Alcohol Preference Research Articles

Pain, Anxiety- and Depression-Like Behaviors in Alcohol-Preferring and -NonPreferring Rats

Introduction: Psychiatric disorders such as anxiety, hyperalgesia, and depression have been associated with excessive alcohol drinking, but the neuronal mechanisms involved are only partially understood. Alcoholism more often occurs in individuals with a family history, indicating that genes may play a critical role. Chronic alcohol exposure alters calcium/calmodulin-dependent protein kinase II (CaMKII) signaling in the lateral habenula (LHb), and the LHb is implicated in mediating aversive behaviors, including those related to alcohol. We compared the CaMKII signaling in the LHb and the aberrant behaviors in the selectively bred alcohol-preferring (P) and alcohol-non-preferring (NP) lines of rats. Materials and Methods: The responses to mechanical (Von Frey) and thermal (Hargreaves) nociception tests, anxiety- (elevated plus maze, Marble burying) and depressive-like behaviors (forced swimming) were examined in the alcohol-naïve P and NP rats, as well as in P rats after 4-8 weeks of alcohol consumption; their LHb tissues were also collected for Western blot analysis of CaMKII expression. Results: Compared to NP rats, the P rats had a higher sensitivity to mechanical stimuli, and displayed depressive- and anxiety-like behaviors, as well as a higher level of CaMKII in the LHb. Alcohol consumption alleviated all these behaviors, except for anxiety, and decreased CaMKII levels in the LHb of P rats. Conclusions: The results show that selective breeding for different oral alcohol preference has produced differences in nociception, anxiety, and depression, as well as CaMKII expression in the LHb of P and NP rats. P rats may deal with pain and depression by self-medicating with alcohol.

Brainstem expression of SLC6A4, HTR2C, NGF, BDNF, TRKANGF, TRKBBDNF and P75NTR following paternal alcohol exposure in the male mouse

We previously showed in the mouse that paternal preconception alcohol exposure (PPAE) affects alcohol sensitivity by analyzing postnatal alcohol preference in the offspring. In this mouse study by using the same animals of the previous investigation we aimed at examining whether or not PPAE may disrupt the epigenetic regulation of postnatal alcohol sensitivity in the offspring by investigating pathways regulating mood, emotion, serotonergic tone and neurotrophins such as nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF). We analyzed the brainstem gene expression of serotonin transporter Solute Carrier Family 6 Member4 (SLC6A4), 5-Hydroxytryptamine Receptor 2C (HTR2C) binding the neurotransmitter serotonin, and NGF, BDNF and their tropomyosin receptor kinase A (TrkANGF) and B (TrKBBDNF) (high-affinity NGF and BDNF receptors) and p75NTR (low-affinity, pan-neurotrophins receptor) in adult offspring that underwent or not postnatal alcohol exposure. We found SLC6A4 elevation and decreased HTR2C in the offspring of chronic alcohol-exposed sires. We also disclosed p75NTR elevation in the offspring of chronically exposed sires as well as postnatal sensitization to low alcohol doses in the offspring of chronically exposed sires for both TrKBBDNF and BDNF. In our PPAE mouse model, where genotype effects can be carefully measured, we observed that the sires’ exposure to alcohol before mating might disrupt the sensitivity to the serotonergic/neurotrophic-associated effects of alcohol influencing the postnatal alcohol preference in the offspring.

A novel pharmacotherapy approach using P-glycoprotein (PGP/ABCB1) efflux inhibitor combined with ivermectin to reduce alcohol drinking and preference in mice.

Alcohol use disorder (AUD) has a major national impact, affecting over 18 million people, causing approximately 88,000 deaths, and costing upward of $250 billion annually in the United States. Unfortunately, FDA-approved AUD pharmaceuticals are few, and clinical benefits are mostly ineffective in patients suffering from AUD. Therefore, the identification of novel targets and/or innovative methods for the development of safe and effective medications represents a critical public health need. Previously, we reported that avermectin compounds (ivermectin [IVM] and moxidectin [MOX]) significantly reduced ethanol intake in male and female mice. However, avermectin compounds are readily effluxed by P-glycoprotein (Pgp/ABCB1) in the blood-brain barrier (BBB), resulting in reduced retention time by the drugs in the central nervous system (CNS). As such, the doses of IVM or MOX and the time frame for significant reductions of ethanol intake are not ideal. Here we evaluate a novel combinatorial strategy involving IVM and tariquidar (TQ), a third-generation efflux inhibitor of Pgp, to reduce the dosing necessary for improving alcohol (ethanol) consumption behavior. We tested male C57BL/6J mice using a two-bottle choice study to evaluate ethanol consumption and preference. We found that injecting 10mg/kg of TQ 30min prior to IVM resulted in a five-fold improvement in the efficacy of IVM (dosed at 0.5mg/kg), resulting in a significant reduction in ethanol intake and preference. Notably, the reduction by IVM was well tolerated, and no adverse effects were identified when tested at doses ranging from 0.50mg/kg to 2.0mg/kg. Collectively, our findings indicate that IVM, in combination with TQ, increases its efficacy in the CNS for reducing ethanol consumption. This work demonstrates a novel combinatorial drug strategy that allows new opportunities for drugs with poor CNS retention, such as IVM, to demonstrate improved potency and potentially improved safety.

Predicting relapse in patients with severe alcohol use disorder: The role of alcohol insight and implicit alcohol associations

Low insight is reported as a risk factor for relapse among patients treated for alcohol use disorders. However, to date, little is known on why patients with low insight are at higher risk for relapse. In this study, we tested the hypothesis that an implicit preference for alcohol over abstinence predicts relapse in patients with low, but not high, alcohol insight. Participants consisted of 77 patients who had received treatment for severe alcohol use disorder in a hospital in France. During hospitalization, they completed a self-report measure of insight and an implicit association test to assess implicit preference for alcohol over abstinence. The primary outcome was relapse assessed one month after discharge. Control variables were gender, age, cognitive deficit, anxiety, depression, craving, and impulsivity. Data were analysed using logistic regression analysis. After adjusting for demographic and clinical variables, relapse was predicted by the interaction between insight and implicit preference for alcohol but not by their main effects alone. Implicit preference for alcohol predicted relapse among patients with relatively low insight, but not among those with relatively high insight. These findings suggest that patients with low insight and strong implicit preference for alcohol are at a higher risk of relapse. Clinicians may therefore focus on and tailor specific interventions to prevent relapse in this vulnerable and at-risk population.

Inhibition of Receptor Protein Tyrosine Phosphatase β/ζ Reduces Alcohol Intake in Rats.

Pleiotrophin (PTN) and midkine (MK) are cytokines that are up-regulated in the prefrontal cortex (PFC) after alcohol administration and have been shown to reduce alcohol intake and reward. Both cytokines are endogenous inhibitors of receptor protein tyrosine phosphatase (RPTP) β/ζ (a.k.a. PTPRZ1). Recently, a new compound named MY10 was designed with the aim of mimicking the activity of PTN and MK. MY10 has already shown promising results regulating alcohol-related behaviors in mice. We have now tested the effects of MY10 on alcohol operant self-administration and Drinking In the Dark-Multiple Scheduled Access (DID-MSA) paradigms in rats. Gene expression of relevant genes in the PTN/MK signaling pathway in the PFC was analyzed by real-time PCR. MY10, at the highest dose tested (100mg/kg), reduced alcohol consumption in the alcohol operant self-administration paradigm (p=0.040). In the DID-MSA paradigm, rats drank significantly less alcohol (p=0.019) and showed a significant decrease in alcohol preference (p=0.002). We observed that the longer the exposure to alcohol, the greater the suppressing effects of MY10 on alcohol consumption. It was demonstrated that the effects of MY10 were specific to alcohol since saccharin intake was not affected by MY10 (p=0.804). MY10 prevented the alcohol-induced down-regulation of Ptprz1 (p=0.004) and anaplastic lymphoma kinase (Alk; p=0.013) expression. Our results support and provide further evidence regarding the efficacy of MY10 on alcohol-related behaviors and suggest the consideration of the blockade of RPTPβ/ζ as a target for reducing excessive alcohol consumption.

Assessing effects of oxytocin on alcohol consumption in socially housed prairie voles using radio frequency tracking.

Alcohol use disorder affects millions of people each year. Currently approved pharmacotherapies have limited success in treating this disorder. Evidence suggests that this lack of success is partly due to how these pharmacotherapies are tested in preclinical settings. The vast majority of preclinical studies assessing the effects of pharmacotherapies on alcohol or drug self-administration are done in individually housed animals. However, it is known that alcohol and drug intake are heavily influenced by social settings. Here, we adapted radio frequency tracking technology to determine the effects of oxytocin, a potential therapy for alcohol use disorder, on alcohol consumption in socially housed male and female prairie voles. Voluntary alcohol consumption in these animals resulted in high daily alcohol intakes, blood ethanol concentrations that are considered intoxicating, and central changes in FosB immunoreactivity, indicative of changes in neural activity. Prairie voles that received oxytocin temporarily reduced alcohol consumption but not alcohol preference, compared with control prairie voles regardless whether their cagemates received a similar treatment or not. Our results demonstrate that oxytocin can decrease consummatory behaviors in the presence of peers that are not receiving this treatment, and therefore, its potential use in clinical trials is warranted. Moreover, effectiveness of other pharmacotherapies in preclinical studies can be tested in mixed-treatment socially housed animals similarly to clinical studies in humans.

Differential regulation of alcohol consumption and reward by the transcriptional cofactor LMO4.

Repeated alcohol exposure leads to changes in gene expression that are thought to underlie the transition from moderate to excessive drinking. However, the mechanisms by which these changes are integrated into a maladaptive response that leads to alcohol dependence are not well understood. One mechanism could involve the recruitment of transcriptional co-regulators that bind and modulate the activity of transcription factors. Our results indicate that the transcriptional regulator LMO4 is one such candidate regulator. Lmo4-deficient mice (Lmo4gt/+) consumed significantly more and showed enhanced preference for alcohol in a 24 h intermittent access drinking procedure. shRNA-mediated knockdown of Lmo4 in the nucleus accumbens enhanced alcohol consumption, whereas knockdown in the basolateral amygdala (BLA) decreased alcohol consumption and reduced conditioned place preference for alcohol. To ascertain the molecular mechanisms that underlie these contrasting phenotypes, we carried out unbiased transcriptome profiling of these two brain regions in wild type and Lmo4gt/+ mice. Our results revealed that the transcriptional targets of LMO4 are vastly different between the two brain regions, which may explain the divergent phenotypes observed upon Lmo4 knockdown. Bioinformatic analyses revealed that Oprk1 and genes related to the extracellular matrix (ECM) are important transcriptional targets of LMO4 in the BLA. Chromatin immunoprecipitation revealed that LMO4 bound Oprk1 promoter elements. Consistent with these results, disruption of the ECM or infusion of norbinaltorphimine, a selective kappa opioid receptor antagonist, in the BLA reduced alcohol consumption. Hence our results indicate that an LMO4-regulated transcriptional network regulates alcohol consumption in the BLA.

Impact of Social Conformity on Ethanol Preference in Wistar Rats

Introduction: Social conformity is considered a possible promoter of alcohol use disorder in humans. The goal of this study was to explore the impact of conformity as one of the social factors that might contribute to the alcohol preference in a rat model of ethanol intake. Methods: To model social conformity, 105 Wistar rats were group housed (3 animals per cage) with a different number of rats drinking either 10% ethanol or water during daily drinking sessions. Ethanol preference tests were performed. Results: Ethanol preference significantly increased if the majority of cage mates received ethanol during drinking sessions. The analysis also showed an increase in the number of approaches to the ethanol bottle versus the water bottle and an increased duration of a single ethanol approach during the 2 bottle preference test in such groups. Conclusion: These results demonstrate that social conditions promote the ethanol consumption in the novel conformity model used in this study.

Effects of pair housing on voluntary alcohol intake in male and female Wistar rats.

A number of different voluntary alcohol intake paradigms are available for home cage drinking studies. Traditionally, these paradigms involve single housing in order for individual intake to be measured. This study aimed at investigating the effects of pair housing on voluntary alcohol intake. Male and female Wistar rats were housed in pairs or individually for studies of voluntary alcohol intake using the modified intermittent access paradigm with alcohol access during three consecutive days per week followed by four days of water only. Individual intake of 20% alcohol solution and water was measured during 12 sessions, i.e., 4 weeks. Pair-housed animals could interact freely with their cage mate for four consecutive days each week and were then separated by an inserted mesh divider for three consecutive days each week during alcohol intake sessions. Alcohol intake and preference were compared between pair-housed and individually housed rats. The results revealed higher alcohol intake in females than in males. Pair-housed males had a higher alcohol intake and preference during the first 3 weeks, but not during the fourth week, compared to individually housed males No effect of housing condition was observed in female rats. The alcohol intake was higher on the first day of access relative to the two consecutive days in pair-housed males and higher on the first two days relative to the third day in female rats. Social rank or female estrus cycle had no effect on alcohol intake or preference. Taken together, the use of a divider during alcohol intake sessions had no impact on alcohol intake in female rats and may not exert long-term influences in male rats. Future studies are needed in order to elucidate whether the use of a divider can constitute an experimental refinement as an alternative to individual housing in studies of voluntary alcohol intake using the limited access and/or intermittent access paradigms.

DNA methylation in the medial prefrontal cortex regulates alcohol-related behavior in rats.

Alcohol abuse causes tissue and organ damage, and may participate neuropsychiatric diseases. Studies have shown that DNA methylation plays an important role in gene expression and behavioral changes induced by alcohol, however the causative neurobiological mechanisms have not been clarified. In this study, 32 healthy adult male SD rats were randomly divided into a drinking water control group (n=16) and a chronic alcohol exposure group (n=16). The alcohol preference and locomotor activity of rats were evaluated by two-bottle choice test (TBCT) and open-field test (OFT). DNA methylation in the medial prefrontal cortex (mPFC) tissue was detected by the reduced representative bisulfite sequencing (RRBS) technology. The methylation differential genes closely related to alcohol abuse were screened. qRT-PCR was used to verify the mRNA expression patterns of differential genes. qRT-PCR and Western blot were used to detect the expression of DNA methyltransferases (DNMTs) and methyl CpG binding protein 2 (MeCP2). Furthermore, the effect of short-term alcohol exposure (7 days) on DNMTs and MeCP2 in the mPFC of rats was tested (n=8/group). The results indicated that the methylation level of promoter region in the mPFC of rats exposed to chronic alcohol was significantly increased. In addition, the increased methylation levels in the promoter of Ntf3 and Ppm1G were accompanied by down-regulated mRNA levels in the chronic alcohol exposure group. The decreased methylation levels in the promoter of Hap1 and DUSP1 were accompanied by up-regulated mRNA levels. Furthermore, chronic alcohol exposure increased the mRNA and protein levels of DNMT3B and MeCP2. However, short term alcohol exposure did not affect their expression. This present study provides evidence that DNA methylation is associated with the development of alcohol abuse, which may be regulated by DNMT3B and MeCP2. The target genes Ntf3, Ppm1G, Hap1, and DUSP1 related to alcohol abuse were discovered as well, providing new insights into the neurobiological mechanism of alcohol abuse and the potential pharmacological targets for the treatment of alcohol abuse.

The Physiological Effects of FGF21 on Alcohol Preference and Glucose Metabolism

The Physiological Effects of FGF21 on Alcohol Preference and Glucose Metabolism

RNA Editing of Serotonin 2C Receptor and Alcohol Intake.

Serotonin 2C receptor (5-HT2CR) belongs to the superfamily of seven transmembrane domain receptors coupled to G proteins (GPCR). It is broadly distributed in the CNS and its expression is relatively high in the limbic system including the amygdala, nucleus accumbens (NAc), hippocampus, and hypothalamus. Based on its expression patterns and numerous pharmacological studies, 5-HT2CR is thought to be involved in various brain functions including emotion, appetite, and motor behavior. Here, we review 5-HT2CR and its relationship with alcohol intake with a particular focus on the involvement of 5-HT2CR mRNA editing and its association with alcohol preference in mice. RNA editing is a post-transcriptional modification mechanism. In mammals, adenosine is converted to inosine by the deamination enzymes ADAR1 and ADAR2. 5-HT2CR is the only GPCR subjected to RNA editing within the coding region. It has five editing sites in exon 5 that encode the second intracellular loop. Consequently, three amino acids residues (I156, N158, and I160) of the unedited receptor (INI) may be altered to differently edited isoforms, resulting in a change of receptor activity such as 5-HT potency and G-protein coupling. 5-HT2CR in the NAc is involved in enhanced alcohol drinking after chronic alcohol exposure and alterations in 5-HT2CR mRNA editing is important in determining the alcohol preference using different strains of mice and genetically modified mice. RNA editing of this receptor may participate in the development of alcoholism.

Differential sensitivity of alcohol drinking and partner preference to a CRFR1 antagonist in prairie voles and mice

Available pharmacotherapies to treat alcohol use disorder (AUD) show limited efficacy. Preclinical studies in mice and rats suggested that antagonists of the corticotropin releasing factor receptor 1 (CRFR1) could be more efficacious for such treatment. However, clinical trials with CRFR1 antagonists were not successful. While a number of potential explanations for this translational failure have been suggested, we hypothesized that the lack of success in clinical trials could be in part due to different neuroanatomical organization of the CRFR1 system in mice and rats versus humans. The CRF system in prairie voles (Microtus ochrogaster), a socially monogamous rodent species, also shows differences in organization from mice and rats. To test our hypothesis, we compared the efficacy of a potent CRFR1 antagonist, CP-376,395, to modulate alcohol drinking in male and female prairie voles versus male and female C57BL/6J mice using an almost identical 2-bottle choice drinking procedure. CP-376,375 (10 and 20 mg/kg, i.p.) significantly decreased alcohol intake (but not alcohol preference) in mice, but not prairie voles. Furthermore, administration of this antagonist (20 mg/kg, i.p.) prior to the partner preference test (PPT) decreased partner preference (PP) in male prairie voles. These findings support our hypothesis that the greater efficacy of CRFR1 antagonists to suppress alcohol consumption in mice and rats versus other mammalian species could be due to the differences in organization of the CRFR1 system between species. They further indicate that activity of the CRFR1 system is necessary for the formation of pair-bonds, but not consumption of high doses of alcohol. Overall, we suggest that testing potential pharmacotherapies should not rely only on studies in mice and rats.

Inhibition of the Inflammasome Signaling Cascade Reduces Alcohol Consumption in Female But Not Male Mice.

Alcohol use disorder is a significant societal and medical burden that is associated with both organ pathology and addiction. Excessive alcohol use results in neuroinflammation characterized by activation of the inflammasome, a multiprotein complex, and IL-1β increase in the brain. Recent studies suggest that inflammation could contribute to alcohol addiction. Here, we targeted components of the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome cascade, which senses and responds to immunologic stimuli, to determine whether NLRP3 inhibition modulates alcohol consumption. C57BL/6J male and female mice were provided a 2-bottle choice of alcohol at increasing concentrations (3, 6, 9, and 12%, 4days each) or water, and some were treated with daily injections of an NLRP3 inhibitor (MCC950), a caspase-1 inhibitor (VX765), IL-1 receptor antagonist (IL-1ra; anakinra), or vehicle injection. Treatment with VX765, MCC950, and IL-1ra significantly reduced alcohol consumption and preference in female mice (p<0.05). Treatment with MCC950 and IL-1ra reduced alcohol consumption, while IL-1ra reduced alcohol preference in male mice (p<0.05). VX765 did not affect alcohol consumption or preference in male mice. These findings highlight gender differences in alcohol preference and demonstrate that inhibition of different steps in inflammasome signaling can reduce alcohol consumption in females. Inhibition of NLRP3 inflammasome activation and the inflammasome-IL-1β cascade opens novel insights into the development of new therapies to address alcohol use disorder in an era of targeted and precision medicine.

Effect of Lesioning the Ventral Tegmental Area on Food Intake, Water Intake, Body Weight and Alcohol Consumption in Wistar Albino Rats.

To study the effect of lesion of the ventral tegmental area (VTA) on food intake, water intake, alcohol consumption, and alcohol preference in the post-lesion period. A group of 38 young adult healthy male Wistar albino rats was included in this experiment. The groups of rats were subjected to the bilateral electrolytic lesion of VTA, and the effect on water intake, food intake, alcohol consumption, and alcohol preference in the post-lesion period was analyzed. A sham lesioned control group was maintained for all experimental groups. There was no change observed in food intake and the body weight in lesioned animals (p > 0.05). It was found that increased water intake was observed if only water was given. There was also increased alcohol intake when alcohol was only provided (p < 0.05). However, two bottle-free choice tests for alcohol preference revealed that the rats preferred to consume water and not alcohol when the choice was given. There was an increase in the total volume consumed (p < 0.05). There was an increase in water intake and no notable changes in the food intake and body weight following the lesion. When offered alone, alcohol consumption was raised, but when a choice of alcohol and water was given in a two-bottle freechoice test, rats preferred to drink water. The present study suggests that VTA lesions may be associated with increased thirst and high fluid consumption, which may have implications in water balance.

The regulatory role of neurotransmitters in orexin b induced nucleus accumbens dependent alcohol ingestion in Wistar albino rats

Objective: The Present study mainly focussed on the influential role of local neurotransmitter level in Orexin B induced Nucleus Accumbens (NAc) dependent voluntary ethanol consumption and preference. Methods: NAc in male Wistar rats were infused by Orexin B (low dose-3 nmol/μl and high dose 30nmol/μl) and Orexin B antagonist (TCS-OX2–29) (10μg/μl) sequentially. Food intake, alcohol intake, and two-bottle free choice preference tests (alcohol vs. water) were carried out at one hour, 2 hrs, 4 hrs, 12 hours, and 24 hrs in all the groups. Neurotransmitters level in the Nucleus Accumbens was also estimated at the end of the study. Results: Orexin B (30nm/μl) increased net alcohol intake in single-bottle test as well as in two-bottle free choice test. Whereas, Orexin B antagonist decreased alcohol consumption and preference to ethanol. Glutamate level significantly decreased and Dopamine and noradrenaline concomitantly increased. Conclusions: Orexin B plays a role in the modulation of ethanol consumption and preference confirmed by Orexin B antagonist infusion. The influence of neurotransmitter levels in Orexin B mediated ethanol consumption was also explored.

Differences in Alcohol Consumption and Preferences for Types of Alcoholic Beverages in OECD Countries

Differences in Alcohol Consumption and Preferences for Types of Alcoholic Beverages in OECD Countries

Alcohol dependence and opioid receptor -Pharmacological profile of nalmefene

Alcohol dependence is one of the psychiatric disorders affecting over 1 million people in Japan. Mesolimbic dopamine neuron projecting from ventral tegmental area to nucleus accumbens (Reward system) plays important roles in alcohol dependence including other dependence. Accumulating evidence indicates that the endogenous opioid system regulate this reward system. That is, alcohol stimulates the release of endogenous opioid peptides such as β-endorphin and dynorphin in the brain. β-endorphin activates μ-opioid receptor leading to euphoric mood and positive reinforcement, while dynorphin activates κ-opioid receptor leading to dysphoric mood and negative reinforcement. These euphoric/dysphoric mood and reinforcement effects via endogenous opioid systems are suggested to be implicated in repeated alcohol intake in patients with alcohol dependence. Nalmefene acts as an antagonist at μ- and δ-opioid receptor and a partial agonist at κ-opioid receptor. Preclinical studies have shown that nalmefene reduced the alcohol intake in alcohol preference rats. In clinical trials, as-needed use of nalmefene with psychosocial support reduced the number of heavy-drinking days and total alcohol consumption. These results suggest that nalmefene modulates the alcohol-induced euphoric/dysphoric mood via opioid system and thereby contribute to reduction in alcohol consumption in patients with alcohol dependence. Here, we summarize the implications of opioid system in alcohol dependence and pharmacological profiles of nalmefene in preclinical and clinical studies.

Increased alcohol preference and intake in nicotine-preferring rats

ABSTRACT Background Alcohol and tobacco are among the leading substances that are misused together and shared genetic vulnerability is likely. Increased susceptibility to nicotine self-administration has been shown in alcohol-preferring rat-lines. However, a nicotine-preferring (nP) rat-line has not been studied for alcohol preference. Objectives To evaluate alcohol preference and intake in male and female nP rats. We hypothesized that nP rats and females would drink more ethanol than control rats and males, respectively. Methods nP rats are being selectively outbred for high oral nicotine intake at Ege University. Seventeen nP (18th generation) and 20 naïve female and male SD rats, not previously exposed to alcohol or nicotine, were used. Twelve-week-old rats were given intermittent access to 20% ethanol in a 2-bottle-choice-procedure for six weeks. After one week withdrawal, six weeks of oral nicotine self-administration was applied. Results nP rats drank significantly more ethanol than controls and their preference for ethanol over water was higher. Female rats’ ethanol intake was higher than males’. The nP rats’ nicotine preference and intake were higher than controls, and they gained less weight. Conclusion We have shown for the first time that nP rats also have high alcohol intake. Our results support the hypothesis that shared genetic factors may underlie concurrent addiction to nicotine and alcohol and have translational value in understanding their misuse. Considering the increased vulnerability for alcohol use disorder in smokers and sex differences observed, early preventive measures in families with a history of tobacco addiction, specifically targeting female members, could have public health benefits.

Unequal interactions between alcohol and nicotine co-consumption: suppression and enhancement of concurrent drug intake.

Alcohol and nicotine addiction are prevalent conditions that co-occur. Despite the prevalence of co-use, factors that influence the suppression and enhancement of concurrent alcohol and nicotine intake are largely unknown. Our goals were to assess how nicotine abstinence and availability influenced concurrent alcohol consumption and to determine the impact of quinine adulteration of alcohol on aversion-resistant alcohol consumption and concurrent nicotine consumption. Male and female C57BL/6J mice voluntarily consumed unsweetened alcohol, nicotine, and water in a chronic 3-bottle choice procedure. In experiment 1, nicotine access was removed for 1week and re-introduced the following week, while the alcohol and water bottles remained available at all times. In experiment 2, quinine (100-1000μM) was added to the 20% alcohol bottle, while the nicotine and water bottles remained unaltered. In experiment 1, we found that alcohol consumption and preference were unaffected by the presence or absence of nicotine access in both male and female mice. In experiment 2a, we found that quinine temporarily suppressed alcohol intake and enhanced concurrent nicotine, but not water, preference in both male and female mice. In experiment 2b, chronic quinine suppression of alcohol intake increased nicotine consumption and preference in female mice without affecting water preference, whereas it increased water and nicotine preference in male mice. Quinine suppression of alcohol consumption enhanced the preference for concurrent nicotine preference in male and female mice, suggesting that mice compensate for the quinine adulteration of alcohol by increasing their nicotine preference.