Action Of Alcohol Research Articles

Craving Facebook? Behavioral addiction to online social networking and its association with emotion regulation deficits.

To assess disordered online social networking use via modified diagnostic criteria for substance dependence, and to examine its association with difficulties with emotion regulation and substance use. Cross-sectional survey study targeting undergraduate students. Associations between disordered online social networking use, internet addiction, deficits in emotion regulation and alcohol use problems were examined using univariate and multivariate analyses of covariance. A large University in the Northeastern United States. Undergraduate students (n = 253, 62.8% female, 60.9% white, age mean = 19.68, standard deviation = 2.85), largely representative of the target population. The response rate was 100%. Disordered online social networking use, determined via modified measures of alcohol abuse and dependence, including DSM-IV-TR diagnostic criteria for alcohol dependence, the Penn Alcohol Craving Scale and the Cut-down, Annoyed, Guilt, Eye-opener (CAGE) screen, along with the Young Internet Addiction Test, Alcohol Use Disorders Identification Test, Acceptance and Action Questionnaire-II, White Bear Suppression Inventory and Difficulties in Emotion Regulation Scale. Disordered online social networking use was present in 9.7% [n = 23; 95% confidence interval (5.9, 13.4)] of the sample surveyed, and significantly and positively associated with scores on the Young Internet Addiction Test (P < 0.001), greater difficulties with emotion regulation (P = 0.003) and problem drinking (P = 0.03). The use of online social networking sites is potentially addictive. Modified measures of substance abuse and dependence are suitable in assessing disordered online social networking use. Disordered online social networking use seems to arise as part of a cluster of symptoms of poor emotion regulation skills and heightened susceptibility to both substance and non-substance addiction.

Prenatal alcohol exposure alters response of kisspeptin-ir neurons to estradiol and progesterone in adult female rats.

Prenatal alcohol exposure (PAE) has adverse effects on reproductive function and hypothalamic-pituitary-gonadal (HPG) activity. Kisspeptin neurons play a role in mediating feedback effects of estradiol (E2 ) and progesterone (P4 ) on the HPG axis. We hypothesized that PAE will have long-term effects on the response of kisspeptin neurons to E2 and P4 . Adult female rats (53 to 58days) from prenatal ad libitum-fed control (C), pair-fed (PF), and alcohol-exposed (PAE) groups were subjected to Sham ovariectomy (OVX) or OVX without or with replacement with low or high physiological levels of E2 and P4 , and terminated under basal conditions. E2 and P4 levels, and the response of kisspeptin-ir neurons in the arcuate (ARC) and anteroventral periventricular (AVPV) nuclei to these hormones, were measured. As the E2 signal is conveyed to kisspeptin neurons via estrogen receptor-α (ER-α), we investigated PAE effects on the number of kisspeptin-ir/ER-α-ir neurons. To determine whether PAE alters interactions between kisspeptin and gonadotropin-releasing hormone (GnRH) neurons, close contacts between kisspeptin-ir fibers and GnRH-ir cell bodies were examined. Our data present the novel finding that kisspeptin-ir neurons in the ARC of PAE females show differential responses to E2 and to the combined treatment with E2 and P4 compared with controls: (i) OVX increased the number of kisspeptin-ir neurons in C and PF, but not PAE females compared with their Sham counterparts; (ii) E2 replacement restored kisspeptin-ir cell numbers to Sham levels in C and PF females but caused a robust down-regulation of kisspeptin-ir neurons below Sham levels in PAE females; (iii) OVX and replacement with high physiological concentrations of E2 resulted in fewer kisspeptin-ir cells in PAE than C females; (iv) OVX and replacement with high levels of both E2 and P4 markedly decreased the number of kisspeptin-ir neurons, below levels observed following E2 alone, in PF and C females, but had no significant effect in PAE females. These data suggest that a possible mechanism underlying adverse effects of PAE on HPG function involves actions of alcohol on the kisspeptin system.

A novel cholinergic action of alcohol and the development of tolerance to that effect in Caenorhabditis elegans.

Understanding the genes and mechanisms involved in acute alcohol responses has the potential to allow us to predict an individual's predisposition to developing an alcohol use disorder. To better understand the molecular pathways involved in the activating effects of alcohol and the acute functional tolerance that can develop to such effects, we characterized a novel ethanol-induced hypercontraction response displayed by Caenorhabditis elegans. We compared body size of animals prior to and during ethanol treatment and showed that acute exposure to ethanol produced a concentration-dependent decrease in size followed by recovery to their untreated size by 40 min despite continuous treatment. An increase in cholinergic signaling, leading to muscle hypercontraction, is implicated in this effect because pretreatment with mecamylamine, a nicotinic acetylcholine receptor (nAChR) antagonist, blocked ethanol-induced hypercontraction, as did mutations causing defects in cholinergic signaling (cha-1 and unc-17). Analysis of mutations affecting specific subunits of nAChRs excluded a role for the ACR-2R, the ACR-16R, and the levamisole-sensitive AChR and indicated that this excitation effect is dependent on an uncharacterized nAChR that contains the UNC-63 α-subunit. We performed a forward genetic screen and identified eg200, a mutation that affects a conserved glycine in EAT-6, the α-subunit of the Na(+)/K(+) ATPase. The eat-6(eg200) mutant fails to develop tolerance to ethanol-induced hypercontraction and remains contracted for at least 3 hr of continuous ethanol exposure. These data suggest that cholinergic signaling through a specific α-subunit-containing nAChR is involved in ethanol-induced excitation and that tolerance to this ethanol effect is modulated by Na(+)/K(+) ATPase function.

Reinforcement Efficiency of Modified Carbon Nanofiber in High-Performance Concrete Nanocomposite

Abstract Graphite nanomaterials offer distinct features for effective reinforcement of cementitious matrices in the pre-crack and post-crack ranges of behavior. In the work reported herein, carbon nanofiber was chosen for use in high-performance concrete. Synergistic actions of carbon nanofibers and polyvinyl alcohol (PVA) fibers in high-performance concrete were also investigated. Carbon nanofiber surfaces were modified by introduction of hydrophilic groups in order to improve their dispersion and interfacial interactions in cementitious matrices. An experimental program was conducted in order to assess the contributions of modified carbon nanofiber to diverse engineering properties of high-performance concrete. A statistical optimization program was implemented in order to identify optimum dosage of nano- and micro-scale reinforcement systems in high-performance concrete. The experimental results verified that optimum reinforcement systems comprised both carbon nanofiber and (micro-scale) PVA fiber. The gains in concrete engineering properties realized with optimum (nano- and micro-scale) reinforcement could not be matched by those provided by nano- or micro-scale reinforcement used alone. This finding supports the hypothesis that nano- and micro-scale reinforcement play complementary/synergistic roles in concrete by providing reinforcing effects at different scales and are also due to the benefits rendered by nanomaterials towards interfacial stress transfer and pullout behavior of fibers.

Alcohol alters insulin-like growth factor-1-induced transforming growth factor β1 synthesis in the medial basal hypothalamus of the prepubertal female rat.

Insulin-like growth factor-1 (IGF-1) and transforming growth factor β1 (TGFβ1) are produced in hypothalamic astrocytes and facilitate luteinizing hormone-releasing hormone (LHRH) secretion. IGF-1 stimulates release by acting directly on the LHRH nerve terminals and both peptides act indirectly through specific plastic changes on glial/tanycyte processes that further support LHRH secretion. Because the relationship between these growth factors in the hypothalamus is not known, we assessed the ability of IGF-1 to induce TGFβ1 synthesis and release and the actions of alcohol (ALC) on this mechanism prior to the onset of puberty. Hypothalamic astrocytes were exposed to medium only, medium plus IGF-1 (200ng/ml), or medium plus IGF-1 with 50mM ALC. After 18hours, media were collected and assayed for TGFβ1. For the in vivo experiment, prepubertal female rats were administered either ALC (3g/kg) or water via gastric gavage at 07:30hours and at 11:30hours. At 09:00hours, saline or IGF-1 was administered into the third ventricle. Rats were killed at 15:00hours and the medial basal hypothalamus (MBH) was collected for assessment of TGFβ1, IGF-1 receptor (IGF-1R), and Akt. IGF-1 induced TGFβ1 release (p<0.01) from hypothalamic astrocytes in culture, an action blocked by ALC. In vivo, IGF-1 administration caused an increase in TGFβ1 protein compared with controls (p<0.05), an action blocked by ALC as well as a phosphatidylinositol 3 kinase/Akt inhibitor. IGF-1 stimulation also increased both total (p<0.01) and phosphorylated (p)-IGF-1R (p<0.05) protein levels, and phosphorylated (p)-Akt levels (p<0.01), which were also blocked by ALC. This study shows that ALC blocks IGF-1 actions to stimulate synthesis and release of hypothalamic TGFβ1, total and p-IGF-1R, and p-Akt levels further demonstrating the inhibitory actions of ALC on puberty-related events associated with hypothalamic LHRH release.

Attitudes associated with alcohol and marijuana referral actions by resident assistants.

This exploratory study examined associations between resident assistant (RA) attitudes and referral actions to identify training strategies for strengthening the ability of these paraprofessionals to recognize and refer college students in their living units who misuse alcohol and marijuana. The study's hypotheses were that (1) referral self-efficacy and perceived referral norms would be positively associated with RA referral actions and (2) perceived referral barriers and referral anticipatory anxiety would be negatively associated with RAs' referral actions. A total of 317 RAs at eight residential campuses in different regions of the U.S. took part in the study. All participating RAs had at least one semester of work experience. Just prior to the Fall semester of 2012, RA's responded to an online survey that assessed their alcohol and marijuana referral attitudes and referral actions. Overall, RAs reported considerable anxiety about approaching and referring students who may have an alcohol and/or marijuana problem. Perceived referral norms among RAs indicated substantial variability in perceptions about others' expectations of them for referring students who may have alcohol and marijuana problems. Results from two multivariable logistic regression analyses showed that referral self-efficacy distinguished RAs who took alcohol referral actions and marijuana referral actions from those who did not do so. Neither length of RA service nor time spent on campus was associated with referral actions. RA training programs could give attention to strengthening referral self-efficacy through a series of increasingly difficult skill-building activities during pre- and in-service training. In addition, senior residence life and housing professional staff may consider assessing the extent to which RAs under their supervision follow established protocols for assisting students with possible alcohol and marijuana problems. The development of evidence-based RA training programs will require additional research.

Glycine and GABA(A) ultra-sensitive ethanol receptors as novel tools for alcohol and brain research.

A critical obstacle to developing effective medications to prevent and/or treat alcohol use disorders is the lack of specific knowledge regarding the plethora of molecular targets and mechanisms underlying alcohol (ethanol) action in the brain. To identify the role of individual receptor subunits in ethanol-induced behaviors, we developed a novel class of ultra-sensitive ethanol receptors (USERs) that allow activation of a single receptor subunit population sensitized to extremely low ethanol concentrations. USERs were created by mutating as few as four residues in the extracellular loop 2 region of glycine receptors (GlyRs) or γ-aminobutyric acid type A receptors (GABA(A)Rs), which are implicated in causing many behavioral effects linked to ethanol abuse. USERs, expressed in Xenopus oocytes and tested using two-electrode voltage clamp, demonstrated an increase in ethanol sensitivity of 100-fold over wild-type receptors by significantly decreasing the threshold and increasing the magnitude of ethanol response, without altering general receptor properties including sensitivity to the neurosteroid, allopregnanolone. These profound changes in ethanol sensitivity were observed across multiple subunits of GlyRs and GABA(A)Rs. Collectively, our studies set the stage for using USER technology in genetically engineered animals as a unique tool to increase understanding of the neurobiological basis of the behavioral effects of ethanol.

Supplemental Material for The Validity of Different Measures of Automatic Alcohol Action Tendencies

Supplemental Material for The Validity of Different Measures of Automatic Alcohol Action Tendencies

N-benzyl-N-[(E)-2-phenylethenyl]trifluoromethanesulfonamide

In the search for an approach to N-vinyltriflamides with a free NH group TfNHCH=CHR (Tf = CF3SO2) N-(benzyl)-N-(2-bromo-2-phenylethenyl)triflamide TfN(Bn)CH=CHPh was synthesized through bromination-dehydrobromination of N-(benzyl)-N-(2-phenylethyl)triflamide. At removing the benzyl protecttion by the action of trifluoromethanesulfonic acid benzyl alcohol separated; however instead of the target N-styryltriflamide unexpectedly the product of its hydrogenation was obtained, N-(2-phenylethyl)triflamide. Obviously, the benzyl alcohol was the hydrogen donor, and the easy hydrogenation was facilitated by the high electrophilicity of the double bond in N-styryltriflamide because of strong electron-acceptor effect of the triflyl group.

Alcohol Enhances HIV Infection of Cord Blood Monocyte-Derived Macrophages

Alcohol consumption or alcohol abuse is common among pregnant HIV(+) women and has been identified as a potential behavioral risk factor for the transmission of HIV. In this study, we examined the impact of alcohol on HIV infection of cord blood monocyte-derived macrophages (CBMDM). We demonstrated that alcohol treatment of CBMDM significantly enhanced HIV infection of CBMDM. Investigation of the mechanisms of alcohol action on HIV demonstrated that alcohol inhibited the expression of several HIV restriction factors, including anti-HIV microRNAs, APOBEC3G and APOBEC3H. Additionally, alcohol also suppressed the expression of IFN regulatory factor 7 (IRF-7) and retinoic acid-inducible gene I (RIG-I), an intracellular sensor of viral infection. The suppression of these IFN regulatory factors was associated with reduced expression of type I IFN. These experimental findings suggest that maternal alcohol consumption may facilitate HIV infection, promoting vertical transmission of HIV.

Effects of acute alcohol consumption and processing of emotion in faces: Implications for understanding alcohol-related aggression.

The negative consequences of chronic alcohol abuse are well known, but heavy episodic consumption ("binge drinking") is also associated with significant personal and societal harms. Aggressive tendencies are increased after alcohol but the mechanisms underlying these changes are not fully understood. While effects on behavioural control are likely to be important, other effects may be involved given the widespread action of alcohol. Altered processing of social signals is associated with changes in social behaviours, including aggression, but until recently there has been little research investigating the effects of acute alcohol consumption on these outcomes. Recent work investigating the effects of acute alcohol on emotional face processing has suggested reduced sensitivity to submissive signals (sad faces) and increased perceptual bias towards provocative signals (angry faces) after alcohol consumption, which may play a role in alcohol-related aggression. Here we discuss a putative mechanism that may explain how alcohol consumption influences emotional processing and subsequent aggressive responding, via disruption of orbitofrontal cortex (OFC)-amygdala connectivity. While the importance of emotional processing on social behaviours is well established, research into acute alcohol consumption and emotional processing is still in its infancy. Further research is needed and we outline a research agenda to address gaps in the literature.

An alcohol-sensing site in the calcium- and voltage-gated, large conductance potassium (BK) channel.

Ethanol alters BK (slo1) channel function leading to perturbation of physiology and behavior. Site(s) and mechanism(s) of ethanol-BK channel interaction are unknown. We demonstrate that ethanol docks onto a water-accessible site that is strategically positioned between the slo1 calcium-sensors and gate. Ethanol only accesses this site in presence of calcium, the BK channel's physiological agonist. Within the site, ethanol hydrogen-bonds with K361. Moreover, substitutions that hamper hydrogen bond formation or prevent ethanol from accessing K361 abolish alcohol action without altering basal channel function. Alcohol interacting site dimensions are approximately 10.7 × 8.6 × 7.1 Å, accommodating effective (ethanol-heptanol) but not ineffective (octanol, nonanol) channel activators. This study presents: (i) to our knowledge, the first identification and characterization of an n-alkanol recognition site in a member of the voltage-gated TM6 channel superfamily; (ii) structural insights on ethanol allosteric interactions with ligand-gated ion channels; and (iii) a first step for designing agents that antagonize BK channel-mediated alcohol actions without perturbing basal channel function.

Altered sedative effects of ethanol in mice with α1 glycine receptor subunits that are insensitive to Gβγ modulation.

Alcohol abuse and alcoholism are major health problems and one of the leading preventable causes of death. Before achieving better treatments for alcoholism, it is necessary to understand the critical actions of alcohol on membrane proteins that regulate fundamental functions in the central nervous system. After generating a genetically modified knock-in (KI) mouse having a glycine receptor (GlyR) with phenotypical silent mutations at KK385/386AA, we studied its cellular and in vivo ethanol sensitivity. Analyses with western blotting and immunocytochemistry indicated that the expression of α1 GlyRs in nervous tissues and spinal cord neurons (SCNs) were similar between WT and KI mice. The analysis of synaptic currents recorded from KI mice showed that the glycinergic synaptic transmission had normal properties, but the sensitivity to ethanol was significantly reduced. Furthermore, the glycine-evoked current in SCNs from KI was resistant to ethanol and G-protein activation by GTP-γ-S. In behavioral studies, KI mice did not display the foot-clasping behavior upon lifting by the tail and lacked an enhanced startle reflex response that are characteristic of other glycine KI mouse lines with markedly impaired glycine receptor function. The most notable characteristic of the KI mice was their significant lower sensitivity to ethanol (∼40%), expressed by shorter times in loss of righting reflex (LORR) in response to a sedative dose of ethanol (3.5 g/Kg). These data provide the first evidence to link a molecular site in the GlyR with the sedative effects produced by intoxicating doses of ethanol.

Kappa-Opioid Receptor Antagonism: A Mechanism for Treatment of Relief Drinking?

Of recreational users of alcohol, 15% at some point go on to develop a pattern of alcohol seeking and taking that continues despite adverse consequences—that is, alcohol addiction or simply alcoholism. This proportion is not much different from what is seen with other drugs of abuse, but more than half of all Americans $12 years old report being current drinkers. As a result, in the United States, 12 million people have a current diagnosis of alcoholism, accounting for a greater disease burden than all illicit drugs combined. Few evidencebased treatments are currently available for these patients. Efficacy of existing treatments is limited further by the heterogeneity of alcoholism. Optimal clinical management of these patients ultimately requires personalized approaches that match treatments to pathophysiologically relevant individual characteristics. Some of these characteristics are clearly genetic, but personalized therapies also need to take in account neuroadaptations that develop over time as a result of alcohol use itself. Research over the past decade has demonstrated that the motivational mechanisms driving alcohol use undergo a shift over the course of the addictive process. In initial stages of alcohol use, positively reinforcing, or rewarding, properties of alcohol dominate. These are mediated partly by alcohol-induced release of endogenous opioids that activate mu opioid receptors, a mechanism targeted by the U.S. Food and Drug Administration–approved opioid antagonist naltrexone. However, with increased duration of brain alcohol exposure and dependence, alcohol consumption becomes increasingly driven by negatively reinforcing actions of alcohol. During this stage, negative emotional states emerge in the absence of alcohol. Because these can be temporarily alleviated by resuming alcohol intake, they introduce a novel, powerful incentive for alcohol consumption—often called the “dark side of addiction.” There are currently no clinically approved medications targeting this type of “relief drinking.” Antagonists for corticotropin-releasing factor receptor 1 (CRF1) have been pursued for some time for their potential in this regard, but along the way, other neurochemical mechanisms have emerged that seem to hold similar promise. In one of the most exciting developments, Walker and Koob (1) discovered that intracerebroventricular administration of the kappa opioid receptor (KOR) antagonist norbinaltorphimine selectively suppresses dependence-induced escalation of alcohol consumption in a manner similar to CRF1 antagonists. In this issue of Biological Psychiatry, Kissler et al. (2) provide an

Effects of alcohol on intestinal epithelial barrier permeability and expression of tight junction-associated proteins

The present study aimed to investigate the effects of alcohol on intestinal epithelial barrier permeability and expression of the tight junction-associated proteins, zonula occludens-1 (ZO-1) and claudin-1. An alcohol-treated Caco-2 intestinal epithelial cell monolayer in vitro model was used to investigate whether alcohol is able to induce intestinal barrier dysfunction and decrease expression of ZO-1 and claudin-1. MTT assay results revealed unaltered cell viability at alcohol concentrations of <5%. Caco-2 cells in the 5% alcohol-treated groups exhibited a significant time-dependent decrease in transepithelial electrical resistance (TEER) and an increase in fluorescent yellow flux rate compared with the control cells. ZO‑l expression exhibited a progressive decline following 20 min of incubation, reached its minimum levels at 60 min and then showed an increasing trend following 60 min of incubation. In addition, claudin-1 expression exhibited a progressive increase following 60 min of incubation, reached its maximum levels at 60 min and then showed an increasing trend following 60 min of incubation. Alterations in the expression of the ZO-l and claudin-1 proteins revealed trends consistent with changes in the TEER value and the fluorescent yellow transmittance rate in the Caco-2 cells. The results of this study indicate that alcohol is able to increase the intestinal epithelial barrier permeability in a dose- and time-dependent manner. Alcohol induces a change in the expression of the tight junction-associated proteins, ZO-1 and claudin-1, which are two major sites of alcohol action, thus increasing intestinal epithelial barrier permeability.

Effects of ethanol and acetaldehyde in zebrafish brain structures: An in vitro approach on glutamate uptake and on toxicity-related parameters

Ethanol (EtOH) and its metabolite, acetaldehyde (ALD), induce deleterious effects on central nervous system (CNS). Here we investigate the in vitro toxicity of EtOH and ALD (concentrations of 0.25%, 0.5%, and 1%) in zebrafish brain structures [telencephalon (TE), opticum tectum (OT), and cerebellum (CE)] by measuring the functionality of glutamate transporters, MTT reduction, and extracellular LDH activity. Both molecules decreased the activity of the Na+-dependent glutamate transporters in all brain structures. The strongest glutamate uptake inhibition after EtOH exposure was 58% (TE-1%), and after ALD, 91% (CE-1%). The results of MTT assay and LDH released demonstrated that the actions of EtOH and its metabolite are concentration and structure-dependent, in which ALD was more toxic than EtOH. In summary, our findings demonstrate a differential toxicity in vitro of EtOH and ALD in zebrafish brain structures, which can involve changes on glutamatergic parameters. We suggest that this species may be an interesting model for assessing the toxicological actions of alcohol and its metabolite in CNS.

Acute Effects of Alcohol on Stimulus-Induced Gamma Oscillations in Human Primary Visual and Motor Cortices

Alcohol is a rich drug affecting both the γ-amino butyric acid (GABA) and glutamatergic neurotransmitter systems. Recent findings from both modeling and pharmacological manipulation have indicated a link between GABAergic activity and oscillations measured in the gamma frequency range (30-80 Hz), but there are no previous reports of alcohol's modulation of gamma-band activity measured by magnetoencephalography (MEG) or electroencephalography (EEG). In this single-blind, placebo-controlled crossover study, 16 participants completed two study days, on one day of which they consumed a dose of 0.8 g/kg alcohol, and on the other day a placebo. MEG recordings of brain activity were taken before and after beverage consumption, using visual grating and finger abduction paradigms known to induce gamma-band activity in the visual and motor cortices respectively. Time-frequency analyses of beamformer source reconstructions in the visual cortex showed that alcohol increased peak gamma amplitude and decreased peak frequency. For the motor task, alcohol increased gamma amplitude in the motor cortex. These data support the notion that gamma oscillations are dependent, in part, on the balance between excitation and inhibition. Disruption of this balance by alcohol, by increasing GABAergic inhibition at GABAA receptors and decreasing glutamatergic excitation at N-methyl-D-aspartic acid receptors, alters both the amplitude and frequency of gamma oscillations. The findings provide further insight into the neuropharmacological action of alcohol.

Alcohol Selectivity of β3-Containing GABAA Receptors: Evidence for a Unique Extracellular Alcohol/Imidazobenzodiazepine Ro15-4513 Binding Site at the α+β- Subunit Interface in αβ3δ GABAA Receptors

GABAA receptors (GABARs) have long been the focus for acute alcohol actions with evidence for behaviorally relevant low millimolar alcohol actions on tonic GABA currents and extrasynaptic α4/6, δ, and β3 subunit-containing GABARs. Using recombinant expression in oocytes combined with two electrode voltage clamp, we show with chimeric β2/β3 subunits that differences in alcohol sensitivity among β subunits are determined by the extracellular N-terminal part of the protein. Furthermore, by using point mutations, we show that the β3 alcohol selectivity is determined by a single amino acid residue in the N-terminus that differs between GABAR β subunits (β3Y66, β2A66, β1S66). The β3Y66 residue is located in a region called "loop D" which in γ subunits contributes to the imidazobenzodiazepine (iBZ) binding site at the classical α+γ2- subunit interface. In structural homology models β3Y66 is the equivalent of γ2T81 which is one of three critical residues lining the benzodiazepine binding site in the γ2 subunit loop D, opposite to the "100H/R-site" benzodiazepine binding residue in GABAR α subunits. We have shown that the α6R100Q mutation at this site leads to increased alcohol-induced motor in-coordination in alcohol non-tolerant rats carrying the α6R100Q mutated allele. Based on the identification of these two amino acid residues α6R100 and β66 we propose a model in which β3 and δ containing GABA receptors contain a unique ethanol site at the α4/6+β3- subunit interface. This site is homologous to the classical benzodiazepine binding site and we propose that it not only binds ethanol at relevant concentrations (EC50-17mM), but also has high affinity for a few selected benzodiazepine site ligands including alcohol antagonistic iBZs (Ro15-4513, RY023, RY024, RY80) which have in common a large moiety at the C7 position of the benzodiazepine ring. We suggest that large moieties at the C7-BZ ring compete with alcohol for its binding pocket at a α4/6+β3- EtOH/Ro15-4513 site. This model reconciles many years of alcohol research on GABARs and provides a plausible explanation for the competitive relationship between ethanol and iBZ alcohol antagonists in which bulky moieties at the C7 position compete with ethanol for its binding site. We conclude with a critical discussion to suggest that much of the controversy surrounding this issue might be due to fundamental species differences in alcohol and alcohol antagonist responses in rats and mice.

The Effect of Approach/Avoidance Training on Alcohol Consumption Is Mediated by Change in Alcohol Action Tendency

Training people to respond to alcohol images by making avoidance joystick movements can affect subsequent alcohol consumption, and has shown initial efficacy as a treatment adjunct. However, the mechanisms that underlie the training’s efficacy are unknown. The present study aimed to determine 1) whether the training’s effect is mediated by a change in action tendency or a change in selective attention, and 2) whether the training’s effect is moderated by individual differences in working memory capacity (WMC). Three groups of social drinkers (total N = 74) completed either approach-alcohol training, avoid-alcohol training or a sham-training on the Approach-Avoidance Task (AAT). Participants’ WMC was assessed prior to training, while their alcohol-related action tendency and selective attention were assessed before and after the training on the recently developed Selective-Attention/Action Tendency Task (SA/ATT), before finally completing an alcohol taste-test. There was no significant main effect of approach/avoidance training on alcohol consumption during the taste-test. However, there was a significant indirect effect of training on alcohol consumption mediated by a change in action tendency, but no indirect effect mediated by a change in selective attention. There was inconsistent evidence of WMC moderating training efficacy, with moderation found only for the effect of approach-alcohol training on the AAT but not on the SA/ATT. Thus approach/avoidance training affects alcohol consumption specifically by changing the underlying action tendency. Multiple training sessions may be required in order to observe more substantive changes in drinking behaviour.

Chapter 10 - Molecular and neurologic responses to chronic alcohol use

This chapter provides an overview of current knowledge on the molecular and clinical aspects of chronic alcohol effects on the central nervous system. This drug is almost ubiquitous, widely enjoyed socially, but produces a diverse spectrum of neurologic disease when abused. Acutely, alcohol interacts predominantly with γ-aminobutyric acid-A (GABA-A) and N-methyl-d-aspartate (NMDA) receptors, but triggers diverse signaling events within well-defined neural pathways. These events result in adaptive changes in gene expression that ultimately produce two major states: addiction and toxicity. Epigenetic modifications of chromatin could lead to long-lived or even transgenerational changes in gene expression, thus producing aspects of the heritability of alcohol use disorders (AUD) and long-term behaviors such as recidivism. The diverse clinical syndromes produced by chronic alcohol actions in the central nervous system reflect the molecular pathology and predominantly involve aspects of tolerance/withdrawal, selective vulnerability (manifest as central pontine myelinolysis, Marchiafava-Bignami disease), and additional environmental factors (e.g., thiamine deficiency in Wernicke-Korsakoff's syndrome). Additionally, deleterious aspects of chronic alcohol on signaling, synaptic transmission, and cell toxicity lead to primary alcoholic dementia. Genetically determined aspects of myelin structure and alcohol actions on myelin gene expression may be a prominent molecular mechanism resulting in a predisposition to, or causation of, AUD and multiple other neurologic complications of chronic alcohol. The dramatic progress made in understanding molecular actions of alcohol holds great promise for our eventual treatment or prevention of AUD and neurologic complications resulting from chronic alcohol abuse.