No full-text available
To read the full-text of this research,
you can request a copy directly from the author.
The contribution of electrophysiology to knowledge of the acute and chronic effects of ethanol
Abstract
This review describes the effects of ethanol on the components of neuronal transmission and the relationship of such effects to the behavioural actions of ethanol. The concentrations of ethanol with acute actions on voltage-sensitive ion channels are first described, then the actions of ethanol on ligand-gated ion channels, including those controlled by cholinergic receptors, 5-hydroxytryptamine receptors, the various excitatory amino acid receptors, and gamma-aminobutyric acid receptors. Acute effects of ethanol are then described on brain areas thought to be involved in arousal and attention, the reinforcing effects of ethanol, the production of euphoria, the actions of ethanol on motor control, and the amnesic effects of ethanol; the acute effects of ethanol demonstrated by EEG studies are also discussed. Chronic effects of alcohol on neuronal transmission are described in the context of the various components of the ethanol withdrawal syndrome, withdrawal hyperexcitability, dysphoria and anhedonia, withdrawal anxiety, craving, and relapse drinking. Electrophysiological studies on the genetic influences on the effects of ethanol are discussed, particularly the acute actions of ethanol and electrophysiological differences reported in individuals predisposed to alcoholism. The conclusion notes the concentration of studies on the classical transmitters, with relative neglect of the effects of ethanol on peptides and on neuronal interactions between brain areas and integrated patterns of neuronal activity.
... Полагают, что эффективные концентрации таурина в синаптической щели могут достигать милимолярных уровней. Интересно, что именно милимолярные уровни этанола также необходимы для проявления физиологических эффектов в нервной системе [10]. Таким образом, таурин и этанол, по-видимому, относительно уникальны в необходимости высоких эффективных концентраций в нервной системе по сравнению с другими эндо-и экзогенными нейроактивными соединениями. ...
... Таким образом, таурин, вероятно, осуществляет свои тормозные эффекты, потенцируя функцию ГАМ-Ка-и глициновых рецепторов и модулируя функцию кальциевых каналов. Интересно, что большая часть хорошо известных фармакологических эффектов этанола на нервную систему аналогична -потенцирование функции каналов для хлорид-ионов, ингибирова-ние рецепторов возбуждающих аминокислот и функции кальциевых каналов [10,12]. ...
... Одновременно, если у предпочитающих воду в условиях свободного выбора крыс происходит транзиторное 50% увеличение внеклеточного уровня таурина в n.accumbens после введения этанола (2 г/кг, в/бр), то у предпочитающих этанол только 25% увеличение концентрации таурина. У мышей с отсутствием одной из изоформ протеинкиназы С (эпсилон-изоформа), которые характеризуются как поведенчески, так и биохимически «суперчувствительностью» к этанолу, также имеет место увеличение уровня таурина в n.accumbens [10,12]. Интересно, что у этих мышей также нарушено этанол-стимулируемое высвобождение дофамина в n.accumbens, феномен, который играет важную роль в подкрепляющих эффектах этанола. ...
Taurine and ethanol have the positive allosteric modulatory effects on the glycine- and GABA-receptors (chloride canals) and inhibit other ligand- and voltage-dependent cation channels. Taurine may dose-dependent the ethanol-induced changes in locomotor activity, sedation and motivation. Ethanol raise the extracellular taurine levels in various brain regions, possible because of its enhanced transfer through the blood-brain barrier. Exogenous taurine, its derivatives and analogues decrease the ethanol consumption. Thus, the system of taurine homeostasis may serve as an important modulator of ethanol-induced effects in CNS.
... Ethanol (EtOH) is one of the most commonly used substances in the world and has effects on diverse systems, including digestive, cardiovascular and nervous. Behavioral effects of different concentrations of ethanol are well described (e.g., Little, 1999;Zorumski et al., 2014;Dar, 2015). Intoxicating effects of ethanol on the nervous system start at about 5-20 mM (21.7 mM corresponds to 0.1% blood alcohol concentration (BAC); and about 23 mM corresponds to 1 g/kg), causing mood changes, excitation and impaired cognition (e.g., Little, 1999;Zorumski et al., 2014; http://pubs.niaaa.nih.gov/publications/ ...
... Behavioral effects of different concentrations of ethanol are well described (e.g., Little, 1999;Zorumski et al., 2014;Dar, 2015). Intoxicating effects of ethanol on the nervous system start at about 5-20 mM (21.7 mM corresponds to 0.1% blood alcohol concentration (BAC); and about 23 mM corresponds to 1 g/kg), causing mood changes, excitation and impaired cognition (e.g., Little, 1999;Zorumski et al., 2014; http://pubs.niaaa.nih.gov/publications/ AlcoholOverdoseFactsheet/Overdosefact.htm). ...
... First is the lack of evidence for effects of low concentrations of ethanol on synaptic transmission. Significant effects on synaptic transmission were reported only at ethanol concentrations > 20 mM (typically from 40 to 50 mM), which is higher than concentrations at which clear behavioral effects can be measured (< 20 mM, typically from 5 to 15 mM, for example, Wallgren & Barry, 1970;Givens & McMahon, 1997;Little, 1999). Remarkably, a recent study (Rae et al., 2014) reports that ethanol at a yet lower concentration (0.1 mM) had significant effects on metabolism of a number of biologically active molecules, including glutamate and GABA, and 1 mM ethanol affected all metabolic parameters measured in this study (e.g., decreased incorporation of 13 C-pyruvate and its products in Krebs cycle, glycolytic byproducts alanine and lactate, and decreased total metabolite pool sizes). ...
Ethanol is one of the most commonly used substances in the world. Behavioral effects of alcohol are well described, however cellular mechanisms of its action are poorly understood. There is an apparent contradiction between measurable behavioral changes produced by low concentrations of ethanol, and lack of evidence of synaptic changes at these concentrations. Further, effects of ethanol on synaptic transmission in the neocortex are poorly understood. Here we set to determine effects of ethanol on excitatory synaptic transmission in the neocortex. We show that 1-50 mM ethanol suppress excitatory synaptic transmission to layer 2/3 pyramidal neurons in rat visual cortex in a concentration-dependent manner. To the best of our knowledge, this is the first demonstration of the effects of very low concentrations of ethanol (from 1 mM) on synaptic transmission in the neocortex. We further show that a selective antagonist of A1 adenosine receptors, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), blocks effects of 1-10 mM ethanol on synaptic transmission. However, reduction of EPSP amplitude by 50 mM ethanol was not affected by DPCPX. We propose that ethanol depresses excitatory synaptic transmission in the neocortex by at least two mechanisms, engaged at different concentrations: low concentrations of ethanol reduce synaptic transmission via A1R-dependent mechanism and involve presynaptic changes, while higher concentrations activate additional, adenosine-independent mechanisms with predominantly postsynaptic action. Involvement of adenosine signaling in mediating effects of low concentrations of ethanol may have important implications for understanding alcohol's effects on brain function, and provide a mechanistic explanation to the interaction between alcohol and caffeine. This article is protected by copyright. All rights reserved.
... The co-application of ethanol with TBI. To demonstrate the system's ability to concurrently investigate relevant comorbidities, Ethanol (EtOH) was introduced post-injury at a concentration of 40 mM, a level comparable with mild intoxication in humans 68 and below the EC50 69 . Utilizing a minor protocol modification, both single and multiple-rapid 30 g impacts (with separate controls) were administered, and immediately (~ 2 min) following the final impact application, media from control and impacted networks were replaced with a similar media containing EtOH for a duration of 15 min. ...
... However, it is important to note that while the current, relevant literature has reported acrolein levels up to 14 days post-injury 52 , longer-term studies will ultimately be required for a more comprehensive understanding of acrolein's precise role in chronic-injury. Finally, we have confirmed that clinically relevant concentrations of ethanol (40 mM) at limited exposure periods (15 min) 68 , a treatment that did not cause acrolein elevation when administered alone to un-impacted neuronal cells, can further-significantly elevate acrolein when introduced following single or repeated injuries, even at minimal force intensities (30 g). These results suggest a synergistic effect of ethanol in exacerbating oxidative stress when combined with mechanical injury. ...
While clinical observations have confirmed a link between the development of neurodegenerative diseases and traumatic brain injuries (TBI), there are currently no treatments available and the underlying mechanisms remain elusive. In response, we have developed an in vitro pendulum trauma model capable of imparting rapid acceleration injuries to neuronal networks grown on microelectrode arrays within a clinically relevant range of g forces, with real-time electrophysiological and morphological monitoring. By coupling a primary physical insult with the quantification of post-impact levels of known biochemical pathological markers, we demonstrate the capability of our system to delineate and investigate the primary and secondary injury mechanisms leading to post-impact neurodegeneration. Specifically, impact experiments reveal significant, force-dependent increases in the pro-inflammatory, oxidative stress marker acrolein at 24 h post-impact. The elevation of acrolein was augmented by escalating g force exposures (30–200 g), increasing the number of rapidly repeated impacts (4–6 s interval, 3, 5 and 10×), and by exposing impacted cells to 40 mM ethanol, a known comorbidity of TBI. The elevated levels of acrolein following multiple impacts could be reduced by increasing time-intervals between repeated hits. In addition, we show that conditioned media from maximally-impacted cultures can cause cellular acrolein elevation when introduced to non-impact, control networks, further solidifying acrolein’s role as a diffusive-factor in post-TBI secondary injuries. Finally, morphological data reveals post-impact acrolein generation to be primarily confined to soma, with some emergence in cellular processes. In conclusion, this novel technology provides accurate, physical insults with a unique level of structural and temporal resolution, facilitating the investigation of post-TBI neurodegeneration.
... This could contribute to the amnesic actions of ethanol seen both after acute administration and following chronic high consumption. (Little, 1999). ...
... Glutamatergic upregulation, resulting from the combination of increased NMDA receptor function and increased glutamate release, contributes to the ethanol withdrawal symptoms (Allgaier, 2002;Krystal et al., 2003) and seems to play a major role in withdrawal hyperexcitability and the production of convulsions (Little, 1999). The amplitude of GABA A -mediated IPSP/Cs as well as the frequency and amplitude of spontaneously occurring mIPSCs were found to be robustly enhanced, suggesting enhanced basal GABAergic transmission . ...
There is no specialized alcohol addiction area in the brain; rather, alcohol acts on a wide range of excitatory and inhibitory
nervous networks to modulate neurotransmitters actions by binding with and altering the function of specific proteins. With no hematoencephalic
barrier for alcohol, its actions are strongly related to the amount of intake. Heavy alcohol intake is associated with both
structural and functional changes in the central nervous system with long-term neuronal adaptive changes contributing to the phenomena
of tolerance and withdrawal. The effects of alcohol on the function of neuronal networks are heterogeneous. Because ethanol affects
neural activity in some brain sites but is without effect in others, its actions are analyzed in terms of integrated connectivities in the
functional circuitry of neuronal networks, which are of particular interest because of the cognitive interactions discussed in the manuscripts
contributing to this review. Recent molecular data are reviewed as a support for the other contributions dealing with cognitive
disturbances related to alcohol acute and addicted consumption.
... Alcohol intoxication is often related to social drinking, leading to blood alcohol levels between 5 and 20 mM and reducing anxiety and producing alterations in mood, excitation, mild sedation, impaired attention, and increased accident risk. Yet, it has been reported that the in vivo doses of ethanol that can produce behavioral changes may in fact be lower than has often been thought, both behavioral and electrophysiological changes being reported after doses as low as 0.125-0.25 g/kg ethanol (Little, 1999). Diagnostic criteria (DSM-IV, APA, 1996) are recent alcohol intake, inadequate behavioral changes (sexual or aggressive behaviors, mood instability, disrupt of discernment, social or occupancy activities) developing during or shortly after intake. ...
... Hasin, Van Rossem, McCloud, and Endicott (1997) divided heavy drinkers into three groups: those with a diagnosis of dependence, of abuse, and with no disorder. Higher concentrations of ethanol (50-100 mM) in normal individuals cause loss of consciousness, decreased ventilation, and a risk of death (Deitrich & Harris, 1996;Little, 1999). All of these effects are less pronounced in chronic alcoholics, who routinely tolerate rather high levels of the drug. ...
Common patterns of alcohol consumption are described with their main criteria, blood alcohol levels, and diagnostic criteria. Binge drinking, an acute alcohol intoxication pattern of particularly concern, is also described, as it appears to be the most common pattern among teenagers when the brain is not yet mature. A number of classification schemes have been proposed specially for social drinking and alcohol dependence, and discussions still surround about them. The article summarize a consensus in classification. (PsycINFO Database Record (c) 2012 APA, all rights reserved)
... Action of ethanol on electrographic pattern was found to be biphasic, with potentiation of epileptiform activity in one dose range and depression in another one. Low ethanol doses causing euphoria and behavioral arousal are associated with desynchronization of the EEG, decrease in the mean amplitude, and increase in the theta and alpha activity (Lucas et al. 1986; Cohen et al. 1993a; Little 1999). Literature data (Little 1999; Cohen et al. 1993a ,b), similarly to our results, demonstrated that higher ethanol doses, led to decreased frequency and increased amplitude in the EEG. ...
... Low ethanol doses causing euphoria and behavioral arousal are associated with desynchronization of the EEG, decrease in the mean amplitude, and increase in the theta and alpha activity (Lucas et al. 1986; Cohen et al. 1993a; Little 1999). Literature data (Little 1999; Cohen et al. 1993a ,b), similarly to our results, demonstrated that higher ethanol doses, led to decreased frequency and increased amplitude in the EEG. All aforementioned data on EEG monitoring concerning the ethanol influence on homocysteine-induced epilepsy support the idea that acute ethanol treatment could represent one of the factors of the exogenous stabilization of brain excitability and that high doses of ethanol have depressed EEG power spectra effect. ...
The effects of ethanol on epilepsy are very complex. Ethanol can have depressant as well as excitatory effect on different animal models of epilepsy. Systemic administration of homocysteine can trigger seizures. The aim of the present study was to examine the changes of total spectral power density after ethanol alone and together with homocysteine thiolactone in adult rats. Adult male Wistar rats were divided into following groups: 1. saline-injected, (control) C; 2. D, L-homocysteine thiolactone, H (8 mmol/kg); 3. ethanol, E (E(0.5), 0.5 g/kg; E(1), 1 g/kg; E(2), 2 g/kg) and 4. E (E(0.5), E(1), and E(2)) 30 min prior to H, EH (E(0.5)H, E(1)H and E(2)H). For EEG recordings three gold-plated screws were implanted into the skull. Our results demonstrate that ethanol, when applied alone, increased total EEG spectral power density of adult rats with a marked spectrum shift toward low frequency waves. In EH groups, increasing doses of ethanol exhibited a dose-dependent effect upon spectral power density. Ethanol increased EEG spectral power density in E(0.5)H and E(1)H group, comparing to the H group (p > 0.05), the maximal increase was recorded with the lowest ethanol dose applied. The highest dose of ethanol (E(2)H) significantly decreased total power spectra density, comparing to the H group. We can conclude that high doses of ethanol depressed marked increase in EEG power spectrum induced by D,L-homocysteine thiolactone.
... Ethanol has been shown to exert effects on multiple brain receptors and channels. In many instances, the in vitro or in vivo targets are affected at levels above the driving limit of 17.3 mM, such as the AMPA glutamate receptor [57,58], metabotropic GluR4 receptor [59], T-type and L-type calcium channels [60,61], GABA B receptors [62], 5HT3 receptors [63], adenosine regulation [64], and GIRK2 (G-protein inwardly rectifying potassium current) [65]. A few targets have been reported to be affected by non-intoxicating alcohol levels, including inhibition of NMDA receptors [66], metabotropic GluR1 [67], largeconductance potassium (BK) channels [68], and α6 subunitcontaining nicotinic receptors [69]. ...
Background
Essential tremor patients may find that low alcohol amounts suppress tremor. A candidate mechanism is modulation of α6β3δ extra-synaptic GABAA receptors, that in vitro respond to non-intoxicating alcohol levels. We previously found that low-dose alcohol reduces harmaline tremor in wild-type mice, but not in littermates lacking δ or α6 subunits. Here we addressed whether low-dose alcohol requires the β3 subunit for tremor suppression.
Methods
We tested whether low-dose alcohol suppresses tremor in cre-negative mice with intact β3 exon 3 flanked by loxP, and in littermates in which this region was excised by cre expressed under the α6 subunit promotor. Tremor in the harmaline model was measured as a percentage of motion power in the tremor bandwidth divided by overall motion power.
Results
Alcohol, 0.500 and 0.575 g/kg, reduced harmaline tremor compared to vehicle-treated controls in floxed β3 cre- mice, but had no effect on tremor in floxed β3 cre+ littermates that have β3 knocked out. This was not due to potential interference of α6 expression by the insertion of the cre gene into the α6 gene since non-floxed β3 cre+ and cre- littermates exhibited similar tremor suppression by alcohol.
Discussion
As α6β3δ GABAA receptors are sensitive to low-dose alcohol, and cerebellar granule cells express β3 and are the predominant brain site for α6 and δ expression together, our overall findings suggest alcohol acts to suppress tremor by modulating α6β3δ GABAA receptors on these cells. Novel drugs that target this receptor may potentially be effective and well-tolerated for essential tremor.
Highlights
We previously found with the harmaline essential tremor model that GABAA receptors containing α6 and δ subunits mediate tremor suppression by alcohol. We now show that β3 subunits in α6-expressing cells, likely cerebellar granule cells, are also required, indicating that alcohol suppresses tremor by modulating α6β3δ extra-synaptic GABAA receptors.
... The acute effect of different addictive drugs has been extensively studied. Acute administration of drugs of abuse, such as cocaine (Herning et al., 1985), alcohol (Little, 1999;Lukas et al., 1986;Stenberg et al., 1994), THC (Lukas et al., 1995), and benzodiazepines (Benowitz et al., 1980;Manmaru and Matsuura, 1989) induced an increase in alpha and beta activity in healthy volunteers. By contrast, MDMA administration reveals a decrease in alpha and theta power in MDMA naïve volunteers (Frei et al., 2001). ...
Addiction is a chronic brain disease that has dramatic health and socioeconomic consequences worldwide. Multiple approaches have been used for decades to clarify the neurobiological basis of this disease and to identify novel potential treatments. This review summarizes the main brain networks involved in the vulnerability to addiction and specific innovative technological approaches to investigate these neural circuits. First, the evolution of the definition of addiction across the Diagnostic and Statistical Manual of Mental Disorders (DSM) is revised. We next discuss several innovative experimental techniques that, combined with behavioral approaches, have allowed recent critical advances in understanding the neural circuits involved in addiction, including DREADDs, calcium imaging, and electrophysiology. All these techniques have been used to investigate specific neural circuits involved in vulnerability to addiction and have been extremely useful to clarify the neurobiological basis of each specific component of the addictive process. These novel tools targeting specific brain regions are of great interest to further understand the different aspects of this complex disease.
This article is part of the special issue on ‘Vulnerabilities to Substance Abuse.’.
... For ethanol a spike rate 50% effective concentration of 38.6 mM in cultured murine neuronal networks has been described [34]. Furthermore, Draski et al. reported blood ethanol concentrations in a range of 64 mM to 81 mM around loss and return of the righting reflex in rats [35,36]. A blood ethanol concentration of 0.08%, the limit of legal driving in some countries, would correspond to 17 mM [37]. ...
Abstract Background The pharmacodynamic results of diazepam and ethanol administration are similar, in that each can mediate amnestic and sedative-hypnotic effects. Although each of these molecules effectively reduce the activity of central neurons, diazepam does so through modulation of a more specific set of receptor targets (GABAA receptors containing a γ-subunit), while alcohol is less selective in its receptor bioactivity. Our investigation focuses on divergent actions of diazepam and ethanol on the firing patterns of cultured cortical neurons. Method We used electrophysiological recordings from organotypic slice cultures derived from Sprague–Dawley rat neocortex. We exposed these cultures to either diazepam (15 and 30 µM, n = 7) or ethanol (30 and 60 mM, n = 11) and recorded the electrical activity at baseline and experimental conditions. For analysis, we extracted the episodes of spontaneous activity, i.e., cortical up-states. After separation of action potential and local field potential (LFP) activity, we looked at differences in the number of action potentials, in the spectral power of the LFP, as well as in the coupling between action potential and LFP phase. Results While both substances seem to decrease neocortical action potential firing in a not significantly different (p = 0.659, Mann–Whitney U) fashion, diazepam increases the spectral power of the up-state without significantly impacting the spectral composition, whereas ethanol does not significantly change the spectral power but the oscillatory architecture of the up-state as revealed by the Friedman test with Bonferroni correction (p
... Therefore, ethanol is also capable of interfering with the electrical coupling between two neurons. According to some works, ethanol must decouple neuronal cells by increasing junctional resistance and/or reducing the number of parallel gap junctions (Little, 1999). The Fig. 14.3 shows a schematic illustrating the acute nonsynaptic effects of ethanol. ...
Abuse of alcohol and abstinence from alcohol have been related to the appearance of epileptiform activities in the limbic system. Hippocampal formation appears to be an important source of epileptic activity and for such a condition is particularly vulnerable to pathological changes induced by ethanol. In vitro and in vivo studies have revealed that prolonged use of ethanol promotes disturbances in different subcellular mechanisms, acting directly on the lipid structure of the cell membrane, ion channels, cation-chloride cotransporters, and subunits of several receptors. Although it is complex and poorly understood, the continuous interaction of alcohol in these substrates leads to an imbalance of ionic homeostasis. These modifications, in the long run, promote states of hyperexcitability that, if uncontrolled, can lead to reverberating mechanisms, degeneration and cell death, making hippocampal tissues susceptible to epilepsy.
... It may therefore be implicated that GHSR-1A antagonists and/or agonists for the GLP-1, amylin or NMU receptors may consist novel targets for treatment of addiction disorders, such as AUD. It should however be emphasized that reward and addiction are not limited to the mesolimbic dopamine system, but rather involve various neurotransmitters and brain areas such as endogenous opioids (Engel et al., 1988;Ericson, Chau, Clarke, Adermark, & Soderpalm, 2011;Gilpin & Koob, 2008;Jarjour, Bai, & Gianoulakis, 2009;Koob, 2014;Koob & Volkow, 2016;Little, 1999;Pecina, 2008;Serecigni, 2015;Volkow, Wise, & Baler, 2017). However, the effects of these appetite regulatory peptides on behaviors related to these have yet not been studied. ...
Due to the limited efficacy of existing medications for addictive disorders including alcohol use disorder (AUD), the need for additional medications is substantial. Potential new medications for addiction can be identified through investigation of the neurochemical substrates mediating the ability of drugs of abuse such as alcohol to activate the mesolimbic dopamine system. Interestingly, recent studies implicate neuropeptides of the gut-brain axis as modulators of reward and addiction processes. The present review therefore summarizes the current studies investigating the ability of the gut-brain peptides ghrelin, glucagon-like peptide-1 (GLP-1), amylin and neuromedin U (NMU) to modulate alcohol- and drug-related behaviors in rodents and humans. Extensive literature demonstrates that ghrelin, the only known orexigenic neuropeptide to date, enhances reward as well as the intake of alcohol, and other drugs of abuse, while ghrelin receptor antagonism has the opposite effects. On the other hand, the anorexigenic peptides GLP-1, amylin and NMU independently inhibits reward from alcohol and drugs of abuse in rodents. Collectively, these rodent and human studies imply that central ghrelin, GLP-1, amylin and NMU signaling may contribute to addiction processes. Therefore, the need for randomized clinical trials investigating the effects of agents targeting these aforementioned systems on drug/alcohol use is substantial.
... It should however also be emphasized that rewarding properties of alcohol may include indirect as well as direct effects on various neurotransmitters including acetylcholine, glutamate, GABA, serotonin, noradrenaline, glycine and opioids, as well as hormones and peptides (Engel et al., 1988;Ericson et al., 2011;Little, 1999). Endogenous opioids have been found to modulate the ability of alcohol to induce reward independently as well as dependently on the mesolimbic dopamine system (Jarjour et al., 2009;Pecina, 2008;Serecigni, 2015). ...
Alcohol addiction, affecting approximately four percent of the population, contributes significantly to the global burden of diseases and is a substantial cost to the society. The neurochemical mechanisms regulating alcohol mediated behaviors is complex and in more recent years a new physiological role of the gut-brain peptides, traditionally known to regulate appetite and food intake, have been suggested. Indeed, regulators of alcohol-mediated behaviors. One of these gut-brain peptides is the annorexigenic peptide glucagon-like peptide-1 (GLP-1), Preclinical studies show that GLP-1 receptor activation, either by GLP-1 or analogues, attenuate the ability of alcohol to activate the mesolimbic dopamine system as well as decrease alcohol consumption and operant self-administration. In further support for the endogenous GLP-1 system in addiction processes are the experimental data showing that a GLP-1 receptor antagonist increases alcohol intake. Moreover, GLP-1 receptor agonists prevent the ability of other addictive drugs to activate the mesolimbic dopamine system. The number of clinical studies is limited, but show i) that genetic variation in the GLP-1 receptor gene is associated with alcohol addiction as well as increased alcohol infusion in humans, ii) that plasma levels of GLP-1 are associated with the subjective experience of cocaine and iii) that a GLP-1 receptor agonist reduces alcohol intake in patients with type-2 diabetes mellitus. These experimental and clinical studies raises the concern that clinically available GLP-1 receptor agonists deserves to be tested as potential treatments of patients with addictive disorders including alcohol addiction.
This article is part of the Special Issue entitled ‘Metabolic Impairment as Risk Factors for Neurodegenerative Disorders.’
... les de calcio tipo N, tipo T y, especialmente, sobre los de tipo L, inhibiendo su función (15). ...
Los últimos avances neurocientíficos han permitido profundizar en la fisiopatología del alcoholismo a nivel bioquímico y celular. Actualmente se sabe que los efectos agudos del etanol están fundamentalmente mediados por su interacción con neurotransmisores aminoácidos (primordialmente en los receptores GABAA y NMDA), así como cambios paralelos en determinadas aminas como la dopamina y la noradrenalina. Las respuestas neuroadpatativas en los receptores de aminoácidos subyacen probablemente en componentes importantes del síndrome de abstinencia, contribuyendo a la muerte neuronal que se encuentra en el alcoholismo crónico. Aunque no están tan bien comprendidas, las propiedades reforzadoras del etanol parecen estar mediadas fundamentalmente por la activación de receptores GABAA, la liberación de péptidos opioides, la interacción con receptores nicotínicos y la liberación indirecta de dopamina.
... gamma-aminobutyric acid (GABA), acetylcholine (ACh), serotonin (5-HT), noradrenaline (NA) and opioids, and that DA alone will only explain some of the rewarding effects of addictive drugs (e.g. Engel et al, 1988;Engel et al, 1992;Little, 1999;Engel et al, 1999). The pharmacological properties of ethanol may also be mediated by peptides and hormones ( Fig. 2) (Engel et al, 1999). ...
... Low doses of alcohol ingestion, which cause behavioral arousal and euphoria, decrease mean amplitude of EEG and increase theta and alpha band activity [68,70,72,73]. Higher doses of ingested alcohol produce depression of activity; decrease frequency and increase mean voltage in all frequency bands [74,75]. Reports of ethanol-induced changes in beta activity are somewhat contradictory. ...
Sleep-wake (S-W) disturbances are frequently associated with alcohol use disorders (AUD), occurring during periods of active drinking, withdrawal, and abstinence. These S-W disturbances can persist after months or even years of abstinence, suggesting that chronic alcohol consumption may have enduring negative effects on both homeostatic and circadian sleep processes. It is now generally accepted that S-W disturbances in alcohol-dependent individuals are a significant cause of relapse in drinking. Although significant progress has been made in identifying the socio-economic burden and health risks of alcohol addiction, the underlying neurobiological mechanisms that lead to S-W disorders in AUD are poorly understood. Marked progress has been made in understanding the basic neurobiological mechanisms of how different sleep stages are normally regulated. This review article in seeking to explain the neurobiological mechanisms underlying S-W disturbances associated with AUD, describes an evidence-based, easily testable, novel hypothesis that chronic alcohol consumption induces neuroadaptive changes in the cholinergic cell compartment of the pedunculopontine tegmentum (CCC-PPT). These changes include increases in N-methyl-D-aspartate (NMDA) and kainate receptor sensitivity and a decrease in gamma-aminobutyric acid (GABAB) - receptor sensitivity in the CCC-PPT. Together these changes are the primary pathophysiological mechanisms that underlie S-W disturbances in AUD. This review is targeted for both basic neuroscientists in alcohol addiction research and clinicians who are in search of new and more effective therapeutic interventions to treat and/or eliminate sleep disorders associated with AUD.
... It is also known that even seizure series may occur during the withdrawal period (8). On the other hand, acute administration of high doses of ethanol exerts an inhibitory eff ect on central nervous system and increases the threshold of seizure activity (5,19,8). ...
In different experimental epilepsy models, ethanol may have either proconvulsive or anticonvulsive effects on epileptic activity. The aim of the present study was to determine and compare the influence of ethanol on seizure incidence, main parameter of convulsive behavior, in models of generalized epilepsy induced
by lindane and methaphit. Adult male Wistar albino rats were randomly divided into following groups: control, saline – injected, dimetilsulfoxide – treated, ethanol (2 g/kg, i.p.), lindane (8 mg/kg, i.p.), ethanol (2g/kg, i.p.) + lindane (8mg/kg, i.p) in experiment I and metaphit (10 mg/kg, i.p.) and ethanol (2 g/kg, i.p.) + metaphit (10 mg/kg, i.p.) groups in experiment II. Seizure incidence was defined as percentage of animals with seizure out of total number of animals in group. No signs of seizure behavior were observed in control and ethanol groups. Seizure incidence was significantl lower in groups that received ethanol in comparison with those received convulsive drug (either lindane or metaphit). These results indicate prominent anticonvulsive activity of acute ethanol in high dose in models of generalized seizures induced by lindane and metaphit.
... Chronic consumption of ethanol has a damaging effect in various organs and metabolic functions, including liver, kidney, heart, pancreas, and brain (Sun and Sun, 2001;Bezerra Rde et al., 2005). Additionally, it has been shown that both the acute and chronic ethanol intake induce alteration in voltage-gated channels causing behavioral and electrophysiological changes in the brain (Little, 1999). In the last few years, the effect of ethanol in the electrophysiological phenomenon, known as cortical spreading depression (CSD), has been widely assessed (Sonn and Mayevsky, 2001;Bezerra Rde et al., 2005;Abadie-Guedes et al., 2008) as an important model to predict the damaging effects of ethanol in both young and aged brains. ...
Chronic consumption of ethanol has a damaging effect in various organs and metabolic functions, including liver, kidney, heart, pancreas, and brain (Sun and Sun, 2001; Bezerra Rde et al., 2005). Additionally, it has been shown that both the acute and chronic ethanol intake induce alteration in voltage-gated channels causing behavioral and electrophysiological changes in the brain (Little, 1999). In the last few years, the effect of ethanol in the electrophysiological phenomenon, known as cortical spreading depression (CSD), has been widely assessed (Sonn and Mayevsky, 2001; Bezerra Rde et al., 2005; Abadie-Guedes et al., 2008) as an important model to predict the damaging effects of ethanol in both young and aged brains.
... There are a number of studies showing the changes in resting EEG and ERPs due to the direct effects of alcohol ingestion160161162. However, studies on alcohol-induced alterations in EROs are quite rare. ...
Alcohol dependence is characterized as a multi-factorial disorder caused by a complex interaction between genetic and environmental liabilities across development. A variety of neurocognitive deficits/dysfunctions involving impairments in different brain regions and/or neural circuitries have been associated with chronic alcoholism, as well as with a predisposition to develop alcoholism. Several neurobiological and neurobehavioral approaches and methods of analyses have been used to understand the nature of these neurocognitive impairments/deficits in alcoholism. In the present review, we have examined relatively novel methods of analyses of the brain signals that are collectively referred to as event-related oscillations (EROs) and show promise to further our understanding of human brain dynamics while performing various tasks. These new measures of dynamic brain processes have exquisite temporal resolution and allow the study of neural networks underlying responses to sensory and cognitive events, thus providing a closer link to the physiology underlying them. Here, we have reviewed EROs in the study of alcoholism, their usefulness in understanding dynamical brain functions/dysfunctions associated with alcoholism as well as their utility as effective endophenotypes to identify and understand genes associated with both brain oscillations and alcoholism.
... groups with more intense cellular density reduction then E1. Despite the fact that ethanol has many different pharmacological actions [42] the observed biphasic pattern of NEAs potentiation seems also to be dependent on the neuronal damage. The decreased intensity of the NEAs of the groups E2 and E3 when compared to E1 may also be attributed to the more pronounced neuronal loss in the DG layer. ...
Non-synaptic mechanisms are being considered the common factor of brain damage in status epilepticus and alcohol intoxication. The present work reports the influence of the chronic use of ethanol on epileptic processes sustained by non-synaptic mechanisms. Adult male Wistar rats administered with ethanol (1, 2 e 3 g/kg/d) during 28 days were compared with Control. Non-synaptic epileptiform activities (NEAs) were induced by means of the zero-calcium and high-potassium model using hippocampal slices. The observed involvement of the dentate gyrus (DG) on the neurodegeneration promoted by ethanol motivated the monitoring of the electrophysiological activity in this region. The DG regions were analyzed for the presence of NKCC1, KCC2, GFAP and CD11b immunoreactivity and cell density. The treated groups showed extracellular potential measured at the granular layer with increased DC shift and population spikes (PS), which was remarkable for the group E1. The latencies to the NEAs onset were more prominent also for the treated groups, being correlated with the neuronal loss. In line with these findings were the predispositions of the treated slices for neuronal edema after NEAs induction, suggesting that restrict inter-cell space counteracts the neuronal loss and subsists the hyper-synchronism. The significant increase of the expressions of NKCC1 and CD11b for the treated groups confirms the existence of conditions favorable to the observed edematous necrosis. The data suggest that the ethanol consumption promotes changes on the non-synaptic mechanisms modulating the NEAs. For the lower ethanol dosage the neurophysiological changes were more effective suggesting to be due to the less intense neurodegenertation.
... Intressant i samanhanget är att taurin och alkohol tycks verka synergistiskt via samma mekanismer: potentiering av ligandstyrda Cl-kanaler och inhibering av excitatoriska aminosyror och Ca 2+-kanaler [19]. ...
... The deleterious and dose-dependent effects of alcohol on various cognitive processes such as attention, memory, etc. are well known (Little, 1999; Koob and Moal, 2006). The consequences of long-term use of ethanol were explored in most of the studies revealing deficits in different cognitive mechanisms (Bartholow et al., 2003, and others). ...
Objective and hypothesisNonlinear and linear methods of EEG-complexity analysis and autonomic measures were used to characterize processes accompanying performance in a mental arithmetic task challenged by low (“social”) alcohol doses. It was expected that alcohol in such doses will dampen changes of task-related EEG-synchronization in the theta band, and those of heart rate and electrodermal activity (EDA).
... Conclusions about the potential causes are rather speculative, but some groups reported dominant effects of ethanol on the right hemisphere (Levin et al., 1998;Rhodes, Obitz, & Creel, 1975;Seifritz et al., 2000;Wendt, Risberg, Stenberg, Rosén, & Ingvar, 1994). Additionally, neurotransmitters are distributed asymmetrically (Davies, 2003;Little, 1999;Yeh & Kolb, 1997) indicating an asymmetrical susceptibility to ethanol. The examinations of Eidelberg and Galaburda (1984) yielded cytoarchitectonic differences of the parietal lobes toward a right lateralization. ...
... Conclusions about the potential causes are rather speculative, but some groups reported dominant effects of ethanol on the right hemisphere (Levin et al., 1998;Rhodes, Obitz, & Creel, 1975;Seifritz et al., 2000;Wendt, Risberg, Stenberg, Rosén, & Ingvar, 1994). Additionally, neurotransmitters are distributed asymmetrically (Davies, 2003;Little, 1999;Yeh & Kolb, 1997) indicating an asymmetrical susceptibility to ethanol. The examinations of Eidelberg and Galaburda (1984) yielded cytoarchitectonic differences of the parietal lobes toward a right lateralization. ...
... Authors Kamoun, Bougatef, and Nasri are with Enzymatic Engineering and Microbiology Laboratory (LGEM), Engineer National School, BP 1173 Author Boudawara is with Anatomopathology Laboratory, CHU Habib Bourguiba,3029 Sfax,Univ. of Sfax, have speculated for the pathogenesis of alcoholic cardiomyopathy including cardiotoxicity of alcohol, oxidative stress, and accumulation of ethyl fatty acids. Several evidences indicated that oxidative stress might be a factor in ethanol toxicity, determinating a cascade of events in cells, such as lipid peroxidation and nitric oxide (NO) levels, leading to loss of structural and function integrity at the cellular membrane (Little 1999;Cederbaum 2001). Otherwise antioxidants can decrease the adverse effects of reactive species, such as reactive oxygen and nitrogen, on normal physiological functions (Huang and others 2005). ...
The present study was undertaken to examine the protective effects of sardinelle proteins hydrolysate (SPH) obtained from heads and viscera against ethanol toxicity in the heart of adult rats. Twenty-four male rats of Wistar strain, weighing at the beginning of the experiment 250 to 300 g, were used in this study. They were divided into 4 groups: group (C) served as controls, group (Eth) received 30% ethanol solution at 3 g/kg body weight, group (SPH) received only 7.27 mg of SPH/kg body weight, and group (Eth-SPH) received ethanol and sardinelle proteins hydrolysate simultaneously. All treatments were made by gavage during 15 d. Treatment with ethanol revealed a significant elevation of malondialdehyde and protein carbonyl levels in the heart and of aspartate transaminase and alanine transaminase activities in plasma. Nitric oxide levels and the activities of antioxidant enzymes such as superoxide dismutase, catalase, and glutathione peroxidase decreased. Nonenzymatic antioxidant such as reduced glutathione did not significantly change and ascorbic acid was decreased. SPH intake concomitantly with ethanol restored these parameters to near control values. These modifications confirmed histopathological aspects of the heart. The results revealed that SPH could provide protection of the myocardium against ethanol-induced oxidative damages in rats. This may be due to the high antioxidant potential of SPH.
... Since, surrogate data analysis have same linear properties as power spectrum, a statistically significant difference in the ApEn values between the original data and the surrogate data indicates that original data have the nonlinearity in its structure. [10] Previous studies found that acute alcohol administration induced an increased synchronization of the EEGs, theta, alpha, and beta band power increases, slowing of the dominant alpha frequency, decreases of frequencies in theta, fast alpha and beta, an increase in slow alpha in human healthy subjects [11,12,13,14,15]. Linear methodology is usually used to analyze the EEGs in these studies. ...
The aim of this study was to examine the effect of alcohol on cortical information processing estimated by EEG using Approximate
Entropy (ApEn). The EEG was recorded before alcohol consumption as a baseline and 1 hour after alcohol consumption (alcohol
dose: 1.5g/kg) from fourteen healthy males (mean age: 24.14 ± 2.96) during resting state and mental arithmetic task. ApEn
was estimated for the EEG recordings as a measure of complexity, and the surrogate data method was used to test the validity
of the nonlinearity in the EEG. In a resting condition, EEGs one hour after alcohol administration exhibited significantly
lower ApEn in the left frontal (F3), right central and right parietal (C4 and P4), temporal (T4, T5, and T6), and occipital
lobes (O1 and O2). More interestingly, during mental arithmetic tasks, alcohol significantly reduced the ApEn values in the
left frontal (Fp1 and F3), left central (C3), right temporal (T6), and occipital (O1 and O2) regions. These results suggest
that alcohol intake gives rise to reduced cortical complexity, which is possibly associated with cortical and behavioral impairments
during alcohol consumption. These findings also suggest that the ApEn is useful in evaluating the effect of alcohol on the
brain electrical activity.
... 68) The objective effects of ethanol on the central nervous system (CNS) appear at ~5 mM of the blood ethanol level. Those effects are attributed to the modulation of several neurotransmittergated ion channels in CNS neurons 69) and are characterized by the cutoff effect (potency increases with an increasing alkyl chain length of n-alcohol up to a point but then disappears with a further increase in chain length). 70) In our previous study, we examined the direct effects of ethanol on a concentration range (0.1-30 mM) relevant to normal drinking conditions upon fluid secretion by interlobular ducts isolated from guinea-pig pancreas ( Fig. 8A and B). 14 8C and D). ...
HCO3- -rich fluid in the pancreatic juice (2-3 L/day) is secreted by epithelial cells lining the pancreatic duct tree, while digestive enzymes are secreted by acinar cells with a small amount of Cl- -rich fluid. Ductal HCO3- secretion is not only regulated by gastrointestinal hormones and cholinergic nerves but is also influenced by luminal factors: intraductal pressure, Ca2+ concentration, pathological activation of protease and bile reflux. The maximum HCO3- concentration of the juice under secretin stimulation reaches 140-150 mM. Thus pancreatic duct cells secrete HCO3- against a approximately 7-fold concentration gradient. HCO3- secretion critically depends on the activity of CFTR, a cAMP-dependent anion channel localized in the apical membrane of various epithelia. In the proximal part of pancreatic ducts close to acinar cells HCO3 secretion across the apical membrane is largely mediated by SLC26A6 CI- -HCO3- exchanger. In distal ducts where the luminal HCO3- concentration is already high, most of the HCO3- secretion is mediated by HCO3- conductance of CFTR. CFTR is the causative gene for cystic fibrosis. Loss of function due to severe mutations in both alleles causes typical cystic fibrosis characterized by dehydrated, thick, and viscous luminal fluid/mucus in the respiratory and gastrointestinal tract, pancreatic duct, and vas deferens. A compound heterozygote of mutations/polymorphisms (causing a mild dysfunction of CFTR) involves a risk of developing CFTR-related diseases such as chronic pancreatitis. In cystic fibrosis and certain cases of chronic pancreatitis, the pancreatic duct epithelium secretes a small amount of fluid with neutral-acidic pH, which causes an obstruction of the duct lumen by a protein plug or viscous mucus.
... However, an important feature of its pharmacology is a similar action on the GABA-A receptor to anxiolytic drugs such as benzodiazepines and barbiturates and, as a result, it has similar effects to all other classes of anxiolytic drug on hippocampal theta rhythm (Coop et al., 1990; McNaughton et al., 2007). Perhaps the most consistent result in EEG studies with ethanol in humans is an increase in alpha activity (Ilan and Gevins, 2001; Little, 1999). However, a number of studies have shown changes in the theta range at frontal electrode sites. ...
Electrical recordings from the surface of the skull have a wide range of rhythmic components. A major task of analysis of this EEG is to determine their source and functional significance. The hippocampal “theta rhythm” has been extensively studied in rats and its rhythmicity has recently been shown to be functionally significant, per se. Here, we use relevant aspects of the hippocampal literature to provide perspective on one of the most studied human EEG rhythms: frontal-midline theta. We review its electrographic features, localization, prevalence, age distribution, behavioural modulation (particularly in relation to working memory, spatial navigation, episodic memory, internalised attention and meditation), relationship to personality, drug interactions, neurochemical relationships, and coherence with rhythmic activity at other sites. We conclude that FM-theta, like hippocampal theta, appears to play a role in (or at least occur during) processing of memory and emotion. It is correlated with working memory and/or sustained attention; but this does not entail a role in function since clear behavioural correlates of hippocampal theta have been demonstrated that are not sensitive to hippocampal damage. FM-theta is increased by anxiolytic drug action and personality-related reductions in anxiety, whereas hippocampal theta is decreased by anxiolytic drugs. In animals, frontal theta and hippocampal theta can be phase-locked or independent, depending on behavioural state. So, the cognitive functions of FM-theta, and their relationship to hippocampal theta, are unclear and definitive evidence for functional involvement in cognitive or emotional processing is lacking. One possible solution to this problem is analysis of FM-theta in animals—provided homology can be determined. The issues of sporadicity and low incidence of FM-theta also need to be addressed in the future. Changes in functional connectivity, indicated by changes in coherence, are also a largely untapped resource. We suggest that the most hopeful path to assessing the functions of FM-theta will be through the use of drugs, and the variation of their effects depending on baseline levels of FM-theta. Finally, we review some theories of theta function. Despite the apparent richness of the current data, we conclude that it is difficult (and may ultimately be impossible) to formulate a theory that attributes a specific cognitive function to FM-theta. However, the theories share some general computational assumptions and these should be a useful guide to future work and, ultimately, a definite theory of the function or functions of FM-theta.
... However, alcohol does not suppress neural activity indiscriminately . Rather, primary stimulus processing (e.g., as reflected by N1 or P2 components of the ERP) appears to be spared at mild to moderate levels of intoxication, as are ERP responses to stimuli within the focus (as opposed to the periphery) of attention (e.g., P3b vs. P3a; Jääsekeläinen et al. 1996; Little 1999). Furthermore, that alcohol-related reductions in the amplitude of ERN are greater following errors versus correct responses (Easdon et al. 2005; Ridderinkhof et al. 2002) supports the idea that alcohol selectively impairs error detection rather than generally disrupting processing in performance contexts. ...
Alcohol impairs the brain's detection of performance errors as evidenced by attenuated error-related negativity (ERN), an event-related potential (ERP) thought to reflect a brain system that monitors one's behavior. However, it remains unclear whether alcohol impairs performance-monitoring capacity across a broader range of contexts, including those entailing external feedback.
This study sought to determine whether alcohol-related monitoring deficits are specific to internal recognition of errors (reflected by the ERN) or occur also in external cuing contexts. We evaluated the impact of alcohol consumption on the feedback-related negativity (FRN), an ERP thought to engage a similar process as the ERN but elicited by negative performance feedback in the environment.
In an undergraduate sample randomly assigned to drink alcohol (n = 37; average peak BAC = 0.087 g/100 ml, estimated from breath alcohol sampling) or placebo beverages (n = 42), ERP responses to gain and loss feedback were measured during a two-choice gambling task. Time-frequency analysis was used to parse the overlapping theta-FRN and delta-P3 and clarified the effects of alcohol on the measures.
Alcohol intoxication attenuated both the theta-FRN and delta-P3 brain responses to feedback. The theta-FRN attenuation was stronger following loss than gain feedback.
Attenuation of both theta-FRN and delta-P3 components indicates that alcohol pervasively attenuates the brain's response to feedback in this task. That theta-FRN attenuation was stronger following loss trials is consistent with prior ERN findings and suggests that alcohol broadly impairs the brain's recognition of negative performance outcomes across differing contexts.
... L-type voltage-gated calcium channels (LVGCC) are notably interesting, since altered LVGCC function seems to occur during early withdrawal from many abused drugs including alcohol, and thus could represent a common mechanism (for review, see Brooks et al. 2008;Buck and Harris 1991;Little 1999). Chronic alcohol exposure increases LVGCC levels in brain regions such as the hippocampus, with more mixed results in the few studies from the striatum (Lucchi et al. 1985;Woodward and Gonzales 1990). ...
Neuroplastic changes in the CNS are thought to be a fundamental component of learning and memory. While pioneering studies in the hippocampus and cerebellum have detailed many of the basic mechanisms that can lead to alterations in synaptic transmission based on previous activity, only more recently has synaptic plasticity been monitored after behavioral manipulation or drug exposure. In this chapter, we review evidence that drugs of abuse are powerful modulators of synaptic plasticity. Both the dopaminergic neurons of the ventral tegmental area as well medium spiny neurons in nucleus accumbens show enhanced excitatory synaptic strength following passive or active exposure to drugs such as cocaine and alcohol. In the VTA, both the enhancement of excitatory synaptic strength and the acquisition of drug-related behaviors depend on signaling through the N-methyl-D: -aspartate receptors (NMDARs) which are mechanistically thought to lead to increased synaptic insertion of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs). Synaptic insertion of AMPARs by drugs of abuse can be long lasting, depending on the route of administration, number of drug exposures, or whether the drugs are received passively or self-administered.
Alcohol consumption is associated with alterations in memory and learning processes in humans and animals. In this context, research models such as the zebrafish (Danio rerio) arise as key organisms in behavioral and molecular studies that attempt to clarify alterations in the Central Nervous System (CNS), like those related to alcohol use. Accordingly, we used the zebrafish as a model to evaluate the effects of ethanol on the learning and memory process, as well as its relationship with behavior and transcriptional regulation of lrfn2, lrrk2, grin1a, and bdnf genes in the brain. To this end, for the memory and learning evaluation, we conducted the Novel Object Recognition test (NOR); for behavior, the Novel Tank test; and for gene transcription, qPCR, after 2 h, 24 h, and 8 days of ethanol exposure. As a result, we noticed in the NOR that after 8 days of ethanol exposure, the control group spent more time exploring the novel object than when compared to 2 h post-exposure, indicating that naturally zebrafish remember familiar objects. In animals in the Treatment group, however, no object recognition behavior was observed, suggesting that alcohol affected the learning and memory processes of the animals and stimulated an anxiolytic effect in them. Regarding transcriptional regulation, 24 h after alcohol exposure, we found hyper-regulation of bdnf and, after 8 days, a hypo-regulation of lrfn2 and lrrk2. To conclude, we demonstrated that ethanol exposure may have influenced learning ability and memory formation in zebrafish, as well as behavior and regulation of gene transcription. These data are relevant for further understanding the application of zebrafish in research associated with ethanol consumption and behavior.
The neuroimmune system of the brain, which is comprised primarily of astrocytes and microglia, regulates a variety of homeostatic mechanisms that underlie normal brain function. Numerous conditions, including alcohol consumption, can disrupt this regulatory process by altering brain levels of neuroimmune factors. Alcohol and neuroimmune factors, such as proinflammatory cytokines IL-6 and TNF-alpha, act at similar targets in the brain, including excitatory and inhibitory synaptic transmission. Thus, alcohol-induced production of IL-6 and/or TNF-alpha could be important contributing factors to the effects of alcohol on the brain. Recent studies indicate that IL-6 plays a role in alcohol drinking and the effects of alcohol on the brain activity following the cessation of alcohol consumption (post-alcohol period), however information on these topics is limited. Here we used homozygous and heterozygous female and male transgenic mice with increased astrocyte expression of IL-6 to examined further the interactions between alcohol and IL-6 with respect to voluntary alcohol drinking, brain activity during the post-alcohol period, IL-6 signal transduction, and expression of synaptic proteins. Wildtype littermates (WT) served as controls. The transgenic mice model brain neuroimmune status with respect to IL-6 in subjects with a history of persistent alcohol use. Results showed a genotype dependent reduction in voluntary alcohol consumption in the Drinking in the Dark protocol and in frequency-dependent relationships between brain activity in EEG recordings during the post-alcohol period and alcohol consumption. IL-6, TNF-alpha, IL-6 signal transduction partners pSTAT3 and c/EBP beta, and synaptic proteins were shown to play a role in these genotypic effects.
Background: The pharmacodynamic results of diazepam and ethanol administration are similar, in that each can mediate amnestic, sedative-hypnotic effects. Although each of these molecules effectively reduces the activity of central neurons, diazepam does so through modulation of a more specific set of receptor targets (GABAA receptors containing a γ-subunit), while alcohol is less selective in its receptor bioactivity. Our investigation focuses on divergent actions of diazepam and ethanol on the firing patterns of cultured cortical neurons. Method: We used electrophysiological recordings from organotypic slice cultures derived from Sprague-Dawley rat neocortex. We exposed these cultures to either diazepam (15 and 30 µM) or ethanol (30 and 60 mM) and recorded the electrical activity at baseline and experimental conditions. For analysis, we extracted the episodes of spontaneous activity, i.e., cortical up-states. After separation of action potential and local field potential (LFP) activity, we looked at differences in the number of action potentials, in the spectral power of the LFP, as well as in the coupling between action potential and LFP phase. Results: While both substances seem to decrease neocortical action potential firing in a similar fashion, diazepam seems to increase the spectral power of the up-state without impacting the spectral composition, whereas ethanol does not change the spectral power but the oscillatory architecture of the up-state. Further, the action potential to LFP-phase coupling reveals a synchronizing effect of diazepam and a (rather weak) de-synchronizing effect for ethanol. Conclusion: Diazepam and ethanol, induce specific patterns of network depressant actions. Diazepam, via gamma subunit containing GABAA receptors, induces cortical network inhibition and increased synchronicity. Ethanol, via a wider span of molecular targets, also induces cortical network inhibition, but without an increase in synchronicity.
Background: The pharmacodynamic results of diazepam and ethanol administration are similar, in that each can mediate amnestic, sedative-hypnotic effects. Although each of these molecules effectively reduce the activity of central neurons, diazepam does so through modulation of a more specific set of receptor targets (GABAA receptors containing a g-subunit), while alcohol is less selective in its receptor bioactivity. Our investigation focuses on divergent actions of diazepam and ethanol on the firing patterns of cultured cortical neurons. Method: We used electrophysiological recordings from organotypic slice cultures derived from Sprague-Dawley rat neocortex. We exposed these cultures to either diazepam (15 and 30 µM, n = 7) or ethanol (30 and 60 mM, n = 11) and recorded the electrical activity at baseline and experimental conditions. For analysis, we extracted the episodes of spontaneous activity, i.e., cortical up-states. After separation of action potential and local field potential (LFP) activity, we looked at differences in the number of action potentials, in the spectral power of the LFP, as well as in the coupling between action potential and LFP phase. Results: While both substances seem to decrease neocortical action potential firing in a not significantly different (p=0.659, Mann-Whitney U) fashion, diazepam increases the spectral power of the up-state without significantly impacting the spectral composition, whereas ethanol does not significantly change the spectral power but the oscillatory architecture of the up-state as revealed by the Friedman test with Bonferroni correction (p
Background: The pharmacodynamic results of diazepam and ethanol administration are similar, in that each can mediate amnestic, sedative-hypnotic effects. Although each of these molecules effectively reduce the activity of central neurons, diazepam does so through modulation of a more specific set of receptor targets (GABAA receptors containing a g-subunit), while alcohol is less selective in its receptor bioactivity. Our investigation focuses on divergent actions of diazepam and ethanol on the firing patterns of cultured cortical neurons. Method: We used electrophysiological recordings from organotypic slice cultures derived from Sprague-Dawley rat neocortex. We exposed these cultures to either diazepam (15 and 30 µM, n = 7) or ethanol (30 and 60 mM, n = 11) and recorded the electrical activity at baseline and experimental conditions. For analysis, we extracted the episodes of spontaneous activity, i.e., cortical up-states. After separation of action potential and local field potential (LFP) activity, we looked at differences in the number of action potentials, in the spectral power of the LFP, as well as in the coupling between action potential and LFP phase. Results: While both substances seem to decrease neocortical action potential firing in a not significantly different (p=0.659, Mann-Whitney U) fashion, diazepam increases the spectral power of the up-state without significantly impacting the spectral composition, whereas ethanol does not significantly change the spectral power but the oscillatory architecture of the up-state as revealed by the Friedman test with Bonferroni correction (p
Accumulating evidence from preclinical and clinical studies has implicated a role for the cytokine IL-6 in a variety of CNS diseases including anxiety-like and depressive-like behaviors, as well as alcohol use disorder. Here we use homozygous and heterozygous transgenic mice expressing elevated levels of IL-6 in the CNS due to increased astrocyte expression and non-transgenic littermates to examine a role for astrocyte-produced IL-6 in emotionality (response to novelty, anxiety-like, and depressive-like behaviors). Our results from homozygous IL-6 mice in a variety of behavioral tests (light/dark transfer, open field, digging, tail suspension, and forced swim tests) support a role for IL-6 in stress-coping behaviors. Ex vivo electrophysiological studies of neuronal excitability and inhibitory GABAergic synaptic transmission in the central nucleus of the amygdala (CeA) of the homozygous transgenic mice revealed increased inhibitory GABAergic signaling and increased excitability of CeA neurons, suggesting a role for astrocyte produced IL-6 in the amygdala in exploratory drive and depressive-like behavior. Furthermore, studies in the hippocampus of activation/expression of proteins associated with IL-6 signal transduction and inhibitory GABAergic mechanisms support a role for astrocyte produced IL-6 in depressive-like behaviors. Our studies indicate a complex and dose-dependent relationship between IL-6 and behavior and implicate IL-6 induced neuroadaptive changes in neuronal excitability and the inhibitory GABAergic system as important contributors to altered behavior associated with IL-6 expression in the CNS.
Interleukin-6 (IL-6) is an important neuroimmune factor that is increased in the brain by alcohol exposure/withdrawal and is thought to play a role in the actions of alcohol on the brain. To gain insight into IL-6/alcohol/withdrawal interactions and how these interactions affect the brain, we are studying the effects of chronic binge alcohol exposure on transgenic mice that express elevated levels of IL-6 in the brain due to increased astrocyte expression (IL-6 tg) and their non-transgenic (non-tg) littermate controls. IL-6/alcohol/withdrawal interactions were identified by genotypic differences in spontaneous brain activity in electroencephalogram (EEG) recordings from the mice, and by Western blot analysis of protein activation or expression in hippocampus obtained from the mice after the final alcohol withdrawal period. Results from EEG studies showed frequency dependent genotypic differences in brain activity during withdrawal. For EEG frequencies that were affected by alcohol exposure/withdrawal in both genotypes, the nature of the effect was similar, but differed across withdrawal cycles. Differences between IL-6 tg and non-tg mice were also observed in Western blot studies of the activated form of STAT3 (phosphoSTAT3), a signal transduction partner of IL-6, and subunits of GABAA receptors (GABAAR). Regression analysis revealed that pSTAT3 played a more prominent role during withdrawal in the IL-6 tg mice than in the non-tg mice, and that the role of GABAAR alpha-5 and GABAAR alpha-1 in brain activity varied across genotype and withdrawal. Taken together, our results suggest that IL-6 can significantly impact mechanisms involved in alcohol withdrawal.
CNS actions of the chemokine CCL2 are thought to play a role in a variety of conditions that can have detrimental consequences to CNS function, including alcohol use disorders. We used transgenic mice that express elevated levels of CCL2 in the CNS (CCL2-tg) and their non-transgenic (non-tg) littermate control mice to investigate long-term consequences of CCL2/alcohol/withdrawal interactions on hippocampal synaptic function, including excitatory synaptic transmission, somatic excitability, and synaptic plasticity. Two alcohol exposure paradigms were tested, a two-bottle choice alcohol (ethanol) drinking protocol (2BC drinking) and a chronic intermittent alcohol (ethanol) (CIE/2BC) protocol. Electrophysiological measurements of hippocampal function were made ex vivo, starting ∼0.6 months after termination of alcohol exposure. Both alcohol exposure/withdrawal paradigms resulted in CCL2-dependent interactions that altered the effects of alcohol on synaptic function. The synaptic alterations differed for the two alcohol exposure paradigms. The 2BC drinking/withdrawal treatment had no apparent long-term consequences on synaptic responses and long-term potentiation (LTP) in hippocampal slices from non-tg mice, whereas synaptic transmission was reduced but LTP was enhanced in hippocampal slices from CCL2-tg mice. In contrast, the CIE/2BC/withdrawal treatment enhanced synaptic transmission but reduced LTP in the non-tg hippocampus, whereas there were no apparent long-term consequences to synaptic transmission and LTP in hippocampus from CCL2-tg mice, although somatic excitability was enhanced. These results support the idea that alcohol-induced CCL2 production can modulate the effects of alcohol exposure/withdrawal on synaptic function and indicate that CCL2/alcohol interactions can vary depending on the alcohol exposure/withdrawal protocol used.
Ethanol, or ethyl alcohol, is a central nervous system depressant. Although it has no unique medicinal value, it is regularly consumed for recreational purposes. Ethanol intake is often referred to in terms of units, with 1 unit being equal to 8 grams of ethanol, the amount contained in 1/2 pint of normal strength beer, 1 standard glass of wine, or 1 measure of spirits. Although ethanol depresses central nervous system function, causing sedation, hypnosis, and, if consumed in sufficient quantities, coma and death, the initial effects, particularly at lower doses, are often perceived as stimulation due to suppression of inhibitory systems. In high doses, ethanol causes "blackouts"; after which, the drinker is unable to recollect memory or behavior during the period of intoxication .... .
Alcohol is the most commonly used and abused recreational drug, and one effect of ethanol administration, regardless of whether it is acute or chronic, is the disruption of learning and memory. Although recent studies have demonstrated that ethanol does not produce global deficits but, rather, acts on specific substrates to alter neural function, our understanding of the effects of ethanol on cognitive processes remains incomplete. The studies discussed herein offer support for the specificity of the effects of ethanol on learning-related processes and examine how these effects vary with both the task and the phase of ethanol administration examined. Acute ethanol impairs emotional learning as measured by standard contextual and cued fear conditioning, as well as trace fear conditioning and passive avoidance. However, the effects of acute ethanol on these tasks are influenced by multiple factors, such as genetics and age. Furthermore, as ethanol administration transitions into chronic and withdrawal from chronic ethanol, the pattern of impairments in emotional learning changes. This suggests that acute, chronic, and withdrawal from chronic ethanol differentially alter behavior and therefore may also differentially alter neuronal function. Thus, the current review compares and contrasts the effects of acute, chronic, and withdrawal from chronic ethanol within fear conditioning and passive avoidance tasks, and across these two models of aversive/emotional learning.
In vivo brain imaging enables the systematic examination of trait and state variables that contribute to the etiology of human diseases. This review highlights the use of in vivo imaging in nonhuman primate models of drug abuse. In efforts to translate findings from laboratory animals to humans, monkey models offer considerable advantages over those that use rodents and other species because of their neurobiological similarity to humans and their longer life span, which makes it possible to study individual subjects over several years. This article provides a brief overview of positron emission tomography (PET), magnetic resonance imaging (MRI)-based techniques, and encephalographic approaches, with a focus on methodological issues that investigators new to the field should consider. We discuss PET imaging studies involving the dopamine (DA) system, with a special emphasis on DA D2 receptors, and describe experimental approaches through which PET imaging data can provide information about the neuropharmacological and neurochemical actions of drugs that modify behavior. We also consider the use of imaging to understand the impact and interactions of genetic predispositions and environmental and physiological modulators on disease states. For MRI-based and encephalographic studies, we describe approaches that can provide new information about brain function. Although much work remains to be done to adapt and apply these techniques for routine use in nonhuman primates, there has been much progress. These techniques will provide the foundation for future studies aimed at developing behavioral and pharmacological treatments for many human diseases.
The reward systems are important for rewards, natural and artificial. An important part of these systems is the mesolimbic dopamine system, consisting of a dopamine projection from the ventral tegmental area to nucleus accumbens. There is an underlying disruption in the reward systems in individuals with alcohol dependence. Elucidation of the neurochemical mechanisms involved in the ability of alcohol to activate the mesolimbic dopamine system could identify novel targets for the treatment of alcohol dependence. The role of dopamine, for example, by using the dopamine stabilizer (-)-OSU6162, in alcohol dependence will be revised. Data showing that local perfusion of alcohol into reward nodes activates the mesolimbic dopamine system will be reviewed. The effects of alcohol on ligand-gated ion channels will be introduced. Finally, the findings demonstrating that gut-brain peptides, such as ghrelin and glucagon-like peptide-1, are important for alcohol-mediated will be presented.
Acute pancreatitis is a sudden, severe inflammation of the pancreas which may eventually lead to life-threatening complications associated with digestive necrosis of the gland. Premature, intracellular activation of zymogens is believed to be responsible for the onset of acute pancreatitis; however, the underlying mechanisms remain unidentified. Alcohol is one of the most common risk factors in the development of this condition and may promote its deleterious effects by directly sensitizing the pancreatic acini to CCK, an important gastrointestinal peptide hormone and a digestive enzyme regulator which physiologically activates Ca2+ channels, thus serving an integral role in the physiological regulation of digestive enzyme secretion by pancreatic acinar cells. Nicotine exposure presents an accessory agonist and predisposing factor which may render the pancreas more susceptible to the injurious effects of alcohol-induced gland deficiency. It is important to evaluate the possible cumulative effect of these two high-risk factors in the pathophysiology of acute pancreatitis. The present study addresses the modulatory effects of ethanol and/or nicotine on CCK-evoked Ca2+ alterations and premature intracellular trypsin activation in murine pancreatic acinar cells. Our results indicate that alterations in Ca2+ signaling are often associated with pH modifications and may occasionally complement the conversion of trypsinogen to active trypsin in a time- and concentration dependent manner. We found corroborative evidence that ethanol affects cell signaling and sensitizes cells to the effects of CCK stimulation. Moreover, we found that the initiation of premature trypsin activity does not always succeed changes in [Ca2+]i. We also found evidence to support one existing pathophysiological theory which states that changes in [Ca2+]i are not a necessary indicator of premature trypsin activation. This initiating mechanism pathway may serve to complicate the development of therapeutic treatment and would suggest that other intrinsic factors may play a role in premature intracellular trypsin activation. These results not only indicate that CCK, ethanol and/or nicotine can trigger Ca2+ and pH responses, which may lead to autoactivation of digestive enzymes, but more importantly, may provide further evidence that Ca2+ is not the only initiating indicator of acute pancreatitis. Understanding the underlying cellular mechanism(s) by which ethanol and nicotine modulate pancreatic acinar cell activity and lead to premature intracellular activation of zymogens is paramount in design considerations which would identify pharmaceuticals effective in preventative and therapeutic treatment for acute pancreatitis.
In vivo studies in our laboratory have shown that the function of hippocampal neurons is altered by both acute and chronic ethanol treatment, as is the sensitivity of these neurons to cholinergic agonists. Recently, we have begun to use substrateembedded multi-electrode arrays (Med64, Panasonic) to investigate hippocampal neuronal network activity. Recordings of neuronal activity obtained through the use of multi-electrode arrays (MEAs) provide information about regional variations in treatment effects and allow examination of neuronal circuit activity. Because drug actions in the CNS may depend upon alterations in the function of complex neuronal networks, MEAs may allow evaluation of effects on emergent properties that may only be observed by monitoring network activity (Faingold 2004). The long-term goal of the following research is to develop an understanding of the neuronal mechanisms that mediate the actions of ethanol in the central nervous system and the effects of withdrawal from a period of chronic ethanol treatment, with the aim of developing treatments for those suffering from this addiction. In particular, these studies examine the effects of ethanol on an identified population of neurons within the hippocampus using Med64 arrays for the evaluation of neuronal function. The rationale for such an investigation is based upon previous research that has suggested that ethanol alters the function and morphology of hippocampal cholinergic systems and upon studies that have implicated the hippocampus in many of the behavioral and physiological responses to acute and chronic ethanol. Many of the effects of ethanol on behavior are similar to those resulting from experimental manipulations of hippocampal function (Devenport et al., 1981; Hughes, 1982; Arendt et al., 1989; Devenport and Hale, 1989), including impairments in operant responding, attentional deficits, and deficits in spatial memory. Chronic ethanol treatment can result in prominent morphological changes in the hippocampus of rats and humans, and these changes are correlated with a variety of deficits in cognitive functioning (Tarter, 1975; Walker et al., 1981; Arendt et al., 1983). Heavy use of alcohol is associated with the development of physical dependence, and withdrawal from chronic alcohol exposure results in a syndrome of physiological and psychological symptoms (Victor, 1953; Isbell et al., 1955;
A successful therapy requires an understanding and investigation of the aetiology of a disease. Psychiatric diseases represent a special challenge, because environmental factors may play a crucial role in their development as well as possible physiological and genetic causes. Therefore, epigenetics has established itself to be a branch of research that studies the effect of environmental factors on the development of psychiatric diseases, leading to promising new approaches for diagnosis and therapy.
© Georg Thieme Verlag KG Stuttgart · New York.
Ethanol withdrawal syndrome is characterized by somatic and behavioral symptoms, including increased anxiety and anhedonia. In animal models, however, there are many studies on the anxiogenic effects occurring during the first 24h after ethanol withdrawal, while anhedonia has been overlooked. Recently, we have found that amphetamine withdrawal reduced novelty seeking and enhanced environmental habituation in mice, two motivation-related behaviors. We now investigate the effects of withdrawal from ethanol, a drug of abuse with a different pharmacological profile, on these two motivation-related behaviors. Swiss male mice (3months old) were treated with 1.8g/kg ethanol for 21 consecutive days in their home cages. Seven days after ethanol withdrawal, mice were tested in a free-choice novelty apparatus containing one familiar and one novel compartment. Novelty-seeking behavior was assessed by comparing time spent in the novel compartment versus the familiar compartment, whereas environmental habituation was concomitantly evaluated by the time-response curve of total locomotion (novel+familiar). Novelty seeking was decreased and environmental habituation was enhanced during ethanol withdrawal. These anhedonic responses were not associated with concurrent changes in the anxiety-like behavior of mice (as confirmed in the elevated plus-maze test). We propose that the concomitant evaluation of novelty-seeking behavior and environmental habituation can be useful to study the behavioral consequences not only of amphetamine withdrawal but also of ethanol withdrawal. Furthermore, the present data support recent clinical findings that suggest the occurrence of protracted anhedonia well beyond the limited period immediately following the abrupt cessation of ethanol intake.
Sleep laboratory investigations constitute a unique noninvasive tool to analyze brain functioning, Polysomnographic recordings, even in the very early phase of development in humans, are mandatory in a developmental plan of a new sleep-acting compound. Sleep is also an interesting tool for the development of other drugs acting on the central nervous system (CNS), Indeed, changes in sleep electroencephalographic (EEG) characteristics are a very sensitive indication of the objective central effects of psychoactive drugs, and these changes are specific to the way the drug acts on the brain neurotransmitter systems. Moreover, new compounds can be compared with reference drugs in terms of the sleep EEG profile they induce. For instance, cognitive enhancers involving cholinergic mechanism have been consistently demonstrated to increase rapid eye movement (REM) sleep pressure, and studying drug-induced slow wave sleep (SWS) alteration is a particularly useful tool for the development of CNS compounds acting at the 5-HT(2A/C) receptor, such as most atypical antipsychotics and some antidepressant drugs. The sleep EEG profile of antidepressants, and particularly their effects on REM sleep, are specific to their ability to enhance noradrenergic or serotonergic transmission, it is suggested that the effects of noradrenergic versus serotonergic reuptake inhibition could be disentangled using specific monoamine depletion tests and by studying drug effects on sleep microsiructure.
The effect of a moderate dose of ethanol (0.55 g/kg of body weight), administered 6 hours before scheduled bedtime, on performance, nocturnal sleep, and the sleep electroencephalogram (EEG) was investigated in 10 healthy, middle-aged men (mean age: 61.6 +/- 0.9 years). By the beginning of the sleep episode, breath-ethanol concentrations had declined to zero in all subjects. Compared with the control condition (mineral water), sleep was perceived as more superficial. Sleep efficiency, total sleep time, stage I, and rapid eye movement (REM) sleep were reduced. In the second half of the sleep episode, wakefulness exhibited a twofold increase. EEG power density in low delta frequencies was enhanced in non-REM sleep (1.25-2.5 Hz) and REM sleep (1.25-1.5 Hz). In slow wave sleep (i.e., stages 3 + 4), power density was increased not only in the low-frequency range (1.25-1.5, 2.25-4.0, 4.75-5.0 Hz) but also within the alpha. (8.25-9.0 Hz) and sigma (12.25-13.0 Hz) band. The data demonstrate that late-afternoon ethanol intake in middle-aged men disrupts sleep consolidation, affects the sleep stage distribution, and alters the sleep EEG.
Background:
In 1979 through 1980, electroencephalographic (EEG) responses to an alcohol challenge in 19-year-old sons of alcoholics as well as in sons of nonalcoholic control subjects were examined. The familial risk status of the subjects and greater EEG sensitivity to alcohol were hypothesized to predict the development of alcoholism 10 years later.
Methods:
In 1990 through 1992, diagnostic interviews were completed to ascertain alcohol and other substance use disorders in these subjects and to update their family history.
Results:
Updated family history of alcoholism predicted the development of substance dependence. Density of alcoholic relatives (the number of alcoholic relatives divided by the number of known relatives) was positively related to the severity of alcohol use disorders in the probands. Contrary to expectation, a greater EEG response at age 19 years was not related to the later development of alcohol dependence. Instead, the opposite was observed: a smaller EEG alpha frequency response to alcohol at age 19 years was related to the development of alcohol dependence and high quantity and frequency of alcohol consumption 10 years later.
Conclusions:
Lower EEG response to a small dose of alcohol may be associated with the later development of alcohol dependence. This result is based on a small number of subjects and should be interpreted with caution. Although this result is opposite to our 1980 hypothesis, it is consistent with much of the recent literature.
The P300 component of the event-related potential (ERP) and reaction time (RT) were recorded during a simulated driving task using an oddball paradigm. ERPs and RTs were recorded from heavy social drinkers (n = 11) and low social drinkers (n = 11). A pharmacological challenge (lorazepam-ATIVAN) was administered to both groups in a double-blind procedure. In both groups, P300 amplitude was reduced and RT was increased by the presence of lorazepam; however, heavy social drinkers had longer latency P300 than low social drinkers regardless of the drug condition. The P300 amplitude results are consistent with reduced information processing being induced by lorazepam, or with reduced effectiveness of the eliciting stimuli. On the other hand, the P300 latency results suggest that P300 latency may reflect deficits in information processing induced by alcohol abuse or may have preceded the alcohol abuse. The P300 latency results are consistent with heavy social drinkers occupying an early point on the hypothesized continuum of alcohol-related brain damage.
This year marks the 90th anniversary of the publication of Hans Horst Meyer's classic paper in which he proposed that the ability of a substance to produce narcosis or anesthesia is governed by its partition coefficient. In this article, Robert Lipnick describes the experiments carried out by Meyer and his colleagues which disproved the earlier theories that potency was determined by the presence of particular functional groups or their metabolites or by water or fat solubility, and which led to the formulation of the lipoid theory of narcosis.
The role of magnesium ions in the inhibitory effect of ethanol on NMDA receptor-mediated population synaptic potentials (pEPSPs) in area CA1 of the hippocampus of the adult rat, was studied. The excitatory amino acid (non-NMDA) receptor antagonist, DNQX and the GABAA channel antagonist, picrotoxin, were used to pharmacologically isolate NMDA-mediated pEPSPs. In the presence of a physiological concentration of magnesium (1.0 mM), ethanol (25–100 mM) inhibited NMDA-mediated pEPSPs, with an apparent EC50 of approximately 50 mM. The ability of ethanol to inhibit NMDA-mediated pEPSPs was reduced when the slices were incubated in the absence of magnesium. Concentrations of ethanol, in the range of 50–200 mM (apparent EC50 100 mM), were required to inhibit NMDA-mediated pEPSPs, in the absence of added magnesium. Combination studies of these two antagonists indicated that the sensitivity of NMDA-mediated pEPSPs to one antagonist was not altered by the presence of the other. This finding suggests that the affinity of each antagonist binding site is not affected by the presence of the other antagonist. In the case of ethanol, its low maximum antagonist efficacy may require larger concentrations of ethanol to inhibit NMDA-mediated pEPSPs, in the absence of other non-competitive antagonists such as magnesium.
Physiological, behavioral, and biochemical evidence demonstrating the excitatory and depressant effects of ethanol in man and experimental animals is reviewed. An excitatory action is noted on exposure of an organism to low doses of ethanol. Thus stimulatory effects of ethanol on motor activity, various behaviors, EEG activation, and gastric acid secretion are well documented. A stimulatory effect of ethanol is also noted as a delayed response (after 7–18 hr) with large doses of ethanol. Examples here include seizure susceptibility, some neurotransmitter mechanisms (norepinephrine, acetylcholine), and sensitivity to pain. It is likely that differences in dosage and of the time of observation after ethanol treatment have contributed to some extent to the variability of results reported in the literature. Some implications and possible mechanisms for the biphasic actions of ethanol are discussed.
The key signal transduction enzyme protein kinase C (PKC) contains a hydrophobic binding site for alcohols and anesthetics
(Slater, S. J., Cox, K. J. A., Lombardi, J. V., Ho, C., Kelly, M. B., Rubin, E., and Stubbs, C. D. (1993) Nature 364, 82-84). In this study, we show that interaction of n-alkanols and general anesthetics with PKCα results in dramatically different effects on membrane-associated compared with
lipid-independent enzyme activity. Furthermore, the effects on membrane-associated PKCα differ markedly depending on whether
activity is induced by diacylglycerol or phorbol ester and also on n-alkanol chain length. PKCα contains two distinct phorbol ester binding regions of low and high affinity for the activator,
respectively (Slater, S. J., Ho, C., Kelly, M. B., Larkin, J. D., Taddeo, F. J., Yeager, M. D., and Stubbs, C. D. (1996) J. Biol. Chem. 271, 4627-4631). Short chain n-alkanols competed for low affinity phorbol ester binding to the enzyme, resulting in reduced enzyme activity, whereas high
affinity phorbol ester binding was unaffected. Long chain n-alkanols not only competed for low affinity phorbol ester binding but also enhanced high affinity phorbol ester binding.
Furthermore, long chain n-alkanols enhanced phorbol ester induced PKCα activity. This effect of long chain n-alkanols was similar to that of diacylglycerol, although the n-alkanols alone were weak activators of the enzyme. The cellular effects of n-alkanols and general anesthetics on PKC-mediated processes will therefore depend in a complex manner on the locality of the
enzyme (e.g. cytoskeletal or membrane-associated) and activator type, apart from any isoform-specific differences. Furthermore, effects
mediated by interaction with the region on the enzyme possessing low affinity for phorbol esters represent a novel mechanism
for the regulation of PKC activity.
Human CNS sodium channels provide a protein model system for our continuing study of anaesthetic drug interactions at the molecular level. The impact of ethanol, an alcohol with general anaesthetic properties, on sodium channel function and their significance for the overall anaesthetic effect was quantified.Sodium channels from human brain cortex tissue were incorporated into voltage-clamped planar lipid bilayers in the presence of batrachotoxin and studied at various ethanol concentrations (0.085 – 0.84 M). Ethanol caused a concentration-dependent and membrane potential independent reduction of the single channel amplitude (major effect) and of the fractional channel open-time (minor effect) with no effect on channel steady-state activation. Severe membrane perturbing effects at the highest ethanol levels terminated the measurements. The weighted computer fit of the concentration-response curve with an estimate of a maximal conductance block of 40% yielded an EC50 of 1.03 M. The EC50 for the 100% maximal theoretical block was calculated to be 3.3 M.These effects occurred at levels far beyond toxic human serum levels (0.1 M; 0.5%). Thus, the human CNS sodium channel is not a main target site for the clinical effects of ethanol and other, more sensitive central receptors are involved in ethanol's mechanism of action. © 1997 John Wiley & Sons, Ltd.
The effects of chronic alcohol exposure during development on the responses evoked by glutamate and the selective excitatory amino acid receptor agonists quisqualate (Quis) and kainate were studied in cultured cerebellar Purkinje neurons. The cultures were treated with 22 mM or 44 mM ethanol continuously for one or two weeks during the main period of morphological and physiological development. Extracellualr recordings used for most studies characterized the responses to all 3 agonists as initial increase in simple spike firing, usually including a period of burst activity, followed by reduced activity or total inhibition, then return to control firing pattern. Analysis of these responses and background spontaneous activity showed several significant differences between control and ethanol treated Purkinje neurons. Background spontaneous firing, agonist evoked firing, the initial period of activity of the response to Quis, and the inhibitory period of the response to glutamate were all significantly reduced in the chronically treated neurons; the inhibitory period of the response to kainate was significantly increased. In contrast to the effects of chronic ethanol exposure, acutely administered ethanol significantly increased background spontanenous firing and the inhibitory period of the response to Quis. Thus, administering both acute and chronic ethanol altered the responses evoked by excitatory amino acids in the developing Purkinje neurons. The effect of chronic ethanol exposure on some response components was similar for all agonists tested and may be linked to changes in intrinsic membrane properties. However, alterations in the inhibitory component of the agonist responses were agonist specific, indicating that receptor-linked actions of ethanol were involved. The differing sensitivity of the Quis and kainate responses to ethanol may be due to a contribution of the metabotropic Quis receptor to the responses evoked by Quis.
This study assessed the relationship between neuropsychological and electrophysiological functioning and four alcohol-related measures: the Michigan Alcoholism Screening Test (MAST), the age at which the first drink was taken, frequency of drinking to “get high”, and frequency of drinking to “get drunk”. Ninety-one young adult men with no history of alcohol dependence were recruited. Subjects completed a variety of alcohol-related scales and a battery of neuropsychological tests. Resting EEG activity was also recorded. Stepwise regression analysis found that neuropsychological tests commonly regarded as measuring frontal and/or temporal neocortex functioning predicted the age at which subjects took their first drink and their scores on the MAST. Tests of frontal functioning, along with tests of memory, also predicted the frequency with which subjects reported drinking to “get drunk”. Tests of memory also predicted the frequency at which subjects drank to “get high”. On two of the alcohol measures, including age at which the first drink was taken and frequency of drinking to “get high”, left-frontal slow alpha EEG activity was a significant predictor. These results suggest that markers of anterior brain functioning/dysfunctioning are associated with self-reports of alcohol-related behaviors, and that disturbances in the integrity of the anterior neocortex may be a risk factor in the development of alcohol-related behaviors.
The NMDA receptor/channel has been shown to be inhibited by ethanol in the clinically relevant range 25–100 mM. We studied heteromeric assemblies (NR1b/NR2) of the NMDA receptor, expressed in oocytes, to address three questions regarding this inhibition, and discovered the following: (1) The inhibition was nearly equivalent when ethanol was coapplied with the agonist, and when ethanol was introduced after steady-state current was established, suggesting that ethanol does not act by interfering with the activation process of the NMDA receptor. (2) The degree of inhibition was controlled by the NR2 subunit, with both NR2A and NR2B significantly more sensitive to ethanol than NR2C and NR2D. (3) Manipulation of the NMDA receptor with a number of agents that normally modulate it did not alter the degree of inhibition produced by ethanol. The presence of Mg2+ (3 and 12.5 µM), Zn2+ (1 and 10 µM), or the glycine antagonist 7-chlorokynurenic acid (1.25 or 5 µM), did not alter the ethanol sensitivity of heteromeric (NR1b/NR2A, NR1b/NR2B, NR1b/NR2C) NMDA receptors. Redox modulation of the NMDA receptor by dithiothreitol (2 mM) or 5,5′-dithiobis(2-nitrobenzoic acid) (1 mM) also did not alter the degree to which ethanol inhibits NMDA receptors. Taken together, these results indicate that the ethanol sensitivity of native NMDA receptors, which likely exist in heteromeric form, results from actions at a site different from those of known modulators of the receptor.
The time course of visually evoked responses (VER's) recorded at the cortex were studied in rats during addiction and withdrawal. Data for peak-to-peak amplitudes, latencies and photic afterdischarges (PhAD's) were collected on the fifth, eleventh and seventeenth days of addiction, on the day of withdrawal and on the first, second and seventh days postwithdrawal. For the ethanol group during the addiction phase, amplitude and PhAD measures were depressed at the first recording session (day 5) and remained so throughout the addiction phase. Latency data, however, revealed a progressive increase to major peaks throughout the addiction phase that reached significance for P2 on day 17. VER amplitudes and PhAD excursion values were depressed and latencies increased, relative to controls, at the end of the addiction phase. On the day of withdrawal (day 0), P3-N3 amplitudes and PhAD excursion values remained significantly depressed relative to controls. Amplitude measures for other individual components had returned to control levels but had not yet exhibited rebound (neural hyperexcitability). Latency measures remained unchanged during day 0 testing and demonstrated a recovery to control levels by day 1 or 2 postwithdrawal. On day 1 postwithdrawal, amplitude and PhAD measures reflected neural hyperexcitability that remained throughout the seventh day although the decline in amplitudes between the second and seventh day of postwithdrawal testing suggested a trend toward neural recovery. The time course of VER amplitudes and latencies and the PhAD during addiction and withdrawal are discussed.
Chronic bipolar electrodes were implanted in forebrain structures of mice including dorsal hippocampus, dorsal-frontal cortex, dorsal-lateral thalamus and septum. Two weeks after surgery, the mice were reduced to 85-90% of free-feeding weight, and physical dependence on alcohol was established by maintaining the mice on an alcohol-containing liquid diet for 6 days. A control group was pair-fed an identical liquid diet except sucrose was substituted isocalorically for alcohol. Following 6 days of consumption alcohol was withdrawn and the development of both EEG and behavioral sequelae of withdrawal was monitored for 6-8h. Only mice withdrawn from alcohol exhibited behavioral signs of withdrawal which included hyperactivity, severe tremor, ataxia, sudden sprawling movements, and clonic-tonic convulsions. No abnormal behavior and no abnormal EEG activity resulted from the withdrawal of the sucrose control diet. EEG recordings during withdrawal from alcohol, however, indicated a progressive development of widespread neural epileptiform activity beginning with EEG slowing and increased amplitudes, followed by single spike events and often leading to sustained epileptic seizure discharge. Similar abnormal EEG patterns were observed throughout the forebrain including cortex, thalamus, hippocampus and septal area. The development of abnormal EEG activity was more severe during the second alcohol withdrawal period following 4 days of alcohol exposure than during the first alcohol withdrawal period following 6 days of alcohol exposure. It is hypothesized that the widespread forebrain epileptiform activity originates in, or is organized from, a central pacemaking region such as midline thalamus or reticular formation.
1. P300 event-related electroencephalographic potentials were recorded from 79 young adult males, cross-classified with respect to the presence/absence of a family history of alcoholism (FHA) and the presence/absence of a personal history of antisocial personality (ASP) disorder. P300s were elicited using visual and auditory oddball tasks. Each oddball task was repeated with a tracking task added as a distractor.2. In general, distraction increased the latencies and reduced the amplitudes of P300s elicited by the oddball stimuli. The P300 latency increase occurred only in low risk ASP- and FHA- groups. There was no adaptive increase in P300 latency in the higher risk ASP+ and FHA+ groups.3. Group differences in P300 were restricted to visual tasks. No interpretable group differences in P300 latency or amplitude were found during the auditory tasks.
Acute ethanol ingestion impairs memory in humans at concentrations associated with mild intoxication. A possible neurophysiological correlate of this effect is the suppression by ethanol of long-term potentiation (LTP), a persistent increase in synaptic efficiency which has been proposed as a substrate for memory. However, in previous studies ethanol has been shown to impair LTP only at very high concentrations, near the lethal level in humans. We now report that ethanol can significantly reduce LTP in rat hippocampus at concentrations as low as 5 mM, a level attainable following ingestion of a single alcoholic drink. We also demonstrate that the potency of ethanol in depressing LTP correlates well with its potency in inhibiting the response to N-methyl-d-aspartate, an agonist at the glutamate receptors implicated in LTP induction. The influence of low ethanol concentrations on LTP may contribute to the memory impairment associated with its used in humans.
Recent studies have shown that large genetic differences exist in the extent to which animals will work to obtain drugs abused by humans. These findings suggest that there may be human populations with elevated risk for developing drug addictions. Frank George and Steven Goldberg describe the behavioral genetic and self-administration methods used in these studies of addiction processes, review the findings obtained in genetic studies of drug addiction, and present hypotheses that can be explored in the attempt to better understand and prevent drug addiction.
It has been suggested that ethanol may interact with the central nicotinic acetylcholine receptor, thus providing a basis for the often observed high consumption of both ethanol and nicotine. In the present in vivo microdialysis study, ethanol (2.5 g/kg) moderately increased dopamine overflow in the rat nucleus accumbens. The central nicotinic acetylcholine receptor antagonist mecamylamine totally counteracted this effect in a dose (1.0 mg/kg) that did not alter dopamine overflow per se. Ethanol also increased the overflow of dihydroxyphenylacetic acid and homovanillic acid, but this effect was not altered by mecamylamine (1.0 mg/kg). Furthermore, the ethanol-induced enhancement of 3,4-dihydroxyphenylalanine accumulation in the mesolimbic dopamine terminal area after NSD 1015 (an inhibitor of l-aromatic amino acid decarboxylase) was completely antagonized by mecamylamine in doses (3.0 and 6.0 mg/kg) that exerted no effects per se. Neither ethanol nor mecamylamine changed the catecholamine synthesis rate in the striatum or the cerebral cortex. These results provide further evidence that ethanol-induced activation of the mesolimbic dopamine system (increased dopamine synthesis and release) may be mediated via stimulation of central nicotinic acetylcholine receptors. It is suggested that antagonists of central nicotinic acetylcholine receptors may be useful in the treatment of alcoholism.
Previous electrophysiological studies suggested that GABAA receptors in rat hippocampal neurons might be less sensitive to ethanol than mouse neurons. Therefore, we examined the effects of ethanol (0.5–850 mM) in cultured mouse (C57BL/6) and rat (Sprague-Dawley) neurons. In 35% of the mouse neurons, the Cl− current was potentiated by ethanol starting at 0.5 mM. In all of the rat neurons examined, on the other hand, the current was potentiated by concentrations starting at 200 mM. We also studied the effects of GABA and other GABAergic ligands. GABAA receptors in rat and mouse neurons displayed EC50s for GABA of 9 ± 0.3 and 17 ± 0.8 μM, respectively and ethanol did not significantly change these values. The EC50 for diazepam was 92 ± 3 and 120 ± 8 nM in rat and mouse, respectively. Pentobarbital enhanced the current with EC50s of 84 ± 3 and 106 ± 6 μM in rat and mouse, respectively. The sensitivity for Cl-218,872, which binds preferentially to the Type I benzodiazepine receptor, was similar in all the neurons. RO 15–4513, an inverse partial agonist to the benzodiazepine receptor, was not effective in reversing the potentiation of the Cl− current in rat neurons and only slightly reduced the potentiation in mouse neurons. The receptors in rat neurons were more sensitive to external Zn2+; the current was inhibited by 50% with a concentration of 93 ± 3 and 244 ± 9 μM in rat and mouse, respectively. Analysis of mRNA encoding for the γ2L receptor subunit showed similar levels in rat and mouse neurons. The data suggest that most pharmacological properties of hippocampal GABAA mouse and rat receptors are comparable, with the exception of the sensitivity to ethanol and Zn2+. These differences can not be explained by differential expression of γ2L subunits. We provide good experimental evidence indicating a difference in the sensitivity of the GABAA receptor to GABAergic ligands in two distinct animal species.
Studies have shown that the neuronal NMDA receptor is a target for the actions of ethanol. Recently, a number of subunits of the NMDA receptor have been cloned and functionally expressed in various combinations. We have expressed four splice variants of the NMDAR1 subunit in Xenopus oocytes, and find that homomeric assemblies of this subunit, in the absence of other subunits, exhibit ethanol sensitivity comparable to that seen in neurons. In the presence of calcium, the reduction of total current was greatest in the NMDAR1-LL splice variant, and was significantly less in the NMDAR1-SS variant. The increased sensitivity of NMDAR1-LL may be attributed to a particularly sensitive slow current ‘hump’ which is more pronounced in NMDAR1-LL than in NMDAR1-SS. The reduction of NMDA-evoked current by ethanol was significantly different when calcium was replaced by barium in the external medium. In this case, the slow current hump was significantly reduced, current through NMDAR1-LL was less reduced by ethanol, and the percent reduction of NMDAR1-LL and NMDAR1-SS currents was similar. NMDA-evoked currents in heteromeric receptors formed by coinjection of the mouse epsilon-1 subunit with the NMDAR1 splice variants responded to ethanol similarly to homomeric assemblies.
Intracellular recordings were made in a pontine slice preparation of the rat brain containing the nucleus locus coeruleus (LC). In a first series of experiments, various parameters of spontaneous action potentials were evaluated. It turned out that ethanol (100 mM) does not alter the firing rate, the spike amplitude and the afterhyperpolarization following a spike. In subsequent experiments, the generation of action potentials was prevented by passing continuous hyperpolarizing current via the recording electrode. Under these conditions, ethanol (100 mM) had no effect on the membrane potential or input resistance. Pressure-applied N-methyl-D-aspartate (NMDA), (S)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and alpha,beta-methylene ATP (alpha,beta-meATP) reproducibly depolarized LC neurons. While ethanol (100 mM) depressed the NMDA- and AMPA-induced depolarization to a similar extent, it did not interact with alpha,beta-meATP. Lower concentrations of ethanol (10 and 30 mM) had no effect on depolarizing responses to NMDA or AMPA. Noradrenaline applied by pressure pulses reproducibly hyperpolarized LC cells. These hyperpolarizations were unchanged by ethanol (100 mM). Biphasic synaptic potentials consisting of early depolarizing (PSP) and late hyperpolarizing (IPSP) components were evoked by electrical stimulation. Ethanol (100 mM) depressed the PSP and increased the IPSP. Glutamatergic PSPs recorded in the combined presence of picrotoxin (100 microM) and suramin (100 microM) were also inhibited by ethanol (100 mM). However, IPSPs recorded under these conditions were insensitive to ethanol (100 mM). In conclusion, ethanol may interfere with the AMPA (or NMDA) receptor-mediated fraction of the PSP and slightly facilitate the alpha2 adrenoceptor-mediated fraction of the IPSP.
Dopaminergic neurons in the ventral tegmental area of Tsai (VTA) have been implicated in the mediation of the rewarding effects of ethanol and many other drugs of abuse. Our previous extracellular studies in brain slices have demonstrated that ethanol increases the firing rate of dopaminergic neurons in the VTA. In the present intracellular study, ethanol (40-160 mM) increased the spontaneous firing rate of most (77%) VTA neurons. In addition, most (75%) VTA neurons were depolarized by ethanol. Ethanol also changed the shape of the spontaneous action potential in VTA neurons, reducing the amplitude of the spike after-hyperpolarization (in 74% of neurons) and also reducing the amplitude of the depolarizing phase of the action potential (in 86% of neurons tested). Furthermore, analysis of Voltage/Current curves in the presence and absence of ethanol showed that ethanol had little effect on the resistance of the cell membrane at membrane potentials near rest, but enhanced the time-dependent inward rectification activated at more hyperpolarized membrane potentials (Ih). This intracellular study identifies several electrophysiological effects of ethanol that may underlie the ethanol-induced excitation of VTA neurons and, therefore, may be important for the rewarding effects of ethanol.
Spontaneous electrical activity was recorded from three cortical and five subcortical sites, via permanently implanted electrodes, in five conscious, freely-moving adult cats. Initial observations were made during and after an intravenous infusion of ethanol, 1 g/kg. The animals then received ethanol by gastric intubation, in doses of 1.5 g/kg every 8, 12 or 24 h, for a period of 5 weeks. Electrical and behavioral observations were repeated on the day following the last gavage, before and during another intravenous infusion of ethanol 1 g/kg. All animals showed EEG changes which are interpreted as signs of tolerance to and dependence on alcohol. EEG changes appeared up to a day earlier than gross behavioral signs of alcohol withdrawal.
Auditory brainstem potentials were recorded from human subjects before and after an intoxicating dose of alcohol. Following
alcohol ingestion there were significant, progressive increases in the latencies of brainstem potential peaks III through
VII. No changes in peak amplitudes were found. The results indicate that alcohol has a depressive effect on neural transmission
within the primary auditory brainstem pathway.
Periodic brain stimulation, particularly in the limbic system, at stimulus intensities initially too low to produce any behavioural or EEG effects, progressively produces EEG changes, motor automatisms, and eventually convulsions, an effect called kindling. Data are presented and reviewed that suggest that the severity of alcohol withdrawal symptoms progressively increases over years of alcohol abuse in a stepwise fashion similar to the kindling process. The model is presented that the limbic system hyperirritability which accompanies each alcohol withdrawal serves over time to kindle increasingly widespread subcortical structures. These long-term changes in neuronal excitability might relate to the progression of alcohol withdrawal symptoms from tremor to seizures and delirium tremens, as well as the alcoholic personality changes between episodes of withdrawal.
Small doses of apomorphine (0.03–0.25 mg/kg i.p.) caused a dose-dependent suppression of the ethanol-induced (2.36 g/kg, 15% v/v, i.p.) locomotor stimulation in mice and higher doses (0.5–2 mg/kg i.p.) caused a delayed suppression. The delay increased with increased doses. Very small doses of clonidine (0.025 or 0.05 mg/kg i.p.), which per se did not or only slightly affect the activity of control mice, also markedly suppressed the ethanol-induced motor stimulation. Ethanol alone (2.36 g/kg i.p.) did not significantly affect the amount of Dopa accumulating in various mouse brain regions (limbic system, corpus striatum, hemispheres and brain stem) during 30 min following administration of 3-hydroxybenzylhydrazine (NSD 1015), an inhibitor of aromatic amino-acid decarboxylase. Both the hypothermia and the locomotor stimulation by ethanol were antagonized by NSD 1015. The reduction in Dopa accumulation induced by a small dose of apomorphine (0.25 mg/kg i.p.) in the dopamine-rich regions in the mouse brain was slightly enhanced by ethanol, whereas the clonidine-induced decrease in Dopa accumulation was, if anything, reduced.
In conclusion, ethanol's behavioural stimulant action in mice can be largely suppressed by apomorphine or clonidine, drugs which in the small doses used probably inhibit central catecholamine (CA) neurons.
The effects of ethanol and meperidine on the auditory evoked potential (AEP) to stimuli of different intensities were investigated. Sixteen normal male volunteers received ethanol, 0.8 ml/kg, 100 mg meperidine, and a placebo on different days in a double-blind study. AEPs were recorded from Fz, Cz and Pz electrode placements. The stimuli were 500 msec 1000 Hz tones at 50, 60, 70 and 80 dB sound pressure level presented in a pseudo-random sequence. Meperidine had no significant effect on AEP variables. Ethanol reduced AEP activity between 24 and 250 msec but had no effect on the sustained potential measured between 300 and 450 msec.
Auditory brain stem evoked responses were in unrestrained rats during periods of acute and chronic alcohol intoxication, alcohol withdrawal, and recovery. Acute alcohol administration altered the auditory brain stem potentials by a prolongation of both peak latency and central conduction time, beginning with early peaks. Similar but lesser effects affecting only the latter peaks were observed during chronic alcohol intoxication. By contrast, alcohol withdrawal resulted in a decrease in the peak latencies of auditory brain stem potentials and a facilitation of central conduction time. Recovery of the auditory brain stem potentials to the normal form required at least three to four weeks. The present study provides the first quantitative data, to our knowledge, on manifestations of alcohol tolerance and withdrawal.
Rats were implanted with chronic recording electrodes in the caudate nucleus, substantia nigra, red nucleus, and pontine reticular formation and thereafter maintained on ethanol-containing liquid diets for 18 to 22 days. The removal of ethanol resulted in the time-dependent appearance of epileptiform abnormalities in each of the explored brain regions. The abnormalities characteristically began with increases in EEG synchrony and amplitude coupled with the appearance of epileptiform spike activity, which increased in amplitude and frequency during the latter stages of withdrawal. Quantification of preconvulsive epileptiform spike activity revealed major differences in the temporal sequence of development of spiking in the caudate nucleus and substantia nigra compared to the red nucleus and pontine reticular formation. However, a significant equipotentiality existed among these regions as initiation sites for seizure discharge during spontaneous behavioral convulsion. It was concluded that these brain sites, which have previously been considered to serve significant motor functions, play an active, but as yet unspecifiable, role in the genesis of the ethanol withdrawal reaction. It was further hypothesized that an important aspect of the development of epileptiform activity during the ethanol withdrawal reaction may involve interaction of the caudate nucleus, substantia nigra, and red nucleus with existing thalamocortical synchronizing systems in the midline and nonspecific thalamic nuclei.
The effects of ethanol on membrane fluidity at 37° have been assessed by a sensitive electron paramagnetic resonance technique. Erythrocyte and brain membranes from DBA/2J mice were spin-labeled with 5-doxylstearic acid (N-oxyl-4',4'-dimethyloxazolidine derivative of 5-ketostearic acid). The molecular motion of the spin label was measured from the EPR spectrum by determining the order parameter S, an index of membrane fluidity. The fluidity of both erythrocyte and synaptosomal membranes was greater than that of myelin but less than that of mitochondrial membranes. The addition of low concentrations (0.02 or 0.04 M) of ethanol in vitro increased fluidity in erythrocyte, mitochondrial, and synaptosomal membranes. This fluidizing effect of ethanol was dose-related up to 0.35 M in all the membranes except myelin. These data suggest that nonlethal concentrations of ethanol may increase membrane fluidity in vivo.
The effects of ethanol on muscle spindle afferent activity and on the mono- and polysynaptic reflexes were examined in cats. Ethanol was administered incrementally as intravenous infusions of 0.7 g/kg of ethanol 30 minutes apart; mean arterial blood alcohol concentrations reached 30 minutes after the first and fourth infusions were 1.1 and 3.8 mg/ml, respectively. Ethanol produced modest, dose-related increases in the afferent activity from muscle spindles in spinal- and pentobarbital-anesthetized cats. Mean phasic and static discharge frequencies were both increased approximately 10 impulses/sec after infusions of a total of 2.8 g/kg. In unanesthetized animals, comparable blood levels of ethanol were associated with mild to marked motor incoordination. The mean amplitudes of the mono- and polysnaptic reflexes in spinal animals, elicited with supramaximal single shocks to the muscle nerve, were depressed to 92 and 84% of control levels, respectively, after 0.7 g/kg and continued to fall to 50 and 60% of control levels after 2.8 g/kg of ethanol. Ethanol failed to depress preferentially polysynaptic reflexes. It is concluded that the spindle afferent excitation was involved in the motor effects of ethanol but that it was insufficient to explain fully the skeletomotor alterations produced by ethanol; rather, ethanol actions at peripheral and spinal and, perhaps, supraspinal sites all appear to be involved in ethanol-induced impairment of motor function.
The effects of acute and extended ethanol exposure on N-methyl-D-aspartate- and kainate-induced currents were examined electrophysiologically in Xenopus oocytes expressing rat hippocampal mRNA. Ethanol inhibited responses stimulated by low and high concentrations of N-methyl-D-aspartate to a similar degree. However, responses produced by low or high concentrations of kainate were differentially inhibited by ethanol. Low kainate concentration responses were much more sensitive to ethanol than high kainate concentrations (e.g., 50 mM ethanol inhibited 12.5 microM kainate responses by 45% compared to 15% inhibition of 400 microM kainate responses). In oocytes cultured in 100 mM ethanol for 1-5 days, the ethanol inhibition of maximum N-methyl-D-aspartate and kainate responses was not different from that in non-ethanol-exposed oocytes. Ethanol treatment, however, selectively decreased the ethanol sensitivity of low kainate concentration responses. Currents stimulated by N-methyl-D-aspartate or kainate were not different between control and ethanol-treated oocytes, indicating that ethanol exposure did not interfere with channel expression. The selective actions of acute and extended ethanol exposure on low kainate responses may indicate selective actions of ethanol on subtypes of kainate receptors expressed in oocytes.
Simultaneous extracellular and intracellular electrophysiological recordings were made from the CA1 region of rat hippocampal brain slices during superfusion with ethanol. Ethanol (80 mM) had a biphasic effect on the extracellularly recorded population spike, with an initial increase followed by a significant reduction (38%) in this response, which was maximal 10 to 15 min after the start of ethanol application. Concurrent intracellular recordings in the CA1 showed a small (0.7 mV) hyperpolarization of the resting membrane potential, with no significant change in the input impedance, EPSP, GABAA and GABAB IPSPs, or after hyperpolarization (AHP) following depolarizing current injection. Ethanol reduced the amplitude and duration of depolarizing responses to brief, localized pressure-ejection of N-methyl-D-aspartate (NMDA) onto pyramidal neuron dendrites, but did not affect the GABAA receptor-mediated depolarizing responses to the dendritic application of GABA. In parallel studies, the effect of ethanol on GABA-stimulated 36Cl- flux was measured in microsac preparations from rat hippocampus, cerebellum, and cerebral cortex. Ethanol application caused substantial enhancement of the chloride uptake from cerebellar and cerebral cortical microsacs, but had no effect on 36Cl- influx in hippocampal microsacs. These results suggest that there are important brain region-dependent differences in the sensitivity of the GABAA receptor/chloride channel to modulation by ethanol.
A single dose of ethanol (0.60 g/kg of body weight) was administered to eight young healthy male subjects 35 minutes before bedtime. Compared to the average value of two baseline nights, subjective sleep and polysomnographically determined sleep parameters were not significantly affected. In the first 2 hours of sleep after ethanol intake, the combined value of wakefulness, stage 1, and movement time was reduced. In this interval, visually scored stage 4 sleep was increased, and electroencephalographic (EEG) power density in nonrapid-eye-movement (nonREM) sleep was enhanced in the lowest delta frequencies and reduced in the beta range. Computed for the entire sleep episode, power density in REM sleep was enhanced in some theta frequencies. In the sleep episode initiated 24 hours after ethanol intake, power density in nonREM and REM sleep was enhanced in delta and theta frequencies, and the subjectively perceived number of awakenings was reduced. The effects of ethanol on EEG power spectra during sleep differ from those published for benzodiazepine and nonbenzodiazepine hypnotics. This indicates that the effects of ethanol on the human sleep EEG are not mediated by the benzodiazepine receptor.
Intracellular recordings were made from pyramidal cells in area CA1 in mouse isolated hippocampal slices, after chronic ethanol treatment in vivo .
Fast i.p.s.ps were isolated by injection of the impaled neurones with QX314 (to block fast sodium currents and the slow i.p.s.p.) and stimulating the interneurones in the presence of the glutamatergic blockers, CNQX and APV.
The isolated fast‐inhibitory postsynaptic potential (f.‐i.p.s.p.) was measured at intervals during the 7 h withdrawal period. The reversal potential and sensitivity to bicuculline suggested that the isolated f.‐i.p.s.p. was mediated by activation of the GABA A receptor‐chloride ionophore complex.
Measurement of stimulus‐response relationships for the f.‐i.p.s.ps revealed an initial increase in the maximum size of the i.p.s.p., evoked from a membrane potential of −50 mV, seen at 2 h into ethanol withdrawal. This was attributed to a negative shift in the reversal potential, E i.p.s.p. , with no observed change in conductance, G i.p.s.p. .
No differences in f.‐i.p.s.ps evoked during ethanol withdrawal or in control slices were seen at 4 h or 6 h. At these times, epileptiform activity was seen in previous field potential recordings.
6 Paired pulse depression of the f.‐i.p.s.p. was significantly increased at 2 h into withdrawal, when a 150 ms pulse interval was used. No differences were seen at later times in the ethanol withdrawal period.
7 The results suggest that ethanol withdrawal hyperexcitability in isolated hippocampal slices is not caused by primary decreases in inhibition mediated by the GABA A receptor‐chloride ionophore complex. The increase in the f.‐i.p.s.p. during the initial stages of the withdrawal might prevent the overt expression of epileptiform activity at this time.
The mammalian GABAA receptor is a multisubunit protein containing a variety of binding sites for psychotropic agents. One of the most widely used of these drugs, ethanol, enhances the function of GABAA receptors in certain circumstances but not others. Previous studies have demonstrated that alternative splicing of the gamma 2L GABA subunit results in an ethanol sensitive and an ethanol-insensitive form, when combined with alpha and beta subunits. We have used in vitro mutagenesis and expression in Xenopus oocytes to show that the consensus site for phosphorylation by protein kinase C contained in the gamma 2L insert is critical for modulation by ethanol but not benzodiazepines, and manipulation of the phosphorylating enzymes in oocytes containing alpha 1 beta 1 gamma 2L can prevent ethanol enhancement. It is likely that phosphorylation or dephosphorylation of a specific site on the GABAA receptor protein can act as a control mechanism for neuronal responses to alcohol exposure.
Seventy male alcohol-dependent patients participated in a 12-week, double-blind, placebo-controlled trial of naltrexone hydrochloride (50 mg/d) as an adjunct to treatment following alcohol detoxification. Subjects taking naltrexone reported significantly less alcohol craving and days in which any alcohol was consumed. During the 12-week study, only 23% of the naltrexone-treated subjects met the criteria for a relapse, whereas 54.3% of the placebo-treated subjects relapsed. The primary effect of naltrexone was seen in patients who drank any alcohol while attending outpatient treatment. Nineteen (95%) of the 20 placebo-treated patients relapsed after they sampled alcohol, while only eight (50%) of 16 naltrexone-treated patients exposed to alcohol met relapse criteria. Naltrexone was not associated with mood changes or other psychiatric symptoms. Significant side effects (nausea) occurred in two naltrexone-treated subjects, and one naltrexone-treated subject complained of increased pain from arthritis. These results suggest that naltrexone may be a safe and effective adjunct to treatment in alcohol-dependent subjects, particularly in preventing alcohol relapse.
The effects of chronic alcohol exposure during development on the responses evoked by glutamate and the selective excitatory amino acid receptor agonists quisqualate (Quis) and kainate were studied in cultured cerebellar Purkinje neurons. The cultures were treated with 22 mM or 44 mM ethanol continuously for one or two weeks during the main period of morphological and physiological development. Extracellular recordings used for most studies characterized the responses to all 3 agonists as initial increase in simple spike firing, usually including a period of burst activity, followed by reduced activity or total inhibition, then return to control firing pattern. Analysis of these responses and background spontaneous activity showed several significant differences between control and ethanol treated Purkinje neurons. Background spontaneous firing, agonist evoked firing, the initial period of activity of the response to Quis, and the inhibitory period of the response to glutamate were all significantly reduced in the chronically treated neurons; the inhibitory period of the response to kainate was significantly increased. In contrast to the effects of chronic ethanol exposure, acutely administered ethanol significantly increased background spontaneous firing and the inhibitory period of the response to Quis. Thus, administering both acute and chronic ethanol altered the responses evoked by excitatory amino acids in the developing Purkinje neurons. The effect of chronic ethanol exposure on some response components was similar for all agonists tested and may be linked to changes in intrinsic membrane properties. However, alterations in the inhibitory component of the agonist responses were agonist specific, indicating that receptor-linked actions of ethanol were involved.(ABSTRACT TRUNCATED AT 250 WORDS)
The effect of ethanol (EtOH) on kainate (KA), DL-alpha-amino-3-hydroxy-5-methyl-4-isoxalone proprionic acid and N-methyl-D-aspartate (NMDA) receptor-operated channels was examined electrophysiologically in Xenopus laevis oocytes expressing mRNA from rat hippocampus and cerebellum. EtOH (50, 100 mM) inhibited KA-induced currents but did not alter the EC50 for KA (approximately 78 microM). For a series of n-alcohols, potency for inhibition of KA responses was related to chain length. 6,7-dinitroquinoxaline-2,3-dione inhibited maximum KA responses with an IC50 of approximately 1 microM; EtOH (50, 100 mM) did not alter the IC50 for 6,7-dinitroquinoxaline-2,3-dione but did not produce further inhibition of KA-induced currents. Despite the apparent noncompetitive inhibition produced by EtOH on KA receptor-mediated responses, the EtOH inhibition increased as the KA concentration decreased in hippocampal and cerebellar mRNA expressing oocytes. This differential inhibition was not due to the different current amplitudes stimulated by low vs. high KA concentrations. In contrast, oocytes expressing NMDA channels demonstrated a constant percent inhibition by EtOH in the presence of 25 to 200 microM NMDA. Altering the extracellular Ca++ concentration did not affect the ability of EtOH to inhibit NMDA responses. Maximal NMDA-stimulated currents were inhibited by 100 mM EtOH to a lesser extent (31%) in oocytes injected with rat cerebellar mRNA than oocytes expressing rat hippocampal mRNA (47%), suggesting brain regional differences in NMDA channel inhibition by EtOH.(ABSTRACT TRUNCATED AT 250 WORDS)
The effects of ethanol on a number of electrophysiological parameters were examined in 10 different voltage-gated potassium channels expressed in Xenopus oocytes. None of the channels examined was highly sensitive to ethanol, but there was significant variability among the channels tested at concentrations of ethanol of 200 mM and greater. The response to ethanol was not determined exclusively by membership in a genetic subfamily. In addition, the relative sensitivity among different channels could vary independently for different electrical parameters. For example, current amplitude in DRK1 was insensitive to ethanol, even at concentrations as high as 600 mM, whereas this was one of the more sensitive channels with respect to the kinetics of current inactivation. The opposite situation was true for ShA1. Therefore, ethanol at high concentrations may selectively perturb discrete regions of channel proteins. This is supported by the finding that removal of 318 amino acids from the cytoplasmic carboxyl terminus of DRK1 results in a channel whose current amplitude shows greater sensitivity to ethanol than does DRK1. Thus, the effects of ethanol on the channel may not be limited to interactions at the lipid-protein interface.
Topographic measures of electroencephalographic (EEG) amplitude were used to compare recovered alcoholics (n = 14) with sex- and age-matched control subjects. Delta, alpha, and beta activity did not distinguish the groups, but regional differences in theta distribution did. Recovered alcoholics showed more uniform distributions of theta amplitudes in bilateral anterior and posterior regions compared with controls. Because a minimum of 5 years had elapsed since the recovered alcoholic subjects fulfilled DSM-III-R criteria for alcohol abuse or dependence, it is unlikely these EEG theta differences reflect the effects of withdrawal.
The electrophysiological activity of mesoaccumbens dopaminergic neurons was monitored during the ethanol-withdrawal syndrome in ethanol-dependent and in control rats. Spontaneous firing was reduced by about half in ethanol-dependent rats as compared to controls. Likewise, the number of spikes/burst was also reduced in ethanol-dependent rats. These results are consistent with the reduction in dopamine release observed during ethanol-withdrawal syndrome and may provide the basis for the aversive effects of the ethanol-withdrawal syndrome.