing how alcohol exposure causes demyelination in different brain regions, often accompanied by deficits in cognition and emotion. Next, they discuss postulated molecular and cellular mechanisms underlying alcohol's impact on myelin. It is clear that more extensive investigations are needed in this important but underexplored research field in order to gain a better understanding of the myelin‐behavior relationship and to develop new treatment strategies for AUDs.     

Depression‐like symptoms of withdrawal in a genetic mouse model of binge methamphetamine intake

Binge methamphetamine (MA) users have higher MA consumption, relapse rates and depression‐like symptoms during early periods of withdrawal, compared with non‐binge users. The impact of varying durations of MA abstinence on depression‐like symptoms and on subsequent MA intake was examined in mice genetically prone to binge‐level MA consumption. Binge‐level MA intake was induced using a multiple‐bottle choice procedure in which mice were offered one water drinking tube and three tubes containing increasing concentrations of MA in water, or four water tubes (control group). In two studies, depression‐like symptoms were measured using a tail‐suspension test and a subsequent forced‐swim test, after forced abstinence of 6 and 30 hours from a 28‐day course of chronic MA intake. An additional study measured the same depression‐like symptoms, as well as MA intake, after prolonged abstinence of 1 and 2 weeks. MA high drinking mice and one of their progenitor strains DBA/2J escalated their MA intake with increasing MA concentration; however, MA high drinking mice consumed almost twice as much MA as DBA/2J mice. Depression‐like symptoms were significantly higher early after MA access was withdrawn, compared to levels in drug‐naïve controls, with more robust effects of MA withdrawal observed in MA high drinking than DBA/2J mice. When depression‐like symptoms were examined after 1 or 2 weeks of forced abstinence in MA high drinking mice, depression‐like symptoms dissipated, and subsequent MA intake was high. The MA high drinking genetic mouse model has strong face validity for human binge MA use and behavioral sequelae associated with abstinence.     

Knowledge, Attitudes, and Practices of Physicians in Tomsk Oblast Tuberculosis Services Regarding Alcohol Use Among Tuberculosis Patients in Tomsk, Russia

In recent years, the Russian Federation has seen a dramatic rise in morbidity and mortality from tuberculosis (TB), attributed in part to an increase in alcohol use disorders (AUDs), which are associated with worse TB treatment outcomes. This study describes the knowledge, attitudes and practices of physicians who treat TB patients in Tomsk, Russia. We conducted semistructured interviews with 16 TB physicians and 1 addiction specialist. Interviews were audiorecorded, transcribed, translated and systematically analyzed. We identified four key domains: definitions of alcohol use and abuse and physicians’ knowledge, attitudes and practices regarding these problems. Physicians described patients as largely precontemplative and reluctant to seek treatment. Physicians recognized their limited knowledge in diagnosing and treating AUDs but expressed interest in acquiring these skills. Few options are currently available for treatment of AUDs in TB patients in Tomsk. These findings suggest that Tomsk physicians are aware of the need to engage AUDs in TB patients but identify a knowledge gap that restricts their ability to do so. Training TB physicians to use simple screening instruments and deliver evidence-based alcohol interventions improves TB outcomes among patients with co-occurring AUDs.     

Chronic melatonin administration mitigates behavioral dysfunction induced by γ-irradiation

Melatonin, a ‘hormone of darkness,’ has been reported to play a role in a wide variety of physiological responses including reproduction, circadian homeostasis, sleep, retinal neuromodulation, and vasomotor responses. Our recent studies reported a prophylactic effect of exogenous melatonin against radiation-induced neurocognitive changes. However, there is no reported evidence for a mitigating effect of chronic melatonin administration against radiation-induced behavioral alterations. In the present study, C57BL/6 mice were given either whole day chronic melatonin administration (CMA) or chronic night-time melatonin administration (CNMA) by a low dose of melatonin in drinking water for a period of 2 weeks and 1 month following exposure to 6 Gy of γ-radiation. Various behavioral endpoints, such as locomotor activities, gross behavioral traits, basal anxiety level, and depressive tendencies were scored at different time points. Radiation exposure significantly impaired gross behavioral traits as observed in the open field exploratory paradigms and forced swim test. Both the CMA and CNMA significantly ameliorated the radiation-induced changes in exploratory tendencies, risk-taking behavior and gross behavior traits, such as rearing and grooming. Melatonin administration afforded anxiolytic function against radiation in terms of center exploration tendencies. The radiation-induced augmentation of immobility time in the forced swim test, indices of depression-like behavior was also inhibited by chronic melatonin administration. The results demonstrated the mitigating effect of chronic melatonin administration on radiation-induced affective disorders in mice.     

Dihydromyricetin Prevents Fetal Alcohol Exposure-Induced Behavioral and Physiological Deficits: The Roles of GABAA Receptors in Adolescence

Fetal alcohol exposure (FAE) can lead to a variety of behavioral and physiological disturbances later in life. Understanding how alcohol (ethanol, EtOH) affects fetal brain development is essential to guide the development of better therapeutics for FAE. One of EtOH’s many pharmacological targets is the γ-aminobutyric acid type A receptor (GABA_AR), which plays a prominent role in early brain development. Acute EtOH potentiates inhibitory currents carried by certain GABA_AR subtypes, whereas chronic EtOH leads to persistent alterations in GABA_AR subunit composition, localization and function. We recently introduced a flavonoid compound, dihydromyricetin (DHM), which selectively antagonizes EtOH’s intoxicating effects in vivo and in vitro at enhancing GABA_AR function as a candidate for alcohol abuse pharmacotherapy. Here, we studied the effect of FAE on physiology, behavior and GABA_AR function of early adolescent rats and tested the utility of DHM as a preventative treatment for FAE-induced disturbances. Gavage administration of EtOH (1.5, 2.5, or 5.0 g/kg) to rat dams on day 5, 8, 10, 12, and 15 of pregnancy dose-dependently reduced female/male offspring ratios (largely through decreased numbers of female offspring) and offspring body weights. FAE (2.5 g/kg) rats tested on postnatal days (P) 25–32 also exhibited increased anxiety and reduced pentylenetetrazol (PTZ)-induced seizure threshold. Patch-clamp recordings from dentate gyrus granule cells (DGCs) in hippocampal slices from FAE (2.5 g/kg) rats at P25-35 revealed reduced sensitivity of GABAergic miniature inhibitory postsynaptic currents (mIPSCs) and tonic current (I_tonic) to potentiation by zolpidem (0.3 μM). Interestingly, potentiation of mIPSCs by gaboxadol increased, while potentiation of I_tonic decreased in DGCs from FAE rats. Co-administration of EtOH (1.5 or 2.5 g/kg) with DHM (1.0 mg/kg) in pregnant dams prevented all of the behavioral, physiological, and pharmacological alterations observed in FAE offspring. DHM administration alone in pregnant rats had no adverse effect on litter size, progeny weight, anxiety level, PTZ seizure threshold, or DGC GABA_AR function. Our results indicate that FAE induces long-lasting alterations in physiology, behavior, and hippocampal GABA_AR function and that these deficits are prevented by DHM co-treatment of EtOH-exposed dams. The absence of adverse side effects and the ability of DHM to prevent FAE consequences suggest that DHM is an attractive candidate for development as a treatment for prevention of fetal alcohol spectrum disorders.     

Involuntary hospitalizations in the psychiatric hospital Jankomir before and following the alterations and amendments made to ZZODS

Schizophrenia and other psychotic disorders as well as the delirium caused by abstinence from alcohol and accute state of drunkenness appear at the very top of the list of factors, which are positively correlated with involuntary hospitalization of patients. This is at the same time a confirmation of the data found in literature considering psychosis an essential factor of involuntary hospitalization; the same referring to the male sex was not, however, confirmed by the results obtained in the first and second research period. Regarding the positive correlation between schizophrenia and other psychotic disturbances, dementia, delirium and other cognitive impairments including the delirium caused by abstinence from alcohol and an accute state of drunkenness on the one side and the high rate of involuntary hospitalization on the other, there is no statistically significant difference between the period preceding and the period following the alterations and amendments to the Law on the protection of patients with mental disorders.     

Brain‐derived neurotrophic factor genotype is associated with brain gray and white matter tissue volumes recovery in abstinent alcohol‐dependent individuals

Neuroimaging studies have linked the methionine (Met) allele of the brain‐derived neurotrophic factor (BDNF) gene to abnormal regional brain volumes in several psychiatric and neurodegenerative diseases. However, no neuroimaging studies assessed the effects of this allele on brain morphology in alcohol use disorders and its demonstrated change during abstinence from alcohol. Here we assessed the effects of the BDNF Val66Met (rs6265) polymorphism on regional brain tissue volumes and their recovery during short‐term abstinence in treatment‐seeking alcohol‐dependent individuals. 3D T1 weighted magnetic resonance images from 62 individuals were acquired at 1.5 T at one week of abstinence from alcohol; 41 of the participants were rescanned at 5 weeks of abstinence. The images were segmented into gray matter (GM), white matter (WM) and cerebrospinal fluid and parcellated into regional volumes. The BDNF genotype was determined from blood samples using the TaqMan technique. Alcohol‐dependent Val (Valine)/Met heterozygotes and Val homozygotes had similar regional brain volumes at either time point. However, Val homozygotes had significant GM volume increases, while Val/Met heterozygotes increased predominantly in WM volumes over the scan interval. Longitudinal increases in GM but not WM volumes were related to improvements in neurocognitive measures during abstinence. The findings suggest that functionally significant brain tissue volume recovery during abstinence from alcohol is influenced by BDNF genotype.     

The brain‐derived neurotrophic factor VAL68MET polymorphism modulates how developmental ethanol exposure impacts the hippocampus

Prenatal exposure to alcohol causes a wide range of deficits known as fetal alcohol spectrum disorders (FASDs). Many factors determine vulnerability to developmental alcohol exposure including timing and pattern of exposure, nutrition and genetics. Here, we characterized how a prevalent single nucleotide polymorphism in the human brain‐derived neurotrophic factor (BDNF) gene (val66met) modulates FASDs severity. This polymorphism disrupts BDNF's intracellular trafficking and activity‐dependent secretion, and has been linked to increased incidence of neuropsychiatric disorders such as depression and anxiety. We hypothesized that developmental ethanol (EtOH) exposure more severely affects mice carrying this polymorphism. We used transgenic mice homozygous for either valine (BDNF^val/val) or methionine (BDNF^met/met) in residue 68, equivalent to residue 66 in humans. To model EtOH exposure during the second and third trimesters of human pregnancy, we exposed mice to EtOH in vapor chambers during gestational days 12 to 19 and postnatal days 2 to 9. We found that EtOH exposure reduces cell layer volume in the dentate gyrus and the CA1 hippocampal regions of BDNF^met/met but not BDNF^val/val mice during the juvenile period (postnatal day 15). During adulthood, EtOH exposure reduced anxiety‐like behavior and disrupted trace fear conditioning in BDNF^met/met mice, with most effects observed in males. EtOH exposure reduced adult neurogenesis only in the ventral hippocampus of BDNF^val/val male mice. These studies show that the BDNF val66met polymorphism modulates, in a complex manner, the effects of developmental EtOH exposure, and identify a novel genetic risk factor that may regulate FASDs severity in humans.     

Neuromodulatory role of the endocannabinoid signaling system in alcoholism: an overview

The current review evaluates the evidence that some of the pharmacological and behavioral effects of ethanol (EtOH), including EtOH-preferring behavior, may be mediated through the endocannabinoid signaling system. The recent advances in the understanding of the neurobiological basis of alcoholism suggest that the pharmacological and behavioral effects of EtOH are mediated through its action on neuronal signal transduction pathways and ligand-gated ion channels, receptor systems, and receptors that are coupled to G-proteins. The identification of a G-protein-coupled receptor, namely, the cannabinoid receptor (CB1 receptor) that was activated by Delta(9)-tetrahydrocannabinol (Delta(9)-THC), the major psychoactive component of marijuana, led to the discovery of endogenous cannabinoid agonists. To date, two fatty acid derivatives identified to be arachidonylethanolamide (AEA) and 2-arachidonylglycerol (2-AG) have been isolated from both nervous and peripheral tissues. Both these compounds have been shown to mimic the pharmacological and behavioral effects of Delta(9)-THC. The involvement of the endocannabinoid signaling system in the development of tolerance to the drugs of abuse including EtOH has not been known until recently. Recent studies from our laboratory have demonstrated for the first time the down-regulation of CB1 receptor function and its signal transduction by chronic EtOH. The observed down-regulation of CB1 receptor binding and its signal transduction results from the persistent stimulation of the receptors by the endogenous CB1 receptor agonists, AEA and 2-AG, the synthesis of which has been found to be increased by chronic EtOH treatment. This enhanced formation of endocannabinoids may subsequently influence the release of neurotransmitters. It was found that the DBA/2 mice, known to avoid EtOH intake, have significantly reduced brain-CB1-receptor function consistent with other studies, where the CB1 receptor antagonist SR141716A has been shown to block voluntary EtOH intake in rodents. Similarly, activation of the CB1 receptor system promoted alcohol craving, suggesting a role for the CB1 receptor gene in excessive EtOH drinking behavior and development of alcoholism. Ongoing investigations may lead to the development of potential therapeutic strategies for the treatment of alcoholism.     

Impaired Response Inhibition in the Rat 5 Choice Continuous Performance Task during Protracted Abstinence from Chronic Alcohol Consumption

Impaired cognitive processing is a hallmark of addiction. In particular, deficits in inhibitory control can propel continued drug use despite adverse consequences. Clinical evidence shows that detoxified alcoholics exhibit poor inhibitory control in the Continuous Performance Task (CPT) and related tests of motor impulsivity. Animal models may provide important insight into the neural mechanisms underlying this consequence of chronic alcohol exposure though pre-clinical investigations of behavioral inhibition during alcohol abstinence are sparse. The present study employed the rat 5 Choice-Continuous Performance Task (5C-CPT), a novel pre-clinical variant of the CPT, to evaluate attentional capacity and impulse control over the course of protracted abstinence from chronic intermittent alcohol consumption. In tests conducted with familiar 5C-CPT conditions EtOH-exposed rats exhibited impaired attentional capacity during the first hours of abstinence and impaired behavioral restraint (increased false alarms) during the first 5d of abstinence that dissipated thereafter. Subsequent tests employing visual distractors that increase the cognitive load of the task revealed significant increases in impulsive action (premature responses) at 3 and 5 weeks of abstinence, and the emergence of impaired behavioral restraint (increased false alarms) at 7 weeks of abstinence. Collectively, these findings demonstrate the emergence of increased impulsive action in alcohol-dependent rats during protracted alcohol abstinence and suggest the 5C-CPT with visual distractors may provide a viable behavioral platform for characterizing the neurobiological substrates underlying impaired behavioral inhibition resulting from chronic intermittent alcohol exposure.     

Chronic ethanol consumption impairs the circadian rhythm of pro-opiomelanocortin and period genes mRNA expression in the hypothalamus of the male rat

Certain psychiatric disorders are known to alter the body's biological rhythms. However, currently, very little information is known about the effect of chronic ethanol administration on the circadian clock or the rhythm of beta-endorphin-containing neurons that participate in the control of the reward and reinforcement of alcohol drinking. Here, we report that administration of ethanol, via a liquid diet paradigm for a period of 2 weeks, abolishes the circadian rhythm of pro-opiomelanocortin mRNA expression of beta-endorphin neurons in the arcuate nucleus of the hypothalamus. The circadian expression of the clock governing rat period genes (rPeriod1 mRNA and rPeriod2 mRNA) in the arcuate nucleus was significantly altered, suggesting that ethanol administration disrupted the internal clock. Moreover, ethanol consumption altered the circadian rhythms of rPeriod2 and rPeriod3 mRNA levels in the suprachiasmatic nucleus, suggesting that ethanol also affected the function of the central pacemaker. Our findings identified the vulnerability of the body's clock machinery and its opioidergic system to chronic alcohol drinking.     

Relaxin-3 Receptor (RXFP3) Signalling Mediates Stress-Related Alcohol Preference in Mice

Stressful life events are causally linked with alcohol use disorders (AUDs), providing support for a hypothesis that alcohol consumption is aimed at stress reduction. We have previously shown that expression of relaxin-3 mRNA in rat brain correlates with alcohol intake and that central antagonism of relaxin-3 receptors (RXFP3) prevents stress-induced reinstatement of alcohol-seeking. Therefore the objectives of these studies were to investigate the impact of Rxfp3 gene deletion in C57BL/6J mice on baseline and stress-related alcohol consumption. Male wild-type (WT) and Rxfp3 knockout (KO) (C57/B6J^{RXFP3TM1/DGen}) littermate mice were tested for baseline saccharin and alcohol consumption and preference over water in a continuous access two-bottle free-choice paradigm. Another cohort of mice was subjected to repeated restraint followed by swim stress to examine stress-related alcohol preference. Hepatic alcohol and aldehyde dehydrogenase activity was assessed in mice following chronic alcohol intake and in naive controls. WT and Rxfp3 KO mice had similar baseline saccharin and alcohol preference, and hepatic alcohol processing. However, Rxfp3 KO mice displayed a stress-induced reduction in alcohol preference that was not observed in WT littermates. Notably, this phenotype, once established, persisted for at least six weeks after cessation of stress exposure. These findings suggest that in mice, relaxin-3/RXFP3 signalling is involved in maintaining high alcohol preference during and after stress, but does not appear to strongly regulate the primary reinforcing effects of alcohol.     

Beta-endorphin and endogenous alcohol level of the blood in alcoholic patients

Radioimmunoassay was used to measure the blood content of beta-endorphines in patients with chronic alcoholism. The concentration of endogenous ethanol in these patients was determined by gas chromatography. The blood concentration of beta-endorphines was found to be high in patients who showed atypical affective disorders off the period of abstinence. It is assumed that peripheral beta-endorphine is not linked with the development of the narcomanic syndrome proper but mirrors the pathogenetic mechanisms of psychopathological disorders. The levels of endogenous ethanol vary in alcoholics and healthy subjects within the same ranges. However, the percentage distribution indicates that in patients, they are shifted toward lower concentrations, which is likely to be conditioned by the induction of enzymatic systems that metabolize ethanol.     

Behavioral and neuronal interactions between exercise and alcohol: Sex and genetic differences

Alcohol use disorders (AUDs) lead to early death and many devastating consequences for individuals, families and society. Currently, few effective treatments are available, but emerging research suggests exercise might be beneficial in some individuals. To develop the most effective exercise treatment program, more research on intensity, type, timing, stage of addiction, drug involved, sex of subject and subject population is needed. This review highlights the complexity of the interaction between alcohol behaviors and exercise, with a focus on the role of sex and genetics. Moreover, we describe a variety of rodent models used to investigate the neuronal physiology changes that underlie alcohol consumption and exercise. Specifically, current data indicate that moderate exercise may ameliorate neuronal damage caused by alcohol consumption. Additionally, we describe studies of rodent models in the context of hedonic substitution to draw broad conclusions about shared underlying neurobiological mechanisms. Until recently, most studies in rodents were performed only in males, and few studies have utilized different genetic strains of mice or rats. Comparing similar behavioral paradigms across sex and strain, it has become clear that major sex and genetic differences exist for each behavioral context alone (alcohol consumption and exercise) and combined. Therefore, future research in this area should be developed with careful study design and attention to address both of these factors.     

Circadian misalignment and weekend alcohol use in late adolescent drinkers: preliminary evidence

Alcohol use accelerates during late adolescence, predicting the development of alcohol use disorders (AUDs) and other negative outcomes. Identifying modifiable risk factors for alcohol use during this time could lead to novel prevention approaches. Burgeoning evidence suggests that sleep and circadian factors are cross-sectionally and longitudinally linked to alcohol use and problems, but more proximal relationships have been understudied. Circadian misalignment, in particular, is hypothesized to increase the risk for AUDs, but almost no published studies have included a biological measure of misalignment. In the present study, we aimed to extend existing research by assessing the relationship between adolescent circadian misalignment and alcohol use on a proximal timeframe (over two weeks) and by including three complementary measures of circadian alignment. We studied 36 healthy late (18–22 years old, 22 females) alcohol drinkers (reporting ≥1, standard drink per week over the past 30 days) over 14 days. Throughout the study, participants reported prior day’s alcohol use and prior night’s sleep each morning via smartphone and a secure, browser-based interface. Circadian phase was assessed via the dim light melatonin onset (DLMO) in the laboratory on two occasions (Thursday and Sunday nights) in counterbalanced order. The three measures of circadian alignment included DLMO-midsleep interval, “classic” social jet lag (weekday-weekend difference in midsleep), and “objective” social jet lag (weekday-weekend difference in DLMO). Multivariate imputation by chained equations was used to impute missing data, and Poisson regression models were used to assess associations between circadian alignment variables and weekend alcohol use. Covariates included sex, age, Thursday alcohol use, and Thursday sleep characteristics. As predicted, greater misalignment was associated with greater weekend alcohol use for two of the three alignment measures (shorter DLMO-midsleep intervals and larger weekday-weekend differences in midsleep), while larger weekday-weekend differences in DLMO were associated with less alcohol use. Notably, in contrast to expectations, the distribution of weekday-weekend differences in DLMO was nearly equally distributed between individuals advancing over the weekend and those delaying over the weekend. This unexpected finding plausibly reflects the fact that college students are not subject to the same systematically earlier weekday schedules observed in high school students and working adults. These preliminary findings support the need for larger, more definitive studies investigating the proximal relationships between circadian alignment and alcohol use among late adolescents.     

Effect of ethanol on the levels of dopamine and its metabolites in the brain of rats with different degree of sensitivity to stress

It was shown, that content of dopamine and its metabolites (DOPAC and HVA) are the same in two groups of rats with different time of immobilization in forced swimming test. One group of low active (LA) animals experienced the immobilization more than 300s, other high active (HA) rats for less than 120 s. Ethanol (2 g/kg per oris) increased the level of DA in the striatum and medial prefrontal cortex only in LA rats and besides, the concentration of dopamine after ethanol administration was higher in the n. accumbens of LA rats, than in that of HA rats. The authors suggest that differences in dopamine content between LA and HA rats are connected with different levels of voluntary alcohol consumption. The opportunity to use both groups of HA and LA rats for developing models of pathogenic heterogeneity of alcoholism is discussed.     

Neuro-inflammation induced in the hippocampus of 'binge drinking' rats may be mediated by elevated extracellular glutamate content

The neuropathological and immune changes induced in the brain by 'binge drinking' have been investigated in a rat model. Evidence of neuro-inflammation was identified in the 'binge drinking' rat model of alcohol abuse after 3 weeks of administration of 2 or 3 g/kg ethanol (EtOH), three times per day for two consecutive days, followed by 5 days of abstinence: Firstly, alveolar macrophages, isolated from these animals, showed significant increases in inducible nitric oxide synthase, as assayed by nitrite release, both before and after lipopolysaccaharide stimulation. Secondly, significant numbers of activated microglia were present in the dentate gyrus region of the hippocampus of the 'binge drinking' model, after major histocompatibility complex class II staining, by comparison with the control. Microdialysis studies in the ventral hippocampus identified a significant increase in the basal extracellular concentration of glutamate, in both the 2 and 3 g/kg administered 'binge drinking' rats. In contrast, no changes in the hippocampal extracellular concentrations, of GABA and taurine, or the dopamine and serotonin metabolites were observed under basal conditions. A further dose of EtOH induced a significant decrease in the concentrations of both 3,4-dihydroxyphenylacetic acid and 5-hydroxyindoleacetic acid, whereas glutamate, taurine and GABA levels were unaffected. There was no evidence that EtOH preference was initiated by the 'binge drinking' regimen. Our results suggest that the possible toxicity associated with 'binge drinking' maybe directed by the elevated glutamate levels, which in turn, activate phagocytic cells to release their inflammatory cytokines and chemokines, ultimately leading to neuro-inflammation.