Catechol-O-Methyltransferase inhibition and alcohol use disorder: Evaluating the efficacy of tolcapone in ethanol-dependent rats.

Alcohol Use Disorder (AUD) is a significant public health issue in the United States. It affects millions of individuals and their families and contributes to substantial societal and economic burdens. Despite the availability of some pharmacological treatments, there is still a pressing need to develop more effective therapeutic strategies to address the diverse range of symptoms and challenges associated with AUD.

Removal of the ovaries suppresses ethanol drinking and promotes aversion-resistance in C57BL/6J female mice.

Rationale: Female rodents consume more ethanol (EtOH) than males and exhibit greater aversion-resistant drinking in some paradigms. Ovarian hormones promote EtOH drinking but the contribution of ovarian hormones to aversion-resistant drinking has not been assessed.

Objectives: We aimed to investigate the role of ovarian hormones to aversion-resistant drinking in female mice in a drinking in the dark (DID) task.

Sex chromosome and gonadal hormone contributions to binge-like and aversion-resistant ethanol drinking behaviors in Four Core Genotypes mice.

Introduction: While substantial research has focused on the contribution of sex hormones to driving elevated levels of alcohol drinking in female rodents, fewer studies have investigated how genetic influences may underlie sex differences in this behavior.

Methods: We used the Four Core Genotypes (FCG) mouse model to explore the contribution of sex chromosome complement (XX/XY) and gonad type [ovaries ()/testes ()] to ethanol (EtOH) consumption and quinine-resistant drinking across two voluntary self-administration tasks: limited access consumption in the home cage and an operant response task.

Results: For limited access drinking in the dark, XY/ (vs.

Greater resistance to footshock punishment in female C57BL/6J mice responding for ethanol.

Background: One characteristic of alcohol use disorder is compulsive drinking or drinking despite negative consequences. When quinine is used to model such aversion-resistant drinking, female rodents typically are more resistant to punishment than males. Using an operant response task where C57BL/6J responded for ethanol mixed with quinine, we previously demonstrated that female mice tolerate higher concentrations of quinine in ethanol than males.

Effects of early life stress paired with adolescent alcohol consumption on two-bottle choice alcohol drinking behaviors in mice.

Background: In humans, early life stress (ELS) is associated with an increased risk for developing both alcohol use disorder (AUD) and post-traumatic stress disorder (PTSD). We previously used an infant footshock model that produces stress-enhanced fear learning (SEFL) in rats and mice and increases aversion-resistant alcohol drinking in rats to explore this shared predisposition. The goal of the current study was to extend this model of comorbid PTSD and AUD to male and female C57BL/6J mice.

Crossed high alcohol preferring mice exhibit aversion-resistant responding for alcohol with quinine but not footshock punishment.

A symptom of alcohol use disorder (AUD) is compulsive drinking, or drinking that persists despite negative consequences. In mice, aversion-resistant models are used to model compulsive-like drinking by pairing the response for alcohol with a footshock or by adding quinine, a bitter tastant, to the alcohol solution. crossed High Alcohol Preferring (cHAP) mice, a selectively bred line of mice that consumes pharmacologically relevant levels of alcohol, demonstrate a high level of aversion-resistance to quinine-adulterated alcohol.

Gonadal hormones and sex chromosome complement differentially contribute to ethanol intake, preference, and relapse-like behaviour in four core genotypes mice.

Alcohol use and high-risk alcohol drinking behaviours among women are rapidly rising. In rodent models, females typically consume more ethanol (EtOH) than males. Here, we used the four core genotypes (FCG) mouse model to investigate the influence of gonadal hormones and sex chromosome complement on EtOH drinking behaviours.

Orbitofrontal cortex subregion inhibition during binge-like and aversion-resistant alcohol drinking.

Two important contributors to alcohol-related problems and alcohol use disorder (AUD) are binge- and compulsive-like drinking. The orbitofrontal cortex (OFC), a brain region implicated in outcome valuation and behavioral flexibility, is functionally altered by alcohol exposure. Data from animal models also suggest that both the medial (mOFC) and lateral (lOFC) subregions of the OFC regulate alcohol-related behaviors.

Recent Perspectives on Sex Differences in Compulsion-Like and Binge Alcohol Drinking.

Alcohol use disorder remains a substantial social, health, and economic problem and problem drinking levels in women have been increasing in recent years. Understanding whether and how the underlying mechanisms that drive drinking vary by sex is critical and could provide novel, more targeted therapeutic treatments. Here, we examine recent results from our laboratories and others which we believe provide useful insights into similarities and differences in alcohol drinking patterns across the sexes.

Studying Sex Differences in Rodent Models of Addictive Behavior.

Animal models of addictive behaviors are useful for uncovering neural mechanisms involved in the development of dependence and for identifying risk factors for drug abuse. One such risk factor is biological sex, which strongly moderates drug self-administration behavior in rodents. Female rodents are more likely to acquire drug self-administration behaviors, consume higher amounts of drug, and reinstate drug-seeking behavior more readily.

The contribution of medium spiny neuron subtypes in the nucleus accumbens core to compulsive-like ethanol drinking.

Compulsive alcohol use, or drinking that persists despite negative or aversive consequences, is a defining characteristic of alcohol use disorder. Here, chemogenetic technology (i.e.

Selective enhancement of fear learning and resistance to extinction in a mouse model of acute early life trauma.

Early life stress (ELS) experiences can cause changes in cognitive and affective functioning. This study examined the persistent effects of a single traumatic event in infancy on several adult behavioral outcomes in male and female C57BL/6J mice. Mice received 15 footshocks in infancy and were tested for stress-enhanced fear learning, extinction learning, discrimination and reversal learning, and novel object recognition.

Increased Responding for Alcohol and Resistance to Aversion in Female Mice.

Background: More women are being diagnosed with alcohol use disorder (AUD), are increasing the amount of alcohol they are drinking, and are partaking in risky drinking behaviors. Compulsive drinking which persists despite negative consequences is a hallmark of AUD. Preclinical aversion-resistant models suggest that females may be more vulnerable to the rewarding effects of alcohol such that they show increased compulsivity when drinking is punished with quinine, a bitter tastant.

Additive influences of acute early life stress and sex on vulnerability for aversion-resistant alcohol drinking.

Acute early life stress (ELS) alters stress system functioning in adulthood and increases susceptibility to posttraumatic stress disorder (PTSD) and alcohol use disorder (AUD). The current study assessed the effects of acute, infant ELS on alcohol drinking, including aversion-resistant drinking, in male and female Long Evans rats. Acute ELS was induced using a stress-enhanced fear learning (SEFL) protocol that consisted of 15 footshocks delivered on postnatal day (PND) 17.

Sex Differences in Binge-Like and Aversion-Resistant Alcohol Drinking in C57BL/6J Mice.

Background: Alcohol use disorder is characterized by compulsive alcohol intake, or drinking despite negative consequences. Previous studies have shown that female rodents have a heightened vulnerability to drug use across different stages of the addictive cycle, but no previous studies have studied females in a model of aversion-resistant alcohol intake. Here, we investigated sex differences in binge-like and aversion-resistant alcohol drinking in C57BL/6J mice using a modified drinking-in-the-dark (DID) paradigm.