Alcohol Preference Research Articles

Alcohol consumption and preference in female rats induced by reward downshift reveals sex generality of the modulatory role of physical activity.

Increased voluntary consumption of alcohol has been demonstrated in male rats exposed to frustrative reward downshift (the emotional self-medication effect). Access to a wheel for voluntary running abolished this effect in male rats, suggesting an attenuating effect of physical exercise on the negative affect induced by reward downshift and its consequences on drug intake. The present study analyzed this effect in female rats. Sixty-four food-deprived female Wistar rats received 32% sucrose [4% (Experiment 1) or 2% (Experiment 2) in controls] during 10, 5-min preshift sessions followed by 4% (Experiment 1) or 2% (Experiment 2) sucrose during 5 postshift sessions. Immediately after each consummatory session, animals were exposed to a 2-h, two-bottle preference test involving 32% alcohol vs. water. Half of the animals also had access to a running wheel during the preference test. The results showed (a) lower sucrose consumption in the downshifted groups (32-4% and 32-2%) compared to the unshifted controls (4-4% and 2-2%, respectively); (b) higher alcohol preference in downshifted groups without access to a wheel compared with downshifted groups with access to the wheel (Experiments 1 and 2); and (c) increased alcohol intake (g/kg) after experiencing reward downshift in animals without access to the wheel (Experiment 1). Voluntary wheel running thus reduced alcohol intake in female rats experiencing reward downshift. These findings are comparable to previous results reported in male rats and support the usefulness of physical exercise to prevent alcohol self-medication induced by frustrative nonreward.

Purmorphamine Alters Anxiety-Like Behavior and Expression of Hedgehog Cascade Components in Rat Brain after Alcohol Withdrawal.

Disturbances in the Hedgehog(Hh) signaling play an important role in dysmorphogenesis of bone tissue and central nervous system during prenatal alcohol exposure, which underlies development of fetal alcohol syndrome. The involvement of Hh proteins in the mechanisms of alcohol intake in adults remains obscure. We investigated the role of the Hh cascade in voluntary ethanol drinking and development of anxiety-like behavior (ALB) during early abstinence and assessed changes in the expression of Hh pathway components in different brain regions of male Wistar rats in a model of voluntary alcohol drinking using the intermittent access to 20% ethanol in a two-bottle choice procedure. Purmorphamine (Hh cascade activator and Smoothened receptor agonist) was administered intraperitoneally at a dose of 5mg/kg body weight prior to 16-20 sessions of alcohol access. Purmorphamine had no effect on the ethanol preference; however, rats exposed to ethanol and receiving purmorphamine demonstrated changes in the ALB during the early abstinence period. Alcohol drinking affected the content of the Sonic hedgehog(Shh) and Patched mRNAs only in the amygdala. In rats exposed to ethanol and receiving purmorphamine, the level of Shh mRNA in the amygdala correlated negatively with the time spent in the open arms of the elevated plus maze. Therefore, we demonstrated for the first time that alterations in the Hh cascade induced by administration of purmorphamine did not affect alcohol preference in voluntary alcohol drinking. It was suggested that Hh cascade is involved in the development of anxiety after alcohol withdrawal through specific changes in the Hh cascade components in the amygdala.

Genetic and functional adaptations and alcohol-biased signaling in the mediodorsal thalamus of alcohol dependent mice.

Alcohol Use Disorder (AUD) is a significant health concern characterized by an individual's inability to control alcohol intake. With alcohol misuse increasing and abstinence rates declining, leading to severe social and health consequences, it is crucial to uncover effective treatment strategies for AUD by focusing on understanding neuroadaptations and cellular mechanisms. The mediodorsal thalamus (MD) is a brain region essential for cognitive functioning and reward-guided choices. However, the effects of alcohol (ethanol) dependence on MD neuroadaptations and how dependence alters MD activity during choice behaviors for alcohol and a natural reward (sucrose) are not well understood. Adult C57BL/6J mice treated with chronic intermittent ethanol (CIE) exposure were used to assess genetic and functional adaptations in the MD. Fiber photometry-based recordings of GCaMP6f expressed in the MD of C57BL/6J mice were acquired to investigate in vivo neural adaptations during choice drinking sessions for alcohol (15%) and either water or sucrose (3%). There were time-dependent changes in cFos and transcript expression during acute withdrawal and early abstinence. Differentially expressed genes were identified in control mice across different circadian time points and when comparing control and alcohol dependent mice. Gene Ontology enrichment analysis of the alcohol-sensitive genes revealed disruption of genes that control glial function, axonal myelination, and protein binding. CIE exposure also increased evoked firing in MD cells at 72 hours of withdrawal. In alcohol-dependent male and female mice that show increased alcohol drinking and preference for alcohol over water, we observed an increase in alcohol intake and preference for alcohol when mice were given a choice between alcohol and sucrose. Fiber photometry recordings demonstrated that MD activity is elevated during and after licking bouts for alcohol, water, and sucrose, and the signal for alcohol is significantly higher than that for water or sucrose during drinking. The elevated signal during alcohol bouts persisted in alcohol dependent mice. These findings demonstrate that CIE causes genetic and functional neuroadaptations in the MD and that alcohol dependence enhances alcohol-biased behaviors, with the MD uniquely responsive to alcohol, even in dependent mice.

Distinct genetic signals at the FGF21 locus complicate studies of FGF21's role in diet regulation using human cohort data

ObjectivesExperimental and genetic studies suggest that fibroblast growth factor 21 (FGF21) modulates macronutrient and alcohol preferences, but evidence of such regulation in humans remains scarce. To address this gap in translation, we aimed to map the relationships between plasma FGF21 levels, FGF21 genetic variation and habitual macronutrient intake in a large human population. MethodsWe fine-mapped and performed colocalization of the FGF21 genetic region in GWAS summary statistics of plasma FGF21 levels and macronutrient intake. UK Biobank data were used to investigate the associations between FGF21 genetic variants, plasma FGF21 protein levels, and macronutrient intake (including alcohol) assessed with repeated 24-hour recalls. One- and two-sample mendelian randomization were performed to estimate the effects of plasma FGF21 on macronutrient intake. ResultsWe show that the main macronutrient-associated variant rs838133 and the FGF21 cis-pQTL rs838131, both in the FGF21 gene, are distinct genetic signals. Effect directions also suggest that the influence of FGF21 variation on macronutrient intake appear more complex than by direct mediation through plasma FGF21. Only when considering this complexity at FGF21, is plasma FGF21 estimated to reduce alcohol and increase protein and fat intake using mendelian randomization. Importantly, plasma FGF21 levels also appear markedly elevated by primarily high alcohol and low protein intake. ConclusionsThese findings support the feedback diet-regulatory mechanism of FGF21 in humans, but highlights the need for mechanistic characterization of the complex FGF21 genetic region.

Excessive alcohol intake produces persistent mechanical allodynia and dysregulates the endocannabinoid system in the lumbar dorsal root ganglia of genetically-selected Marchigian Sardinian alcohol-preferring rats

Epidemiological data indicate a strong association between alcohol use disorder (AUD) and neuropathic pain. Genetically-selected Marchigian Sardinian alcohol-preferring (msP) rats exhibit a high preference for alcohol compared with their background strain (Wistar rats), but their sensitivity to mechanical allodynia after chronic alcohol exposure is unknown. The present study compared the development of mechanical allodynia between “low, non-pathological drinker” Wistar rats and “high drinker” msP rats using the two-bottle choice (2BC) free-access procedure. Several studies reported the involvement of endocannabinoids (eCBs) in modulating mechanical allodynia, but there are no data on their role in alcohol-related allodynia. Thus, the present study assessed eCBs and their related lipid species in lumbar dorsal root ganglia (DRG) and correlated them with mechanical allodynia in our model. We found that male and female msP rats developed persistent mechanical allodynia during protracted abstinence from alcohol, presenting no sign of recovery, as opposed to Wistar rats. This effect directly correlated with their total alcohol intake. Notably, we found a correlation between lower lumbar DRG 2-arachidonoylglycerol (2-AG) levels and the development of higher mechanical allodynia during abstinence in msP rats of both sexes but not in Wistar rats. Moreover, alcohol-exposed and abstinent msP and Wistar females but not males exhibited significant alterations of thromboxane B2 and prostaglandin E2/prostaglandin D2 compared with naive rats. These findings demonstrate that DRG 2-AG metabolism is altered in msP rats during prolonged abstinence and represents a potentially interesting pharmacological target for the treatment of mechanical allodynia during alcohol abstinence.

Choice of alcohol over a natural reward: an experimental study in light and heavy social drinkers.

A core symptom of alcohol use disorder (AUD) is a progressively increased choice of alcohol over alternative rewards despite negative consequences. Here, we investigated choice between personalized alcohol vs. natural rewards in a laboratory setting, and compared this behavior between non-treatment-seeking heavy drinkers and light social drinkers. 30 light social drinkers (15 men drinking < 15 drinks/week and 15 women drinking < 10 drinks/week) and 30 heavy, non-treatment-seeking drinkers (drinking more than these levels; 15 women). In the Concurrent Choice Alcohol Food (CCAF) task, participants chose between individually tailored images of alcohol and snack rewards and collected points towards the respective reward. To assess cost sensitivity, points associated to the images varied so that they favored alcohol or snack, or were equal, creating three relative point levels. Choice preference for alcohol was strongly correlated with Alcohol Use Disorder Identification Test (AUDIT) scores, supporting the external validity of the choice procedure. Compared to light drinkers, heavy drinkers showed increased choice preference for alcohol, as indicated by a between-group difference in points of subjective equality, a metric that quantifies the relative point level at which alcohol and snacks were equally likely to be chosen. In both groups, choice preference strongly depended on the relative point level of alcohol compared to snacks, suggesting that responding for alcohol in heavy drinkers was sensitive to costs. Our results replicate previous findings of a relationship between self-reported alcohol use and choice preference for alcohol. We also found that choice behavior was strongly dependent on relative cost of alcohol in both groups, although price sensitivity was lower in heavy compared to light drinkers. An increased choice preference for alcohol in heavy drinkers suggests that they attribute a higher relative reinforcing value to alcohol compared to natural rewards.

Centrally administered growth hormone secretagogue receptor antagonist DLys decreases alcohol intake and preference in male mice.

Alcohol use disorder (AUD) is a highly prevalent public health problem. The ghrelin system has been identified as a potential target for therapeutic intervention for AUD. Previous work showed that systemic administration of the growth hormone secretagogue receptor (GHSR) antagonist DLys reduced alcohol intake and preference in male mice. Yet, it is unclear whether central or peripheral GHSRs mediated these effects. We hypothesized that alcohol consumption is driven by central GHSRs and addressed this hypothesis by testing the effects of central administration of DLys. Male C57BL/6J mice consumed alcohol in a two-bottle choice procedure (10% ethanol versus water). DLys (2 nmol) was administered intracerebroventricularly for 7 days to examine alcohol intake and preference. DLys decreased alcohol intake and preference but had no effect on food intake. The effects on alcohol intake and preference persisted after several administrations, indicating lack of tolerance to DLys' effects. These results suggest that central administration of DLys is sufficient to reduce alcohol drinking and that DLys remains effective after several administrations when given intracerebroventricularly. Moreover, this work suggests that the effects of intracerebroventricularly administered DLys are specific to alcohol and do not generalize to other calorie-driven behaviors.

Exploratory studies of ethanol drinking in the white-tufted marmoset (Callithrix jacchus)

The white-tufted marmoset is a small, nonhuman primate that is rapidly gaining popularity as a model organism, especially for neuroscience research. To date, little work in the alcohol research field has utilized the marmoset. As a step toward establishing the marmoset as a research model for alcohol experimentation, a series of exploratory studies were undertaken to characterize ethanol drinking behavior. A voluntary drinking paradigm was established whereby the common marmoset would consume pharmacologically relevant amounts of ethanol. To facilitate ethanol consumption, ethanol was mixed with a marshmallow flavored solution (hereafter called marshmallow juice) to mask the presumed adverse taste of ethanol. Using marshmallow juice flavored solutions, marmosets readily consumed ethanol up to 1 g/kg during 10 min binge-like drinking sessions or up to 5 g/kg during ∼4 h drinking sessions. Consumption of 1.0–1.5 g/kg during a 30 min session resulted in blood ethanol concentrations of 49–73 mg/dl, which are predicted to be pharmacologically relevant. In animals that were stably consuming ethanol in marshmallow juice, gradually reducing the concentration of the marshmallow juice flavoring resulted in markedly reduced ethanol consumption. Lastly, when offered a choice between ethanol in marshmallow juice and marshmallow juice alone, marmosets displayed a very strong preference for the marshmallow juice solution without ethanol. From these studies, it is concluded that marmosets will voluntarily consume ethanol if the taste is masked with a sweet solution such as marshmallow juice. These studies represent the first report of alcohol consumption and preference in the white-tufted marmoset.

Preliminary Analysis of Genetic Markers for Functional Ethanol Tolerance in Honey Bees (Apis mellifera) Using a Free-Flying Paradigm.

Honey bees are a commonly used species for alcohol research due to their genome being fully sequenced, their behavioral changes following consumption, and their preference for alcohol. The purpose of this article is to provide a preliminary examination of the genetic expression of heat shock protein 70 (HSP70) and big potassium ion channel protein (BKP) in honey bees following the consumption of either 0%, 2.5%, 5%, or 10% ethanol (EtOH) solutions. The foraging behaviors of the bees were observed and recorded through their return and drinking times. There were significant differences in the return and drinking times between some of the groups. The bees in the 10% condition took significantly longer to return compared to the other groups. Additionally, the bees in the 5% group spent significantly more time drinking compared to the bees in the control (0%) group. There were no significant differences in HSP70 or BKP between the different ethanol groups. Cumulatively, these findings suggest that, while bees may exhibit behavioral differences, the differences in gene expression may not be observed at the transcriptional level.

PREVALENCE OF DOMESTIC VIOLENCE AMONGST WOMEN IN PUNJAB: A CROSS-SECTIONAL STUDY

The rise in domestic violence against women in India, especially in the pandemic and post-pandemic period, is an alarming issue that needs immediate attention. The dominant explanation for this emerging trend is structural inequality, internalized patriarchy, and misogyny. Factors such as patriarchal nature of society, hierarchy of relationships, perception of women as housewives, caregivers and child bearers they being the lower sex, encourage their suppression. Domestic violence in families is influenced by instability in relationships, excessive male power, control over the mobility of women, poverty, power relationships, preference for male offspring, alcohol and drug abuse by the male partner, and economic imbalance. This study has attempted to identify frequency of different forms of domestic violence such as physical violence, emotional violence, social violence, economic violence and sexual violence. The study revealed that all forms of violence were reported to be prevalent among the respondents. Considering each type of violence, emotional violence topped the chart, followed by economic violence and social violence. Respondents also reported to suffer from sexual violence and physical violence. The study suggests that for holistic sustainable development and women empowerment, different forms of domestic violence and causes/situations leading to it, needs to be identified. Additionally, the society needs to be sensitized how it affects the physiological, psychosocial and psychological wellness of women, at large, thus hampering their empowerment.

Psychopharmacological interaction of alcohol and posttraumatic stress disorder: Effective action of naringin

Posttraumatic stress disorder (PTSD) and alcohol use disorder (AUD) are prevalently co-occurring, important risk factors for a broad array of neuropsychiatric diseases. To date, how these two contrastive concomitant pairs increase the risk of neuropsychiatric states, notably exacerbating PTSD-related symptoms, remains unknown. Moreover, pharmacological interventions with agents that could reverse PTSD-AUD comorbidity, however, remained limited. Hence, we investigated the neuroprotective actions of naringin in mice comorbidly exposed to PTSD followed by repeated ethanol (EtOH)-induced AUD. Following a 7-day single-prolong-stress (SPS)-induced PTSD in mice, binge/heavy drinking, notably related to AUD, was induced in the PTSD mice with every-other-day ethanol (2 g/kg, p.o.) administration, followed by daily treatments with naringin (25 and 50 mg/kg) or fluoxetine (10 mg/kg), from days 8–21. PTSD-AUD-related behavioral changes, alcohol preference, hypothalamic-pituitary-adrenal (HPA)-axis dysfunction-induced neurochemical alterations, oxidative/nitrergic stress, and inflammation were examined in the prefrontal-cortex, striatum, and hippocampus. PTSD-AUD mice showed aggravated anxiety, spatial-cognitive, social impairments and EtOH intake, which were abated by naringin, similar to fluoxetine. Our assays on the HPA-axis showed exacerbated increased corticosterone release and adrenal hypertrophy, accompanied by marked dopamine and serotonin increase, with depleted glutamic acid decarboxylase enzyme in the three brain regions, which naringin, however, reversed, respectively. PTSD-AUD mice also showed increased TNF-α, IL-6, malondialdehyde and nitrite levels, with decreased antioxidant elements in the prefrontal-cortex, striatum, and hippocampus compared to SPS-EtOH-mice, mainly exacerbating catalase and glutathione decrease in the hippocampus relative SPS-mice. These findings suggest that AUD exacerbates PTSD pathologies in different brain regions, notably comprising neurochemical dysregulations, oxidative/nitrergic and cytokine-mediated inflammation, with HPA dysfunction, which were, however, revocable by naringin.

Effect of the glucagon-like peptide-1 (GLP-1) receptor agonist semaglutide on alcohol consumption in alcohol-preferring male vervet monkeys.

Glucagon-like peptide-1 (GLP-1) receptor agonists reduce alcohol consumption in rodents and non-human primates. Semaglutide is a new long-acting GLP-1 receptor agonist, widely used in the clinic against type 2 diabetes and obesity. It is also reported to reduce alcohol intake in rodents. This study investigates the possible inhibitory effect of semaglutide on alcohol intake in alcohol-preferring African green monkeys. We performed a vehicle-controlled study on male monkeys that had demonstrated a preference for alcohol. In the monkeys selected for voluntary alcohol drinking, alcohol consumption was measured for ten days at baseline (Monday to Friday for two weeks). During this period, the monkeys had access to alcohol 4h per day and free access to water 24h per day. After two weeks of baseline measurements, the monkeys were randomized to semaglutide or vehicle. Each group consisted of ten monkeys, and the two groups were balanced with respect to baseline alcohol intake. Following the baseline period, the monkeys were treated with escalating doses of semaglutide (up to 0.05mg/kg) or vehicle subcutaneously twice weekly for two weeks during which period alcohol was not available. After uptitration, the monkeys had access to alcohol 4h daily for 20 days (Monday to Friday for 4 weeks), and alcohol consumption was measured. During this alcohol exposure period, treatment with semaglutide (0.05mg/kg twice weekly) or vehicle continued for three weeks followed by a one-week washout period. Compared to the vehicle, semaglutide significantly reduced alcohol intake. There were no signs of emetic events or changes in water intake. These data demonstrate for the first time the potent effect of semaglutide in reducing voluntary alcohol intake in non-human primates and further substantiate the need for clinical trials investigating the effect of semaglutide in patients with alcohol-use disorder.

A Pilot Study: Treatment of High Alcohol Consumption in a Novel Minipig Model of Alcohol Use Disorder

ABSTRACT Three medications are FDA approved in the US for treatment of Alcohol Use Disorder (AUD), and a few others are used off-label. Patient compliance and efficacy in the broader population are major hurdles for current AUD medications. As a consequence, there is an urgent need for improved pharmacotherapeutics to complement behavioral approaches. Here, we report pilot testing of a minocycline analog, 10-butylether minocycline (BEM, 10 mg/kg p.o.), in two female minipigs with free-choice drinking to intoxication for nearly two and a half years. Each pig met DSM-5 criteria for diagnosis of severe AUD, and BEM reduced both alcohol intake and preference. BEM is currently undergoing testing for approval as an Investigational New Drug by the FDA for AUD treatment.

Standard rodent diets differentially impact alcohol consumption, preference, and gut microbiome diversity.

Alcohol use disorder (AUD) is a complex and widespread disease with limited pharmacotherapies. Preclinical animal models of AUD use a variety of voluntary alcohol consumption procedures to recapitulate different phases of AUD, including binge alcohol consumption and dependence. However, voluntary alcohol consumption in mice is widely variable, making it difficult to reproduce results across labs. Accumulating evidence indicates that different brands of commercially available rodent chow can profoundly influence alcohol intake. In this study, we investigated the effects of three commercially available and widely used rodent diet formulations on alcohol consumption and preference in C57BL/6 J mice using the 24 h intermittent access procedure. The three brands of chow tested were LabDiet 5,001 (LD5001), LabDiet 5,053 (LD5053), and Teklad 2019S (TL2019S) from two companies (Research Diets and Envigo, respectively). Mice fed LD5001 and LD5053 displayed higher levels of alcohol consumption and preference compared to mice fed TL2019S. We also found that alcohol consumption and preference could be rapidly switched by changing the diet 48 h prior to alcohol administration. Sucrose, saccharin, and quinine preferences were not altered, suggesting that the diets did not alter sweet and bitter taste perception. We also found that mice fed LD5001 displayed increased quinine-resistant alcohol intake compared to mice fed TL2019S, suggesting that diets could influence the development of compulsive behaviors such as alcohol consumption. We profiled the gut microbiome of water- and alcohol-drinking mice that were maintained on different diets and found significant differences in bacterial alpha- and beta-diversities, which could impact the gut-brain axis signaling and alcohol consumption.

Sodium Bicarbonate Decreases Alcohol Consumption in Mice

pH is an important biological factor in the brain as H+ alters the structure and function of many ion channels, transporters and receptors, thus affecting relevant synaptic activities and complex firing patterns. pH may change activities in the neural circuits responsible for motivation and reward, such that drug reward values or modulatory properties are modified to change drinking frequency and amount. In this study, we tested whether alcohol consumption can be affected by systemic pH in mice. C57BL/6J mice were given free access to 0.2 M NaHCO3 for 6 days, which resulted in a 0.2 pH unit increase compared to water-fed control mice ( p &lt; 0.05; n = 6/group). Mice were then subjected to voluntary alcohol consumption in the two-bottle free choice procedure with one bottle containing water and the other containing 5-20% alcohol (5% increment for 4 days each). NaHCO3-fed mice consumed similar amounts of 5-15% alcohol as pair-fed mice but decreased the consumption of 20% alcohol (p &lt; 0.05). Consistent with this result, NaHCO3-fed mice had decreased alcohol preference (i.e., alcohol intake/total fluid intake) at 20%. These changes were observed in both males and females. In separate experiments, mice were subjected to the two-bottle free choice procedure using water and 20% alcohol, with both bottles containing 0.05-0.4 M NaHCO3. The alcohol consumption was significantly decreased in the presence of 0.1 M or higher NaHCO3. The minimum effective dose of NaHCO3 was 0.08 g/kg body weight, calculated from the amount of alcohol mice consumed. Determined by the diarrhea scoring system, mice produced a normal state of feces after receiving 0.4 M NaHCO3 for 2 days, thus indicating negligible abdominal discomfort at this concentration. In other experiments, mice were given NaHCO3 by oral gavage and 1 hour later subjected to 20% alcohol in the drinking in the dark procedure. The alcohol consumption was significantly decreased in NaHCO3-fed mice, compared to pair-fed mice. In conclusion, our study shows that mildly raising blood pH by NaHCO3 decreases alcohol consumption in mice. Given that pH change has been considered as a consequence of alcohol metabolism, our data provide first evidence on the pH as a factor affecting alcohol consumption. This work was supported by the grant from the National Institute of Alcohol Abuse and Alcoholism (R21AA028606). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Inhibition of the Sodium-Calcium Exchanger Reverse Mode Activity Reduces Alcohol Consumption in Rats.

Excessive and uncontrolled consumption of alcohol can cause alcohol use disorder (AUD), but its pharmacological mechanisms are not fully understood. Inhibiting the reverse mode activity of the sodium-calcium exchanger (NCX) can reduce the risk of alcohol withdrawal seizures, suggesting that NCX could play a role in controlling alcohol consumption. Here, we investigated how two potent inhibitors of NCX reverse mode activity, SN-6 (NCX1) and KB-R7943 (NCX3), affect voluntary alcohol consumption in adult male and female rats using the intermittent alcohol access two-bottle choice paradigm. Initially, animals were trained to drink 7.5% ethanol and water for four weeks before administering SN-6 and KB-R7934. Afterward, their alcohol intake, preference, and water intake were recorded 2 and 24 h after exposure to water and 7.5% ethanol. SN-6 significantly reduced alcohol consumption by 48% in male and 36% in female rats without affecting their water intake. Additionally, SN-6 significantly reduced alcohol preference in females by 27%. However, KB-R7943 reduced alcohol consumption by 42% in female rats and did not affect alcohol preference or water intake. These findings suggest that alcohol exposure increased NCX reverse activity, and targeting NCX1 could be an effective strategy for reducing alcohol consumption in subjects susceptible to withdrawal seizures.

Surgical incision pain induced an increase in alcohol consumption in mice

IntroductionLarge population-based studies have suggested a link between increased alcohol use and reduced pain. In addition, these studies suggest that higher levels of pain intensity are associated with an increase in alcohol consumption and rates of hazardous drinking which potentiates the risk of developing alcohol use disorders (AUD). The mechanisms and determinants of the alcohol–pain interaction can be studied in preclinical studies. MethodsThe overall goal of this study is to use animal models to explore the impact of acute postoperative pain on alcohol intake. To achieve this, we characterized the timeline and levels of alcohol intake and preference in mice after laparotomy in the 2-bottle choice paradigm. ResultsOur results show that laparotomy surgery increased alcohol intake and preference in male mice but not females in the 2-bottle choice and 3-bottle choice assays. In addition, ketoprofen administration blocked the increase in alcohol consumption in male mice after laparotomy. We also found that changes in alcohol initial sensitivity and acute functional tolerance, using loss of righting reflex (LORR) response, occur after surgery in mice. ConclusionTaken together, these findings suggests that sex, pain and alcohol sensitivity-related factors may modulate the relationship between alcohol consumption and pain.

Epigenetic regulation of microglia and neurons by proinflammatory signaling following adolescent intermittent ethanol (AIE) exposure and in human AUD.

Adolescent alcohol drinking is linked to high rates of adult alcohol problems and alcohol use disorder (AUD). The Neurobiology of Alcohol Drinking in Adulthood (NADIA) consortium adolescent intermittent ethanol (AIE) models adolescent binge drinking, followed by abstinent maturation to adulthood to determine the persistent AIE changes in neurobiology and behavior. AIE increases adult alcohol drinking and preference, increases anxiety and reward seeking, and disrupts sleep and cognition, all risks for AUD. In addition, AIE induces changes in neuroimmune gene expression in neurons and glia that alter neurocircuitry and behavior. HMGB1 is a unique neuroimmune signal released from neurons and glia by ethanol that activates multiple proinflammatory receptors, including Toll-like receptors (TLRs), that spread proinflammatory gene induction. HMGB1 expression is increased by AIE in rat brain and in post-mortem human AUD brain, where it correlates with lifetime alcohol consumption. HMGB1 activation of TLR increase TLR expression. Human AUD brain and rat brain following AIE show increases in multiple TLRs. Brain regional differences in neurotransmitters and cell types impact ethanol responses and neuroimmune gene induction. Microglia are monocyte-like cells that provide trophic and synaptic functions, that ethanol proinflammatory signals sensitize or "prime" during repeated drinking cycles, impacting neurocircuitry. Neurocircuits are differently impacted dependent upon neuronal-glial signaling. Acetylcholine is an anti-inflammatory neurotransmitter. AIE increases HMGB1-TLR4 signaling in forebrain, reducing cholinergic neurons by silencing multiple cholinergic defining genes through upregulation of RE-1 silencing factor (REST), a transcription inhibitor known to regulate neuronal differentiation. HMGB1 REST induction reduces cholinergic neurons in basal forebrain and cholinergic innervation of hippocampus. Adult brain hippocampal neurogenesis is regulated by a neurogenic niche formed from multiple cells. In vivo AIE and in vitro studies find ethanol increases HMGB1-TLR4 signaling and other proinflammatory signaling as well as reducing trophic factors, NGF, and BDNF, coincident with loss of the cholinergic synapse marker vChAT. These changes in gene expression-transcriptomes result in reduced adult neurogenesis. Excitingly, HMGB1 antagonists, anti-inflammatories, and epigenetic modifiers like histone deacetylase inhibitors restore trophic the neurogenesis. These findings suggest anti-inflammatory and epigenetic drugs should be considered for AUD therapy and may provide long-lasting reversal of psychopathology.

FARESHARE: An open-source apparatus for assessing drinking microstructure in socially housed rats

Social factors have been shown to play a significant and lasting role in alcohol consumption. Studying the role of social context on alcohol drinking is important to understand the factors that contribute to the initiation or maintenance of casual and problematic alcohol use, as well as those that may be protective. A substantial body of preclinical research has shown that social environment such as housing conditions and social rank plays an important role in alcohol consumption and preference, though the extent of these effects have been obfuscated by methodological differences and technical challenges. Robust individual differences in alcohol intake in socially housed animals are difficult to track when animals share a common fluid source. Commercial solutions are prohibitively expensive and are limited by proprietary software and hardware (including caging systems). Here we describe FARESHARE, an affordable, open-source solution for tracking fluid consumption in socially housed rats. The device uses RFID and custom hardware to individually measure and record each rat’s fluid consumption and licking microstructure. Each bout is also timestamped such that the circadian effects of drinking behaviour may be analysed. We provide a validation showing the operation of the device in a two-bottle-choice alcohol-drinking paradigm over a nine-day period in four group-housed female rats. We show that FARESHARE is able to capture traditional measures such as daily intake and preference, as well as circadian effects, microstructure, and individual variations in drinking.

Influence of Inherited Seizure Susceptibility on Intermittent Voluntary Alcohol Consumption and Alcohol Withdrawal Seizures in Genetically Epilepsy-Prone Rats (GEPR-3s).

The link between epilepsy and alcohol consumption is complex, with conflicting reports. To enhance our understanding of this link, we conducted a study to determine how inherited seizure susceptibility affects voluntary alcohol consumption and influences alcohol withdrawal seizures in male and female genetically epilepsy-prone rats (GEPR-3s) compared to Sprague Dawley (SD) rats. In the first experiment, animals were given access to two bottles simultaneously, one containing water and the other 7.5%, 15%, or 30% (v/v) alcohol three times a week for each dose after acclimation to drinking water. In a second experiment, animals were tested for acoustically evoked alcohol seizures 24 h after the last session of voluntary alcohol consumption. Analysis revealed that GEPR-3s (males and females) had lower alcohol intake and preference than SD rats, particularly at lower alcohol concentrations. However, female GEPR-3s consumed more alcohol and had a higher alcohol preference than males. Furthermore, withdrawal from voluntary alcohol consumption facilitated the onset and duration of seizures in GEPR-3s. Our study suggests that genetic seizure susceptibility in GEPR-3s is negatively associated with alcohol consumption. However, withdrawal from low to moderate amounts of alcohol intake can promote epileptogenesis in the epileptic GEPR-3s.