Effects Of Acute Ethanol Administration Research Articles

The role of C1473G polymorphism in triptophanhydroxylase-2 gene in the acute ethanol effects on <i>c-fos</i> gene expression and metabolism of biogenic amines in brain of mice

Tryptophan hydroxylase-2 is a key enzyme in the synthesis of the neurotransmitter serotonin, which plays an important role in the mechanisms of regulation of a wide range of physiological functions and behaviors. In this work, we studied the effect of acute ethanol administration on the expression of the c-fos early response gene and the metabolism of serotonin and catecholamines in the brain structures of B6-1473C and B6-1473G congenic mice, which differ in the C1473G single-nucleotide substitution in the Tph2 gene and enzyme activity. Acute alcoholization led to a significant increase in c-fos gene expression in the frontal cortex and striatum of B6-1473G mice and the hippocampus of B6-1473C mice. The introduction of ethanol caused a decrease in the index of serotonin metabolism in the nucleus accumbens in B6-1473C mice, as well as in the hippocampus and striatum of B6-1473G mice. Also, ethanol led to a decrease in the level of norepinephrine in the hypothalamus in B6-1473C mice. Thus, the C1473G polymorphism in the Tph2 gene has a significant effect on changes in the c-fos gene expression pattern and metabolism of biogenic amines in the brain induced by acute ethanol administration.

The Role of C1473G Polymorphism in Mouse Triptophan Hydroxylase 2 Gene in the Acute Effects of Ethanol on the c-fos Gene Expression and Metabolism of Biogenic Amines in the Brain

Tryptophan hydroxylase 2 is a key enzyme in the synthesis of the neurotransmitter serotonin, which plays an important role in the regulation of behavior and various physiological functions. We studied the effect of acute ethanol administration on the expression of the early response c-fos gene and metabolism of serotonin and catecholamines in the brain structures of B6-1473C and B6-1473G congenic mouse strains differing in the single-nucleotide substitution C1473G in the Tph2 gene and activity of the encoded enzyme. Acute alcoholization led to a significant upregulation of the c-fos gene expression in the frontal cortex and striatum of B6-1473G mice and in the hippocampus of B6-1473C mice and caused a decrease in the index of serotonin metabolism in the nucleus accumbens in B6-1473C mice and in the hippocampus and striatum of B6-1473G mice, as well as to the decrease in the norepinephrine level in the hypothalamus of B6-1473C mice. Therefore, the C1473G polymorphism in the Tph2 gene has a significant effect of acute ethanol administration on the c-fos expression pattern and metabolism of biogenic amines in the mouse brain.

Ethanol enhanced MDPV- and cocaine-induced aggressive behavior in mice: Forensic implications

BackgroundReports concerning the causal link between aggressive behavior and use and abuse of different substances (i.e., alcohol, MDPV) can be found in the literature. Nonetheless, the topic concerning the effects of acute ethanol administration on MDPV and cocaine induced aggressive behavior has yet to be thoroughly investigated. The aim of this study was to investigate such synergistic effects. Materials and methodsA total of 360 male mice were employed in the study. Ethanol was diluted with saline solution and administered 10 min before MDPV or cocaine injection via oral gavage needles. Similarly, MDPV and cocaine were dissolved in saline solution and administered by intraperitoneal injection. Different associations of specific drug doses were then tested. To investigate the acute effects of MDPV and cocaine and their interaction with ethanol on aggression in mice, a resident–intruder test was used. ResultsEthanol alone was ineffective at dosages of 0.05 g/kg and 0.25 g/kg but increased the aggressiveness of the mice at 0.125 g/kg. Similarly, the injection of both cocaine alone and MDPV alone did not significantly increase the aggressiveness of the mice; conversely, the combination of ethanol and cocaine and ethanol and MDPV enhanced aggression at specific ethanol dosages (0.05 g/kg and 0.125 g/kg). ConclusionThis study demonstrated that acute ethanol administration enhances MDPV- and cocaine-induced aggressive behavior in mice. This aggressive response is particularly enhanced when MDVP and cocaine are coupled with specific ethanol dosages, proving that psychostimulant drugs may act synergistically under certain conditions.

Acute ethanol induces behavioral changes and alters c-fos expression in specific brain regions, including the mammillary body, in zebrafish

Ethanol is one of the most commonly abused substances in the world, and ethanol abuse and dependence disorders represent major societal problems. However, appropriate treatment is lacking as we still do not fully understand the molecular bases of these disorders. The zebrafish is one of the model organisms utilized for studying such mechanisms. In this study, we examined the effects of acute ethanol administration on the behavior of zebrafish, and we also analyzed correlated gene expression changes using whole-mount in situ hybridization focusing on a number of genes associated with different neurotransmitter systems, stress response, and neuronal activity. We found ethanol treatment to result in hyperactivity and reduced shoal cohesion compared to control. Analysis of c-fos expression demonstrated altered activity patterns in certain brain regions, including intense activation of the mammillary body in zebrafish with acute ethanol treatment. We also found reduced level of gad1b expression in the cerebellum of ethanol treated fish compared to control. However, we could not detect significant changes in the expression level of other genes, including vglut2b, th, crh, hdc, avp, pomc, and galn in ethanol treated fish compared controls. Our results suggest that zebrafish is a promising animal model for the study of mechanisms underlying alcohol induced behavioral changes and alcohol related human disorders.

Effects of Acute Ethanol Administration on Brain Oxidative Status: The Role of Acetaldehyde.

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

Effect of ethanol on the visual-evoked potential in rat: dynamics of ON and OFF responses.

The effect of acute ethanol administration on the flash visual-evoked potential (VEP) was investigated in numerous studies. However, it is still unclear which brain structures are responsible for the differences observed in stimulus onset (ON) and offset (OFF) responses and how these responses are modulated by ethanol. The aim of our study was to investigate the pattern of ON and OFF responses in the visual system, measured as amplitude and latency of each VEP component following acute administration of ethanol. VEPs were recorded at the onset and offset of a 500 ms visual stimulus in anesthetized male Wistar rats. The effect of alcohol on VEP latency and amplitude was measured for one hour after injection of 2 g/kg ethanol dose. Three VEP components - N63, P89 and N143 - were analyzed. Our results showed that, except for component N143, ethanol increased the latency of both ON and OFF responses in a similar manner. The latency of N143 during OFF response was not affected by ethanol but its amplitude was reduced. Our study demonstrated that the activation of the visual system during the ON response to a 500 ms visual stimulus is qualitatively different from that during the OFF response. Ethanol interfered with processing of the stimulus duration at the level of the visual cortex and reduced the activation of cortical regions.

Effect of single ethanol administration on the behavior, consumption, and preference of ethanol in tame and aggressive rats

According to the stress relief hypothesis, a high level of anxiety or stress may cause greater alcohol consumption and alcohol addiction. However, the data obtained with experimental animals do not always confirm this statement. Strains of Norway rats selected for tame and aggressive attitude to humans can serve as a model for investigating relationships between anxiety, the function of the hypothalamic–pituitary–adrenal (HPA) system, and predisposition to alcohol addiction. Former studies of tame rats, based on the blood levels of the corticosterone and adrenocorticotropic hormone (ACTH) at rest and under stress, revealed a decrease in the manifestation of anxiety-like behavior and in the HPA function compared to aggressive and unselected rats. This work assesses the preferred consumption of ethanol at various concentrations with free access to ethanol and water (two-bottle choice test) and the effect of acute ethanol administration on the behavior of aggressive and tame male rats in an elevated plus maze (EPM). After intraperitoneal alcohol administration, tame and aggressive males show a reduced number of rearings in the center of the EPM, but the reduction is statistically significant only in the former. It points not only to the absence of the anxiolytic action of 12% ethanol but also to an enhancement of anxiety-like behavior in tame rats. After the withdrawal of alcohol for seven days, tame rats show signs of deprivation, because the alcohol consumption becomes greater than before the withdrawal. Thus, the difference between tame and aggressive rats during alcohol consumption varies with the alcohol concentration. Aggressive males drink more alcohol than water only at the 2% concentration. Hence, the hypothesis of stress relief is confirmed only for this concentration.

Effect of Acute Ethanol Administration on the Hippocampal Region Neural Activity Using a Microelectrode Array.

Because acute ethanol (EtOH) administration is known to influence cognitive processes by impairing hippocampal function, electrophysiological responses of the hippocampus following EtOH exposure warrant investigation. To mimic invivo conditions, we recorded and analyzed critical firing characteristics of the neuronal population dynamically, particularly in the hippocampal region, before and after acute EtOH administration. Microelectrodes were inserted in the hippocampus CA1 region of 21 Institute of Cancer Research mice. The mice were divided into 3 groups, including an EtOH injection group (1.5g/kg), a saline injection group (1.5g/kg), and a negative control group that received no injection. A data acquisition system was employed to detect the local field potentials (LFPs) and spike potentials following acute EtOH administration. Various multichannel electrophysiological signals were collected invivo in each group at 60minutes, from which the firing rate and wavelet entropy (WE) were analyzed further. Firing rates began to decline at 20 minutes postinjection and then gradually recovered from 40 to 60 minutes. In contrast, 20minutes post-injection, WE increased maximally and then returned to normal from 40 to 60minutes (p<0.05). Pronounced changes in the relative energy of theta and alpha oscillations were also observed after 20minutes of alcohol exposure and recovery occurred by 60minutes (p<0.05). A major mechanism of EtOH's action on the hippocampus is neurotransmitter blocking in the form of excitatory neuron inhibition invivo. Changes in hippocampal spikes coincided with changes in LFPs during the entire time course of acute EtOH administration. The correlation between spikes and LFPs suggests that they jointly affect encoding in hippocampus.

Effect of single ethanol administration on behavior and the consumption and preference of ethanol in tame and aggressive rats

According to the hypothesis of stress relief, a high level of anxiety or stress may cause greater alcohol consumption and alcohol addiction. However, data obtained with experimental animals do not always confirm this statement. Model strains of Norway rats selected for tame and aggressive attitude to humans are some of the models for investigation of relationships among anxiety, the function of the hypothalamus – pituitary – adrenal (HPA) axis, and predisposition to alcohol addiction. Former studies of tame rats, based on the blood levels of corticosterone and adrenocorticotropic hormone (ACTH) in rest and stress, revealed a decrease of the manifestation of anxiety-like behavior and of the HPA function in comparison to aggressive and unselected rats. This work assesses the preferred consumption of ethanol at various concentrations with free access to ethanol and water (two bottlechoice paradigm) and the effect of acute ethanol administration on the behavior of aggressive and tame male rats in an elevated plus maze. After intraperitoneal alcohol administration, tame and aggressive males showed a reduced number of rearings in the center of the elevated plus maze, but the reduction was statistically significant only in the former. It pointed not only to the absence of an anxiolytic action of 12 % ethanol but also to enhancement of anxietylike behavior in tame rats. After seven-day alcohol withdrawal, tame rats showed signs of deprivation, because the alcohol consumption was greater than before the withdrawal. Thus, the difference between tame and aggressive rats in alcohol consumption varies with alcohol concentration. Aggressive males drank more alcohol than water only at the 2 % concentration. Hence, the hypothesis of stress relief is confirmed only for this concentration.

The Effects of Alcohol on Visual Evoked Potential and Multifocal Electroretinography.

The aim of this study was to investigate the acute effects of ethanol administration on pattern-reversal visual evoked potential (VEP) and multifocal electroretinography (mfERG). Fifteen healthy subjects with no ocular or general disease were recruited. VEP (0.25° pattern sizes) and mfERG with 19 elements in two recording segments were performed before ethanol administration to obtain baseline for each participant. A few days later, the participants visited again for VEP and mfERG measurements after ethanol administration. Ethanol (0.75 g/kg) was administered orally over the course of 30 minutes. VEP and blood alcohol concentration were evaluated one hour after ethanol administration, and mfERG was conducted after pupil dilation. The Wilcoxon signed-rank test was used to compare parameter changes after randomized eye selection. The mean blood alcohol concentration was 0.034% ± 0.05% by volume. VEP revealed a P100 latency delay (109.4 ± 5.3; 113.1 ± 8.2; P = 0.008) after alcohol administration. The P1 implicit time of ring 1 on mfERG showed a trend of shortening after alcohol administration (37.9 ± 1.0; 37.2 ± 1.5; P = 0.048). However, the changes did not show statistical significance after Bonferroni correction. In conclusion, orally administrated ethanol (0.75 g/kg) appears to suppress the central nervous system, but it is not clear whether alcohol intake affects the retina.

Genetic and pharmacological manipulation of glyoxalase 1 regulates voluntary ethanol consumption in mice.

Previous studies have identified an association between the gene glyoxalase 1 (Glo1) and anxiety-like behavior in mice and have shown that the substrate of GLO1, methylglyoxal, is a competitive partial agonist at GABAA receptors. Given the well-established role of GABAA receptors in the behavioral effects of ethanol (EtOH), we investigated the role of Glo1 in voluntary EtOH consumption in mice using the drinking in the dark (DID) paradigm. Transgenic mice overexpressing Glo1 on both FVB/NJ (FVB) or C57BL/6J (B6) backgrounds showed increased voluntary EtOH consumption compared to their wild-type littermates in DID. Furthermore, transgenic Glo1 knockdown mice on a B6 background showed decreased voluntary EtOH consumption in DID. These genetic manipulations of Glo1 had no effect on sucrose, saccharin or water consumption. Finally, we found that a small molecule GLO1 inhibitor (S-bromobenzylglutathione cyclopentyl diester (pBBG; 6.25, 12.5 mg/kg)) reduced EtOH consumption compared to vehicle treated B6 mice without altering saccharin or water consumption. Sucrose consumption was only reduced by the higher (12.5 mg/kg) dose of pBBG. We did not observe differences in the loss of righting reflex (LORR) or EtOH-induced foot slips on the balance beam in response to acute EtOH administration (LORR: 4 g/kg, Balance Beam: 1.25 g/kg) in B6 or FVB mice overexpressing Glo1, nor in B6 mice treated with pBBG. These data are the first to implicate Glo1 in EtOH-related behaviors and suggest that GLO1 inhibitors may have therapeutic potential for the treatment of alcohol use disorders.

Involvement of Inhibitory Receptors in Modulating Dopamine Signaling and Synaptic Activity Following Acute Ethanol Exposure in Striatal Subregions.

Alcohol acts on both inhibitory and excitatory receptor systems resulting in a net increase in dopamine output in the ventral striatum (nucleus accumbens [nAc]), which is implicated in drug reward. However, the dorsal striatum may also be involved in reward-related behaviors. The objectives of this study were to investigate the role of inhibitory receptors in modulating the acute effects of ethanol (EtOH) on dopamine release and synaptic activity in the shell region of the nAc (nAcS) and dorsolateral striatum (DLS). EtOH (300 mM) was administered via reversed microdialysis in the nAcS or DLS of Wistar rats following pretreatment with glycine or GABAA receptor antagonist strychnine and bicuculline, respectively. Dopamine content in dialysate samples was quantified using high-performance liquid chromatography. In addition, local field potential recordings were performed in the nAcS and DLS in slices from Wistar rats. Population spike (PS) amplitude was measured following treatment with EtOH (50 mM) in slices pretreated with strychnine or bicuculline. Local EtOH increased dopamine levels in both regions, an effect that strychnine pretreatment inhibited in the nAcS. EtOH-induced increases in accumbal dopamine were not blocked by a low (5 μM) concentration of bicuculline, but were inhibited by pretreatment with higher bicuculline concentrations. None of the antagonists administered in the DLS prevented the EtOH-induced dopamine increase. Field potential recordings in the nAcS showed that acute EtOH produced an increase in PS amplitude which was blocked by both strychnine and bicuculline. In the DLS, EtOH induced a decrease in PS amplitude which was not influenced by strychnine or bicuculline. The current results show that changes in striatal dopamine output and synaptic activity induced by acute EtOH administration are modulated by inhibitory receptors in a subregion-specific manner.

The effects of acute ethanol administration on ethanol withdrawal-induced anxiety-like syndrome in rats: A biochemical study.

Withdrawal from long-term ethanol consumption results in overexcitation of glutamatergic neurotransmission in the amygdala, which induces an anxiety-like syndrome. Most alcoholics that suffer from such symptoms frequently depend on habitual drinking as self-medication to alleviate their symptoms. Metabotropic glutamate receptor subtype 5 (mGlu5) and protein kinase C (PKC) epsilon have been reported to mediate acute and chronic effects of ethanol. This study explores the changes in mGlu5 and PKC epsilon in the amygdala following acute administration of ethanol during ethanol withdrawal (EW) induced anxiety. Male Wistar rats were fed a modified liquid diet containing low-fat cow milk, sucrose, and maltodextrin, with a gradual introduction of 2.4%, 4.8% and 7.2% ethanol for 20 days. Six hours into EW, the rats were intraperitoneally injected with normal saline and ethanol (2.5 g/kg, 20% v/v), and exposed to open-field and elevated plus maze tests. Then, amygdala tissue was dissected from the rat brain for Western blot and gene expression studies. EW-induced anxiety was accompanied by a significant increase in mGlu5, total PKC epsilon, and phosphorylated PKC epsilon protein levels, and also of mRNA of mGlu5 (GRM5) in the amygdala. Acute administration of ethanol significantly attenuated EW-induced anxiety as well as an EW-induced increase in GRM5. The acute challenge of ethanol to EW rats had little effect on the phosphorylated and total protein levels of PKC epsilon in the amygdala. Our results demonstrate that amygdala PKC epsilon may not be directly involved in the development of anxiety following EW.

Effect of acute ethanol administration on zebrafish tail-beat motion

Zebrafish is becoming a species of choice in neurobiological and behavioral studies of alcohol-related disorders. In these efforts, the activity of adult zebrafish is typically quantified using indirect activity measures that are either scored manually or identified automatically from the fish trajectory. The analysis of such activity measures has produced important insight into the effect of acute ethanol exposure on individual and social behavior of this vertebrate species. Here, we leverage a recently developed tracking algorithm that reconstructs fish body shape to investigate the effect of acute ethanol administration on zebrafish tail-beat motion in terms of amplitude and frequency. Our results demonstrate a significant effect of ethanol on the tail-beat amplitude as well as the tail-beat frequency, both of which were found to robustly decrease for high ethanol concentrations. Such a direct measurement of zebrafish motor functions is in agreement with evidence based on indirect activity measures, offering a complementary perspective in behavioral screening.

Temporal profiles dissociate regional extracellular ethanol versus dopamine concentrations.

In vivo monitoring of dopamine via microdialysis has demonstrated that acute, systemic ethanol increases extracellular dopamine in regions innervated by dopaminergic neurons originating in the ventral tegmental area and substantia nigra. Simultaneous measurement of dialysate dopamine and ethanol allows comparison of the time courses of their extracellular concentrations. Early studies demonstrated dissociations between the time courses of brain ethanol concentrations and dopaminergic responses in the nucleus accumbens (NAc) elicited by acute ethanol administration. Both brain ethanol and extracellular dopamine levels peak during the first 5 min following systemic ethanol administration, but the dopamine response returns to baseline while brain ethanol concentrations remain elevated. Post hoc analyses examined ratios of the dopamine response (represented as a percent above baseline) to tissue concentrations of ethanol at different time points within the first 25–30 min in the prefrontal cortex, NAc core and shell, and dorsomedial striatum following a single intravenous infusion of ethanol (1 g/kg). The temporal patterns of these “response ratios” differed across brain regions, possibly due to regional differences in the mechanisms underlying the decline of the dopamine signal associated with acute intravenous ethanol administration and/or to the differential effects of acute ethanol on the properties of subpopulations of midbrain dopamine neurons. This Review draws on neurochemical, physiological, and molecular studies to summarize the effects of acute ethanol administration on dopamine activity in the prefrontal cortex and striatal regions, to explore the potential reasons for the regional differences observed in the decline of ethanol-induced dopamine signals, and to suggest directions for future research.

Ethanol-induced alterations of amino acids measured by in vivo microdialysis in rats: a meta-analysis.

PurposeIn recent years in vivo microdialysis has become an important method in research studies investigating the alterations of neurotransmitters in the extracellular fluid of the brain. Based on the major involvement of glutamate and γ-aminobutyric acid (GABA) in mediating a variety of alcohol effects in the mammalian brain, numerous microdialysis studies have focused on the dynamical behavior of these systems in response to alcohol.MethodsHere we performed multiple meta-analyses on published datasets from the rat brain: (i) we studied basal extracellular concentrations of glutamate and GABA in brain regions that belong to a neurocircuitry involved in neuropsychiatric diseases, especially in alcoholism (Noori et al., Addict Biol 17:827-864, 2012); (ii) we examined the effect of acute ethanol administration on glutamate and GABA levels within this network and (iii) we studied alcohol withdrawal-induced alterations in glutamate and GABA levels within this neurocircuitry.ResultsFor extraction of basal concentrations of these neurotransmitters, datasets of 6932 rats were analyzed and the absolute basal glutamate and GABA levels were estimated for 18 different brain sites. In response to different doses of acute ethanol administration, datasets of 529 rats were analyzed and a non-linear dose response (glutamate and GABA release) relationship was observed in several brain sites. Specifically, glutamate in the nucleus accumbens shows a decreasing logarithmic dose response curve. Finally, regression analysis of 11 published reports employing brain microdialysis experiments in 104 alcohol-dependent rats reveals very consistent augmented extracellular glutamate and GABA levels in various brain sites that correlate with the intensity of the withdrawal response were identified.ConclusionsIn summary, our results provide standardized basal values for future experimental and in silico studies on neurotransmitter release in the rat brain and may be helpful to understand the effect of ethanol on neurotransmitter release. Furthermore, this study illustrates the benefit of meta-analyses using the generalization of a wide range of preclinical data.

Effects of acute ethanol administration and chronic stress exposure on social investigation and 50 kHz ultrasonic vocalizations in adolescent and adult male Sprague–Dawley rats

Adolescents drink largely in social situations, likely in an attempt to facilitate social interactions. This study sought to examine alterations in the incentive salience of a social stimulus following repeated stress exposure and acute ethanol administration in adolescent and adult male Sprague–Dawley rats. Subjects were either exposed to 5days of restraint stress, chronic variable stress (CVS), which consisted of a different stressor every day, or non-stressed. On test day, the animals were injected with 0, 0.25, 0.5, or 0.75g/kg ethanol and placed in a social approach test in which they could see, hear, and smell a social conspecific, but could not physically interact with it. All the animals showed an interest in the social stimulus, with adolescents engaging in more social investigation than adults. Restraint stressed adults showed ethanol-induced increases in social investigation, while ethanol effects were not seen in any other group. An ethanol-associated increase in 50kHz ultrasonic vocalization (USV) production was only evident in restraint stressed adolescents following 0.75g/kg ethanol. 50kHz USVs were not correlated with time spent investigating the social stimulus in any test condition. These results show that age differences in the facilitatory effects of ethanol on incentive salience of social stimuli are moderated by stress, with the facilitation of social approach by ethanol only evident in restraint stressed adults.

Neurocircuitry for modeling drug effects

The identification and functional understanding of the neurocircuitry that mediates alcohol and drug effects that are relevant for the development of addictive behavior is a fundamental challenge in addiction research. Here we introduce an assumption-free construction of a neurocircuitry that mediates acute and chronic drug effects on neurotransmitter dynamics that is solely based on rodent neuroanatomy. Two types of data were considered for constructing the neurocircuitry: (1) information on the cytoarchitecture and neurochemical connectivity of each brain region of interest obtained from different neuroanatomical techniques; (2) information on the functional relevance of each region of interest with respect to alcohol and drug effects. We used mathematical data mining and hierarchical clustering methods to achieve the highest standards in the preprocessing of these data. Using this approach, a dynamical network of high molecular and spatial resolution containing 19 brain regions and seven neurotransmitter systems was obtained. Further graph theoretical analysis suggests that the neurocircuitry is connected and cannot be separated into further components. Our analysis also reveals the existence of a principal core subcircuit comprised of nine brain regions: the prefrontal cortex, insular cortex, nucleus accumbens, hypothalamus, amygdala, thalamus, substantia nigra, ventral tegmental area and raphe nuclei. Finally, by means of algebraic criteria for synchronizability of the neurocircuitry, the suitability for in silico modeling of acute and chronic drug effects is indicated. Indeed, we introduced as an example a dynamical system for modeling the effects of acute ethanol administration in rats and obtained an increase in dopamine release in the nucleus accumbens-a hallmark of drug reinforcement-to an extent similar to that seen in numerous microdialysis studies. We conclude that the present neurocircuitry provides a structural and dynamical framework for large-scale mathematical models and will help to predict chronic drug effects on brain function.

Neuroprotective effect of acute ethanol administration in cerebral ischemia through inhibiting adenosine phosphate-activated protein kinase (AMPK) pathway

Various epidemiologic studies in recent years have indicated that light/moderate alcohol consumers have lower risks of nerve degenerative disease, suggesting that ethanol have neuroprotective effect. Ethanol is known to be involved in many signaling pathway, such as AMPK, protein kinase B/AKT and protein kinase C. Recently, some researches found that acute ethanol have neuroprotective effect, the mechanisms underlying it (acute ethanol-induced) are not completely understood. Integrating existing related research, it will be interesting to explore whether inhibit AMPK levels after acute ethanol administration is one of the mechanisms for neuroprotective effect.

Ethanol‐Induced Loss‐of‐Righting Response During Ethanol Withdrawal in Male and Female Rats: Associations with Alterations in Arc Labeling

There is increasing evidence for relevant sex differences in responses to ethanol. Several investigations have found differences in expression and recovery from ethanol withdrawal (EW) in people and across various animal models. We have found that female rats recover more quickly than male rats and show differential responses to various behavioral assessments and pharmacological challenges during withdrawal. The purpose of this study was to determine whether sex differences in EW behaviors extend to the hypnotic effects of acute ethanol administration. We used a repeated measures design to assess duration and latency for loss-of-righting reflex following an acute injection of ethanol (4.2 g/kg; 20% w/v) to pair-fed control or ethanol-withdrawn animals at 1 and 3 days EW in male, female, and ovariectomized female (OVX) rats. We determined protein levels of the activity-regulated cytoskeletal protein (Arc), used as a marker for synaptic activity in glutamatergic synapses, in the motor cortex and prefrontal cortex across these same treatment conditions. Ethanol-withdrawn animals had a reduced ethanol-induced sleep time compared to controls at 1 day EW. Sleep time remained shortened at 3 days EW for males and OVX, but not females. Arc protein levels in motor cortex and preoptic nuclei significantly increased at 1 day EW across all sex conditions, suggestive of an association with the reduced ethanol-induced sleep times during EW. Arc levels increased further for males and OVX, but not females, at the 3 days EW time point. These findings add further support to sex differences in effects of and responses to ethanol. They suggest that the more rapid recovery from EW for females than males also includes expression of tolerance to the hypnotic effects of ethanol. These sex differences may involve some differential neuroadaptations in glutamatergic signaling.