Alcohol hangover induces nitric oxide metabolism changes by impairing NMDA receptor-PSD95-nNOS pathway.

Alcohol hangover is defined as the combination of mental and physical symptoms experienced the day after a single episode of heavy drinking, starting when blood alcohol concentration approaches zero. We previously evidenced increments in free radical generation and an imbalance in antioxidant defences in non-synaptic mitochondria and synaptosomes during hangover. It is widely known that acute alcohol exposure induces changes in nitric oxide (NO) production and blocks the binding of glutamate to NMDAR in central nervous system. Our aim was to evaluate the residual effect of acute ethanol exposure (hangover) on NO metabolism and the role of NMDA receptor-PSD95-nNOS pathway in non-synaptic mitochondria and synaptosomes from mouse brain cortex. Results obtained for the synaptosomes fraction showed a 37% decrease in NO total content, a 36% decrease in NOS activity and a 19% decrease in nNOS protein expression. The in vitro addition of glutamate to synaptosomes produced a concentration-dependent enhancement of NO production which was significantly lower in samples from hangover mice than in controls for all the glutamate concentrations tested. A similar patter of response was observed for nNOS activity being decreased both in basal conditions and after glutamate addition. In addition, synaptosomes exhibited a 64% and 15% reduction in NMDA receptor subunit GluN2B and PSD-95 protein expression, respectively. Together with this, glutamate-induced calcium entry was significant decreased in synaptosomes from alcohol-treated mice. On the other hand, in non-synaptic mitochondria, no significant differences were observed in NO content, NOS activity or nNOS protein expression. The expression of iNOS remained unaltered in synaptosomes and non-synaptic mitochondria. Here we demonstrated that hangover effects on NO metabolism are strongly evidenced in synaptosomes probably due to a disruption in NMDAR/PSD-95/nNOS pathway.

Characterization of hangover following intravenous alcohol exposure in social drinkers: methodological and clinical implications.

Hangover refers to the cluster of physiological and behavioral symptoms that occur following the end of a drinking episode. While hangover has been studied after the typical oral consumption of alcohol, the occurrence of hangover following intravenous (IV) alcohol administration in human laboratory studies has not been previously reported. This study characterizes hangover symptoms and post-infusion drinking behavior following acute IV alcohol administration in social drinkers. Twenty-one to thirty-year-old healthy social drinkers (n = 24) underwent an alcohol clamp session at breath alcohol concentration of 0.06 percent. Hangover symptoms as well as any post-infusion drinking that occurred between the end of the session and the following morning were assessed using the Acute Hangover Scale, and examined for influences of recent drinking history, family history of alcoholism and Sex. Results indicated a 79 percent prevalence of hangover symptoms, with the most common symptoms being 'tired', 'thirsty' and 'headache'. Recent drinking measures showed significant effects on Average Hangover Scale scores, with heavier drinkers showing greater hangover symptoms. There was a significant sex difference in average hangover scores, with females reporting higher scores than males. Subjective measures of stimulation and intoxication were also associated with Average Hangover Scale scores. The probability of post-infusion drinking was not predicted by hangover scores, but was related to recent drinking history; subjective response to alcohol was a significant mediator of this relationship. These findings demonstrate that hangover symptoms are experienced following IV alcohol administration, and extend previous studies of influences of risk factors for alcohol use disorders including recent drinking on hangover.

Apoptosis Due to After-effects of Acute Ethanol Exposure in Brain Cortex: Intrinsic and Extrinsic Signaling Pathways.

Alcohol hangover is the combination of negative mental and physical symptoms which can be experienced after a single episode of alcohol consumption, starting when blood alcohol concentration approaches zero. We previously demonstrated that hangover provokes mitochondrial dysfunction, oxidative stress, imbalance in antioxidant defenses, and impairment in cellular bioenergetics. Chronic and acute ethanol intake induces neuroapoptosis but there are no studies which evaluated apoptosis at alcohol hangover. The aim of the present work was to study alcohol residual effects on intrinsic and extrinsic apoptotic signaling pathways in mice brain cortex. Male Swiss mice received i.p. injection of ethanol (3.8 g/kg) or saline. Six hours after injection, at alcohol hangover onset, mitochondria and tissue lysates were obtained from brain cortex. Results indicated that during alcohol hangover a loss of granularity of mitochondria and a strong increment in mitochondrial permeability were observed, indicating the occurrence of swelling. Alcohol-treated mice showed a significant 35% increase in Bax/Bcl-2 ratio and a 5-fold increase in the ratio level of cytochrome c between mitochondria and cytosol. Caspase 3, 8 and 9 protein expressions were 32%, 33% and 20% respectively enhanced and the activity of caspase 3 and 6 was 30% and 20% increased also due to the hangover condition. Moreover, 38% and 32% increments were found in PARP1 and p53 protein expression respectively and on the contrary, SIRT-1 was almost 50% lower than controls due to the hangover condition. The present work demonstrates that alcohol after-effects could result in the activation of mitochondrial and non-mitochondrial apoptosis pathways.

Effects of alcohol hangover on attentional resources during a verbal memory/psychomotor tracking dual attention task.

BACKGROUND: Alcohol hangover (AH) is associated with impaired attention and memory performance. However, whether this effect is related to reduced attentional resources remains unclear. AIMS: A dual-attention paradigm was employed to assess the effects of AH on attentional resources, delayed memory recognition, and the interaction between attentional load and AH. Mental effort and perceived performance during AH and control conditions were also assessed. METHODS: A seminaturalistic, crossover design was used. In total, 25 healthy social drinkers aged 18-35 years, visited the laboratory following a typical night out drinking (Hangover condition) and after alcohol abstinence (control) between 8:30 am and 12:30 pm, with conditions counterbalanced. Attentional load was manipulated via the presence (dual attention) or absence of psychomotor tracking during verbal memory encoding. Perceived mental effort and performance were measured using the NASA-TLX. Participants' recollected alcohol consumption was used to compute estimated blood alcohol level (eBAC). RESULTS: Compared with the control visit, AH was associated with reduced recognition accuracy (particularly more false negatives), higher "tracking costs" (poorer accuracy) in the dual attention condition, increased ratings of "mental demand," "effort," and "frustration," and lower ratings of task performance. There was also a significant main effect of attentional load with poorer recognition accuracy and response time in the dual attention condition. There were no significant interaction effects between hangover and attentional load. CONCLUSION: These findings suggest that reduced attentional resources contribute to the cognitive deficits associated with AH including impaired memory consolidation. They further suggest that while hungover, participants are aware of these deficits but are unable to compensate.

The Relationship between Alcohol Hangover Severity, Sleep and Cognitive Performance; a Naturalistic Study.

Alcohol hangover (AH) has been associated with poor sleep due to the negative effects of alcohol intoxication on sleep quantity and sleep quality. The aim of the current study was to further explore the relationship between AH severity and sleep using a naturalistic study design. A further aim was to determine whether quantitative aspects of sleep were a mediating influence on the relationship between AH severity and cognitive performance. As part of the naturalistic study design, 99 drinkers were recruited following a night of drinking in an Australian state capital, with breath alcohol concentration (BrAC) measured as participants were leaving the entertainment district. The following morning at home, participants answered online questions regarding their drinking behaviour on the previous evening, current AH symptoms and sleep quality. Participants also completed an online version of the Trail-Making Test B (TMT-B) to assess cognitive performance. The findings reveal the duration of nightly awakenings to be negatively related to six individual AH symptoms as well as overall AH severity. The number of nightly awakenings, sleep quality and total sleep time correlated with four AH symptoms including overall AH severity. Total AH severity accounted for a moderate amount of variance (11%) in the time to complete the TMT-B. These findings confirm that alcohol consumption negatively affects sleep, which is related to higher next-day hangover severity ratings and poorer cognitive performance.

The 5HTOL/5HIAA Ratio as a Biomarker of Alcohol Hangover.

Assessment of the presence and severity of alcohol hangovers relies on the subjective method of self-report. Therefore, there is a need of adequate biomarkers that (1) correlate significantly with hangover severity, and (2) correspond to the level of hangover-related performance impairment objectively. In this naturalistic study, n = 35 social drinkers participated. Urine samples were obtained the morning after alcohol consumption and after an alcohol-free control day. Concentrations of 5-hydroxytryptophol (5-HTOL), 5-hydroxyindoleacetic acid (5-HIAA) and the 5-HTOL/5-HIAA ratio were determined. The results confirm previous findings that 5-HTOL and the 5HTOL/5-HIAA ratio are useful biomarkers of recent alcohol consumption. Significant correlations were found with the amount of alcohol consumed, total drink time, and estimated BAC. However, urine concentrations of 5-HTOL and 5-HIAA (and their ratio 5HTOL/5-HIAA) did not significantly correlate with hangover severity. In conclusion, urine 5-HTOL, 5-HIAA, and the 5HTOL/5-HIAA ratio cannot be considered to be suitable biomarkers of alcohol hangover.

Effects of the hangover secret on mitigating hangover symptoms: A pilot study.

BACKGROUND: Due to the popularity of excessive alcohol consumption, there is an increasing need for hangover symptom remedies. Most commercially available hangover treatment products have not been tested for efficacy through clinical study. AIMS: The purpose of this pilot study was to characterize the activity of a commercially available hangover product, The Hangover Secret (THS). METHODS: This was a randomized, double-blinded, placebo-controlled, crossover pilot study. Healthy volunteers of 21- to 40-years-old were eligible for participation, and received either THS or placebo on two different occasions. Participants were given 43 mL of whiskey every twenty minutes for up to 3 hours to achieve a blood alcohol concentration (BrAC) ≥ 0.12%. Hangover severity was assessed using the Acute Hangover Scale (AHS) and Acute Hangover Severity Scale (AHSS) validated tools. RESULTS: Nine participants completed the study. AHS scores increased from baseline to 7 am by 4.11 ± 3.17 and 1.26 ± 2.29 for the placebo and active arms respectively (P = .16). AHS headache scores increased from baseline to 7 am by 2.44 ± 1.67 and 1.11 ± 1.17 for the placebo and active arms respectively (P = .06). AHSS scores increased from baseline to 7 am by 1.0 ± 1.05 and 0.41 ± 1.08, for the placebo and active arms respectively (P = .30). There was no significant difference between average BrAC at 7 am between the placebo and active arms. CONCLUSION: THS showed positive signals in the prevention of alcohol-induced hangover, especially headaches. The improvements with THS surpassed the minimum clinically important difference in overall AHS score and three individual AHS symptoms scores (hangover, headache, and thirsty). THS's reduction in AHS or AHSS scores did not reach statistical significance likely due to the small sample size. Larger studies with appropriate sample sizes are needed in light of these promising findings.

Alcohol hangover effects on brain cortex non-synaptic mitochondria and synaptosomes bioenergetics.

Alcohol hangover (AH) has been associated with oxidative stress and mitochondrial dysfunction. We herein postulate that AH-induced mitochondrial alterations can be due to a different pattern of response in synaptosomes and non-synaptic (NS) mitochondria. Mice received intraperitoneal (i.p.) injections of ethanol (3.8 g/kg) or saline and were sacrificed 6 h afterward. Brain cortex NS mitochondria and synaptosomes were isolated by Ficoll gradient. Oxygen consumption rates were measured in NS mitochondria and synaptosomes by high-resolution respirometry. Results showed that NS-synaptic mitochondria from AH animals presented a 26% decrease in malate-glutamate state 3 respiration, a 64% reduction in ATP content, 28-37% decrements in ATP production rates (malate-glutamate or succinate-dependent, respectively), and 44% inhibition in complex IV activity. No changes were observed in mitochondrial transmembrane potential (ΔΨ) or in UCP-2 expression in NS-mitochondria. Synaptosome respiration driving proton leak (in the presence of oligomycin), and spare respiratory capacity (percentage ratio between maximum and basal respiration) were 30% and 15% increased in hangover condition, respectively. Synaptosomal ATP content was 26% decreased, and ATP production rates were 40-55% decreased (malate-glutamate or succinate-dependent, respectively) in AH mice. In addition, a 24% decrease in ΔΨ and a 21% increase in UCP-2 protein expression were observed in synaptosomes from AH mice. Moreover, mitochondrial respiratory complexes I-III, II-III, and IV activities measured in synaptosomes from AH mice were decreased by 18%, 34%, and 50%, respectively. Results of this study reveal that alterations in bioenergetics status during AH could be mainly due to changes in mitochondrial function at the level of synapses.

Alcohol Hangover Has Detrimental Impact Upon Both Executive Function and Prospective Memory.

The alcohol hangover (AH) is a state of general malaise following an evening of heavy episodic drinking when the blood alcohol concentration of the person reaches/approaches zero. The aim of the current study was to investigate what impact the AH has upon both executive function (EF) and prospective memory (PM). Previous research has shown that the AH has a detrimental effect upon cognitive abilities, including attention, working memory, and PM. The current study focused upon what impact AH might have upon both EF and related PM in the same cohort, both of which underpin everyday remembering. The current study compared an AH group (AHG) with a non-hangover group (NHG) on both EF and PM measures. Forty-one participants aged 18-29 years were tested; 19 comprised the AHG and 22 of whom made up the NHG (individuals who reported no heavy drinking the day before and did not report any significant hangover symptoms). A Verbal Fluency task measured EF and the Prospective Remembering Video Procedure measured PM. The Acute Hangover Rating Scale measured AH symptoms and severity, and a Digital Breath Analyzer Test measured their blood alcohol concentration (BAC). A Recreational Drug Use Questionnaire measured alcohol and other drug use. Anyone reporting having used an illicit substance across their lifetime (e.g., cannabis, ecstasy) or who smoked heavily were omitted from the study. Two univariate analyses of covariance compared the AHG and NHG groups on Verbal Fluency and Prospective Remembering Video Task scores (controlling for age, total alcohol units consumed per week, and the number of years spent drinking). The AHG recalled significantly fewer items on the Verbal Fluency task [F (1, 36) = 7.42, p < 0.01] and on the Prospective Remembering Video Task NHG [F (1, 36) = 14.9, p < 0.001] when compared with the NHG. Overall, it appeared that a state of AH significantly impaired both EF and PM. Given the importance of EF and PM to everyday remembering, these findings may have farther-reaching implications.

Exacerbation of Hangover Symptomology Significantly Corresponds with Heavy and Chronic Alcohol Drinking: A Pilot Study.

Alcohol hangover is a combination of mental, sympathetic, and physical symptoms experienced the day after a single period of heavy drinking, starting when blood alcohol concentration approaches zero. How individual measures/domains of hangover symptomology might differ with moderate to heavy alcohol consumption and how these symptoms correlate with the drinking markers is unclear. We investigated the amount/patterns of drinking and hangover symptomology by the categories of alcohol drinking. We studied males and females in three groups: 12 heavy drinkers (HD; >15 drinks/week, 34-63 years old (y.o.)); 17 moderate drinkers (MD; 5-14 drinks/week, 21-30 y.o.); and 12 healthy controls (social/light drinkers, SD; <5 drinks/week, 25-54 y.o.). Demographics, drinking measures (Timeline followback past 90 days (TLFB90), Alcohol Use Disorders Identification Test (AUDIT)), and alcohol hangover scale (AHS) were analyzed. Average drinks/day was 5.1-times greater in HD compared to MD. Average AHS score showed moderate incapacity, and individual measures and domains of the AHS were significantly elevated in HD compared to MD. Symptoms of three domains of the AHS (mental, gastrointestinal, and sympathetic) showed domain-specific significant increase in HD. A domain-specific relation was present between AUDIT and specific measures of AHS scores in HD, specifically with the dependence symptoms. Exacerbation in hangover symptomology could be a marker of more severe alcohol use disorder.

A State of Alcohol Hangover Impedes Everyday Prospective Memory.

The aim of the current study was to investigate what impact a state of alcohol hangover (AH) has upon everyday prospective memory (PM; memory for future events/intentions). Previous research has shown that the AH has a detrimental effect upon cognitive abilities, including memory and attentional deficits. No published research articles to date have focused upon what impact AH might have upon everyday memory, of which PM is a good example. The current study compared an AH group (AHG) with a non-hangover group (NHG) on PM. Since other drug use, anxiety and depression can affect PM independent of the AH, these covariates were controlled for in the study. Fifty-eight young adults studying at university participated in this between-subjects design study-25 in the AHG and 33 in the NHG. The Prospective Remembering Video Procedure (PRVP) measured PM. The Acute Hangover Rating Scale confirmed a state of AH and a Digital Breath Analyzer Test measured their BAC. The Hospital Anxiety and Depression Scale gauged levels of anxiety and depression and a Recreational Drug Use Questionnaire (RDUQ) measured alcohol and other drug use. Anyone who reported having used an illicit substance (e.g., cannabis, ecstasy) or who smoked, were excluded from the study. After controlling for age, alcohol units per week, years spent drinking alcohol, anxiety and depression scores, a one-way analysis of covariance (ANCOVA) revealed that the AHG (mean = 5.16) recalled significantly fewer items on the PRVP than the NHG (mean = 7.51)-F (1,52) = 5.69, p < 0.05. Overall, it appeared that a state of AH significantly impaired PM, which was not attributable to age, alcohol use, or anxiety or depression indices. Given the importance of PM to everyday activities, such as remembering to keep appointments or to take an important medication on time, this finding may have farther-reaching implications. These findings should also be used to educate young adults and health professionals dealing with the consequences with regards the dangers of alcohol misuse.

Alcohol Hangover Increases Conflict Load via Faster Processing of Subliminal Information.

The detrimental effects of acute alcohol intoxication and long-term alcohol (ab)use on cognition are well-known. Yet, only little is known about the cognitive effects of an acute alcohol hangover, even though it might affect executive functions associated with workplace performance or driving skills. Given that alcohol hangover may increase the speed of information accumulation, we assessed the behavioral effects of conflict load (induced by a subliminal prime) on cognitive control, as assessed via the Flanker effect. We employed a counter-balanced within-subject design, where n = 25 healthy young males were tested once after a sober night and once after a night of experimentally induced heavy drinking of cheap brandy/red wine (2.6375 g alcohol per estimated liter of body water within 2-3 h). Alcohol hangover neither increased the cognitive conflicts induced by consciously processed distractors alone (i.e., the Flanker effect), nor modulated conflict adaptation (i.e., the Gratton effect). Instead, hangover potentiated the detrimental effects of conflicting subliminal primes on top-down cognitive conflicts. This effect was likely due to an increase in the speed of information accumulation from visual stimuli and the resulting increase in subliminal conflict load induced by incompatible primes. We further found the size of this effect to be positively correlated with age and subjective sleepiness during the hangover state, but the hangover effect remained significant even after correcting for those covariates. We further found no correlation of the behavioral effect with the subjective overall rating of hangover symptoms or the maximal breath alcohol concentration reached during prior intoxication. Taken together, our findings suggest that alcohol hangover may affect cognitive performance due to an increase in non-conscious processing of visual distractors. While the size of this effect might increase with age and sleepiness, it is not entirely dependent on those covariates and not necessarily related to subjective ratings of general hangover symptoms/impairment.

Clove Bud Polyphenols Alleviate Alterations in Inflammation and Oxidative Stress Markers Associated with Binge Drinking: A Randomized Double-Blinded Placebo-Controlled Crossover Study.

Acetaldehyde, the major cytotoxin formed by the metabolism of alcohol, is responsible for liver injury, extracellular matrix alterations, inflammation, and hangover in heavy drinkers. This study aimed to demonstrate the efficacy of a standardized polyphenolic extract of clove buds (Clovinol) in ameliorating the oxidative stress and inflammation caused by the accumulation of acetaldehyde after binge drinking. We used a randomized, double-blinded crossover study with 16 male social drinkers. The subjects were randomized into two groups of eight subjects and received either placebo or Clovinol in a single hard shell gelatin capsule (250 mg × 1) per day. The dosage of alcohol was 1 g/kg body weight/day. After 2 weeks of washout period, the treatment regime was reversed. Blood samples were drawn at 0, 0.5, 2, 4, and 12 h after treatment with either placebo or Clovinol, and biochemical parameters were analyzed. Hangover severity score was determined by using a validated questionnaire as reported earlier. Results showed faster elimination of blood acetaldehyde with significant decreases in oxidative stress, lipid peroxidation, C-reactive protein, interleukin-6, and significant enhancement in glutathione and superoxide dismutase as compared with placebo along with an overall reduction of 55.34% in hangover severity in Clovinol-treated subjects. This study demonstrated the efficacy of clove bud polyphenols for alleviating alcohol-related side effects among social drinkers at the studied dose.

Behavioral effects of the combined use of alcohol and energy drinks on alcohol hangover in an experimental mice model.

In last few years it has been a significant increase in the consumption of alcohol combined with energy drink. The aim of this work was to study the effect of this mixture in motor and affective behaviors during an alcohol hangover episode. Male Swiss mice received one of the following treatments: saline + sucrose; saline + energy drink; ethanol + sucrose; ethanol + energy drink. Ethanol dose was 3.8 g/kg BW (i.p.) and energy drink dose was 18 ml/kg BW (gavage) at ZT1 (8 am) (ZT: Zeitgeber time; ZT0: 7 am; lights on). The behavioral tests used were tight rope test to determine motor coordination; hanging wire test to study muscular strength; elevated plus maze and open field tests to evaluate anxiety like-behavior and locomotor activity. Tests were carried out at basal point that matched with lights onset and every 6 h up to 18 h after treatments. Hangover onset was established at ZT7 when blood alcohol concentration (BAC) was almost zero. Our results showed that the mixture of alcohol and energy drink altered significantly motor skills. Specifically, a significant decrease was observed in the performance of the animals in the tightrope and hanging wire tests in groups treated with the mixture of alcohol and energy drink. A significant impairment in the anxiety-like behavior was observed mainly at the beginning of alcohol hangover. These findings suggest that energy drink added to alcohol extends motor disabilities observed during an alcohol hangover episode in comparison with animals that received alcohol alone.

Free radical production and antioxidant status in brain cortex non-synaptic mitochondria and synaptosomes at alcohol hangover onset.

Alcohol hangover (AH) is the pathophysiological state after a binge-like drinking. We have previously demonstrated that AH induced bioenergetics impairments in a total fresh mitochondrial fraction in brain cortex and cerebellum. The aim of this work was to determine free radical production and antioxidant systems in non-synaptic mitochondria and synaptosomes in control and hangover animals. Superoxide production was not modified in non-synaptic mitochondria while a 17.5% increase was observed in synaptosomes. A similar response was observed for cardiolipin content as no changes were evidenced in non-synaptic mitochondria while a 55% decrease in cardiolipin content was found in synaptosomes. Hydrogen peroxide production was 3-fold increased in non-synaptic mitochondria and 4-fold increased in synaptosomes. In the presence of deprenyl, synaptosomal H2O2 production was 67% decreased in the AH condition. Hydrogen peroxide generation was not affected by deprenyl addition in non-synaptic mitochondria from AH mice. MAO activity was 57% increased in non-synaptic mitochondria and 3-fold increased in synaptosomes. Catalase activity was 40% and 50% decreased in non-synaptic mitochondria and synaptosomes, respectively. Superoxide dismutase was 60% decreased in non-synaptic mitochondria and 80% increased in synaptosomal fractions. On the other hand, GSH (glutathione) content was 43% and 17% decreased in synaptosomes and cytosol. GSH-related enzymes were mostly affected in synaptosomes fractions by AH condition. Acetylcholinesterase activity in synaptosomes was 11% increased due to AH. The present work reveals that AH provokes an imbalance in the cellular redox homeostasis mainly affecting mitochondria present in synaptic terminals.

Does familial risk for alcohol use disorder predict alcohol hangover?

AIMS: Positive family history of alcohol use disorder (FHP), a variable associated with propensity for alcohol use disorder (AUD), has been linked with elevated hangover frequency and severity, after controlling for alcohol use. This implies that hangover experiences may be related to AUD. However, inadequate control of alcohol consumption levels, low alcohol dose and testing for hangover during the intoxication phase detract from these findings. Here, we present further data pertinent to understanding the relationship between family history and alcohol hangover. METHODS: Study 1 compared past year hangover frequency in a survey of 24 FHP and 118 family history negative (FHN) individuals. Study 2 applied a quasi-experimental naturalistic approach assessing concurrent hangover severity in 17 FHP and 32 FHN individuals the morning after drinking alcohol. Both studies applied statistical control for alcohol consumption levels. RESULTS: In Study 1, both FHP status and estimated blood alcohol concentration on the heaviest drinking evening of the past month predicted the frequency of hangover symptoms experienced over the previous 12 months. In Study 2, estimated blood alcohol concentration the previous evening predicted hangover severity but FHP status did not. CONCLUSIONS: FHP, indicating familial risk for AUD, was not associated with concurrent hangover severity but was associated with increased estimates of hangover frequency the previous year.

The effect of alcohol hangover on choice response time.

The effect of alcohol hangover on cognitive processing has received little attention. We explored the effect of alcohol hangover on choice response time (RT), a dominant dependent variable (DV) in cognitive research. Prior research of the effect of hangover on RT has produced mixed findings; all studies reviewed relied exclusively on estimates of central tendency (e.g. mean RT), which has limited information value. Here we present novel analytical methods by going beyond mean RT analysis. Specifically, we examined performance in hangover conditions (n=31) across the whole RT distribution by fitting ex-Gaussian models to participant data, providing a formal description of the RT distribution. This analysis showed detriments to performance under hangover conditions at the slower end of the RT distribution and increased RT variance under hangover conditions. We also fitted an explicit mathematical process model of choice RT - the diffusion model - which estimates parameters reflecting psychologically-meaningful processes underlying choice RT. This analysis showed that hangover reduced information processing efficiency during response selection, and increased response caution; changes in these parameters reflect hangover affecting core decisional-components of RT performance. The implications of the data as well as the methods used for hangover research are discussed.

Alcohol hangover induces mitochondrial dysfunction and free radical production in mouse cerebellum.

Alcohol hangover (AH) is defined as the temporary state after alcohol binge-like drinking, starting when ethanol (EtOH) is absent in plasma. Previous data indicate that AH induces mitochondrial dysfunction and free radical production in mouse brain cortex. The aim of this work was to study mitochondrial function and reactive oxygen species production in mouse cerebellum at the onset of AH. Male mice received a single i.p. injection of EtOH (3.8g/kg BW) or saline solution. Mitochondrial function was evaluated 6h after injection (AH onset). At the onset of AH, malate-glutamate and succinate-supported state 4 oxygen uptake was 2.3 and 1.9-fold increased leading to a reduction in respiratory control of 55% and 48% respectively, as compared with controls. Decreases of 38% and 16% were found in Complex I-III and IV activities. Complex II-III activity was not affected by AH. Mitochondrial membrane potential and mitochondrial permeability changes were evaluated by flow cytometry. Mitochondrial membrane potential and permeability were decreased by AH in cerebellum mitochondria. Together with this, AH induced a 25% increase in superoxide anion and a 92% increase in hydrogen peroxide production in cerebellum mitochondria. Related to nitric oxide (NO) metabolism, neuronal nitric oxide synthase (nNOS) protein expression was 52% decreased by the hangover condition compared with control group. No differences were found in cerebellum NO production between control and treated mice. The present work demonstrates that the physiopathological state of AH involves mitochondrial dysfunction in mouse cerebellum showing the long-lasting effects of acute EtOH exposure in the central nervous system.

The effect of constant darkness and circadian resynchronization on the recovery of alcohol hangover.

Alcohol hangover (AH) is a particular state after binge-like drinking. AH begins when ethanol is absent in plasma and is characterized by a cluster of physical and psychological symptoms. Alcohol disrupts circadian patterns of behavioral and physiological parameters; however, the involvement of circadian clock on the recovery of AH was not explored. Our aim was to study the effect of continuous darkness and the possible involvement of the circadian clock in the recovery time of neuromuscular impairment and anxiety related-behavior due to AH. Male Swiss mice were habituated to 12:12 L:D or continuous darkness. Each group was injected i.p. either with saline (control group) or with ethanol (3.8 g/kg BW) (hangover group). Motor performance and anxiety phenotype were evaluated at a basal point (ZT0) and every 2 h up to 20 h after blood alcohol levels were close to zero (hangover onset). A third group was subjected to a phase advance during which a hangover episode was induced and behavioral tests were carried out for each group of treatment and resynchronization day. Constant darkness resulted to be in a faster recovery of both motor and anxiety impairments in AH compared with the recovery pattern observed under normal light-dark conditions. Mice suffering from a phase shift exhibited behavioral disruptions due to both AH and phase advance. Results indicated that a synchronized circadian clock is necessary for an adequate recovery of alcohol hangover symptoms.

Alterations in affective behavior during the time course of alcohol hangover.

Alcohol hangover is a temporary state described as the unpleasant next-day effects after binge-like drinking. Hangover begins when ethanol is absent in plasma and is characterized by physical and psychological symptoms. Affective behavior is impaired during the acute phase of alcohol intoxication; however, no reports indicate if similar effects are observed during withdrawal. The aim of this work was to study the time-extension and possible fluctuations in affective behavior during a hangover episode. Male Swiss mice were injected i.p. either with saline (control group) or with ethanol (3.8g/kg BW) (hangover group). Anxiety, fear-related behavior and despair phenotype were evaluated at a basal point (ZT0) and every 2h up to 20h after blood alcohol levels were close to zero (hangover onset). Also, anhedonia signs and pain perception disabilities were studied. Mice exhibited an increase in anxiety-like behavior during 4h and 14h after hangover onset when evaluated by the elevated-plus maze and open field test respectively (p<0.05). Fear-related behavior was detected in hangover animals by the increase of freezing and decrease of line crossings and rearing frequency during 16h after hangover onset (p<0.001). Depression signs were found in hangover mice during 14h (p<0.05). Hangover mice showed a significant decrease in pain perception when tested by tail immersion test at the beginning of hangover (p<0.05). Our findings demonstrate a time-extension between 14 and 16h for hangover affective impairments. This study shows the long lasting effects of hangover over the phase of ethanol intoxication.