Sex differences in neural networks recruited by frontloaded binge alcohol drinking.

Frontloading is an alcohol drinking pattern where intake is skewed towards the onset of access. This study aimed to identify brain regions involved in frontloading. Whole brain imaging was performed in 63 C57Bl/6J (32 female, 31 male) mice that underwent 8 days of binge drinking using drinking-in-the-dark (DID). On Days 1-7 mice received 20% (v/v) alcohol or water for 2 h. Intake was measured in 1-min bins using volumetric sippers. On Day 8 mice were perfused 80 min into the DID session and brains were extracted. Brains were processed to stain for Fos protein using iDISCO+. Following light sheet imaging, ClearMap2.1 was used to register brains to the Allen Brain Atlas and detect Fos+ cells. For network analyses, Day 8 drinking patterns were used to characterize mice as frontloaders or non-frontloaders using a change-point analysis. Functional correlation matrices were calculated for each group from log10 Fos values. Euclidean distances were calculated from these R values and clustering was used to determine modules (highly connected groups of brain regions). In males, alcohol access decreased modularity (three modules in both frontloaders and non-frontloaders) as compared to water (seven modules). In females, an opposite effect was observed. Alcohol access (nine modules for frontloaders) increased modularity as compared to water (five modules). Further, different brain regions served as hubs in frontloaders as compared to control groups. In conclusion, alcohol consumption led to fewer, but more densely connected, groups of brain regions in males but not females and we identify several brain-wide signatures of frontloading.

Sex-dependent, lateralized engagement of anterior insular cortex inputs to the dorsolateral striatum in binge alcohol drinking.

How does alcohol consumption alter synaptic transmission across time, and do these alcohol-induced neuroadaptations occur similarly in both male and female mice? Previously we identified that anterior insular cortex (AIC) projections to the dorsolateral striatum (DLS) are uniquely sensitive to alcohol-induced neuroadaptations in male, but not female mice, and play a role in governing binge alcohol consumption in male mice (Haggerty et al., 2022). Here, by using high-resolution behavior data paired with in-vivo fiber photometry, we show how similar levels of alcohol intake are achieved via different behavioral strategies across sexes, and how inter-drinking session thirst states predict future alcohol intakes in females, but not males. Furthermore, we show how presynaptic calcium activity recorded from AIC synaptic inputs in the DLS across 3 weeks of water consumption followed by 3 weeks of binge alcohol consumption changes across, fluid, time, sex, and brain circuit lateralization. By time-locking presynaptic calcium activity from AIC inputs to the DLS to peri-initiation of drinking events we also show that AIC inputs into the left DLS robustly encode binge alcohol intake behaviors relative to water consumption. These findings suggest a fluid-, sex-, and lateralization-dependent role for the engagement of AIC inputs into the DLS that encode binge alcohol consumption behaviors and further contextualize alcohol-induced neuroadaptations at AIC inputs to the DLS.

Binge Alcohol Consumption Elevates Sympathetic Transduction to Blood Pressure: A Randomized Controlled Trial.

BACKGROUND: Alcohol consumption is associated with cardiovascular disease, and the sympathetic nervous system is a suspected mediator. The present study investigated sympathetic transduction of muscle sympathetic nerve activity to blood pressure at rest and in response to cold pressor test following evening binge alcohol or fluid control, with the hypothesis that sympathetic transduction would be elevated the morning after binge alcohol consumption. METHODS: Using a randomized, fluid-controlled (FC) crossover design, 26 healthy adults (12 male, 14 female, 25±6 years, 27±4 kg/m2) received an evening binge alcohol dose and a FC. All participants underwent next-morning autonomic-cardiovascular testing consisting of muscle sympathetic nerve activity, beat-to-beat blood pressure, and heart rate during a 10-minute rest period and a 2-minute cold pressor test. Sympathetic transduction was assessed at rest and during the cold pressor test in both experimental conditions. RESULTS: Evening alcohol increased heart rate (FC: 60±9 versus alcohol: 64±9 bpm; P=0.010) but did not alter resting mean arterial pressure (FC: 80±6 versus alcohol: 80±7 mm Hg; P=0.857) or muscle sympathetic nerve activity (FC: 18±9 versus alcohol: 20±8 bursts/min; P=0.283). Sympathetic transduction to mean arterial pressure (time×condition; P=0.003), diastolic blood pressure (time×condition; P=0.010), and total vascular conductance (time×condition; P=0.004) was augmented after alcohol at rest. Sympathetic transduction during the cold pressor test was also elevated after evening binge alcohol consumption (P=0.002). CONCLUSIONS: These findings suggest that evening binge alcohol consumption leads to augmented morning-after sympathetic transduction of muscle sympathetic nerve activity to blood pressure, highlighting a new mechanism whereby chronic or excessive alcohol consumption contributes to cardiovascular disease progression via altered end-organ responsiveness to sympathetic neural outflow. REGISTRATION: URL: https://clinicaltrials.gov/study/NCT03567434; Unique identifier: NCT03567434.

Sex-related differences in young binge drinkers on the neurophysiological response to stress in virtual reality.

Background: Stress is one of the main environmental factors involved in the onset of different psychopathologies. In youth, stressful life events can trigger inappropriate and health-damaging behaviors, such as binge drinking. This behavior, in turn, can lead to long-lasting changes in the neurophysiological response to stress and the development of psychological disorders late in life, e.g., alcohol use disorder. Our aim was to analyze the pattern of neurophysiological responses triggered with the exposition to a stressful virtual environment in young binge drinkers. Methods: AUDIT-3 (third question from the full AUDIT) was used to detect binge drinking (BD) in our young sample (age 18-25 years). According to the score, participants were divided into control (CO) and BD group. Next, a standardized virtual reality (VR) scenario (Richie's Plank) was used for triggering the stress response while measuring the following neurophysiological variables: brain electrical activity by electroencephalogram (EEG) and cortisol levels through saliva samples both measurements registered before and after the stressful situation. Besides, heart rate (HR) with a pulsometer and electrodermal response (EDA) through electrodes placed on fingers were analyzed before, during and after the VR task. Results: Regarding the behavior assessed during the VR task, BD group spent significantly less amount of time walking forward the table and a tendency toward more time walking backwards. There was no statistically significant difference between the BD and the CO group regarding time looking down, but when we controlled the variable sex, the BD women group displayed higher amount of time looking down than the rest of the groups. Neurophysiological measurements revealed that there was not any statistically significant difference between groups in any of the EEG registered measures, EDA response and cortisol levels. Sex-related differences were found in HR response to VR scenario, in which BD women displayed the highest peak of response to the stressor. Also, the change in heartbeat was higher in BD women than men. Conclusion: Unveiling the neurophysiological alterations associated with BD can help us to prevent and detect early onset of alcohol use disorder. Also, from our data we conclude that participants' sex can modulate some stress responses, especially when unhealthy behaviors such as BD are present. Nevertheless, the moment of registration of the neurophysiological variables respect to the stressor seems to be a crucial variable.

Trying to forget alcohol: Brain mechanisms underlying memory suppression in young binge drinkers.

People are able to voluntarily suppress unwanted thoughts or memories, a phenomenon known as suppression-induced forgetting or memory suppression. Despite harmful alcohol use, such as binge drinking, has been linked to impaired inhibitory control (IC) and augmented alcohol-cue reactivity, no study to date has assessed memory inhibition abilities towards alcohol-related cues in binge drinkers (BDs). Thus, the present preregistered study aimed to evaluate the behavioral and neurofunctional mechanisms associated with memory inhibition, specifically those related to the suppression of alcohol-related memories, in young BDs. For this purpose, electroencephalographic activity was recorded in eighty-two college students aged between 18 and 24 years old from the University of Minho (50% females; 40 non/low-drinkers [N/LDS] and 42 BDs) while they performed the Think/No-Think Alcohol task. Brain functional connectivity (FC) was calculated using the phase locking value and, subsequently, a dynamic seed-based analysis was conducted to explore the FC patterns between IC and memory networks. Comparatively to N/LDs, BDs exhibited decreased alpha-band FC between the anterior cingulate cortex and the left fusiform gyrus during attempts to suppress non-alcohol memories, accompanied by unsuccessful forgetting of those memories. Conversely, BDs displayed augmented gamma-band FC between the IC network and memory regions -i.e., hippocampus, parahippocampus and fusiform gyrus- during suppression of alcohol-related memories. Inhibitory abnormalities in BDs may lead to hypoconnectivity between IC and memory networks and deficient suppression of non-alcohol-related memories. However, while suppressing highly salient and reward-predicting stimuli, such as alcohol-related memories, BDs display a hyperconnectivity pattern between IC and memory networks, likely due to their augmented attention towards intrusive alcoholic memories and the attempts to compensate for potential underlying IC deficits. These findings hold important implications for alcohol research and treatment, as they open up new avenues for reducing alcohol use by shifting the focus to empowering suppression/control over alcohol-related memories. CLINICAL TRIAL REGISTRATION: [http://www.ClinicalTrials.gov], identifier [NCT05237414].

Mixing energy drinks and alcohol during adolescence impairs brain function: A study of rat hippocampal plasticity.

In the last decades, the consumption of energy drinks has risen dramatically, especially among young people, adolescents and athletes, driven by the constant search for ergogenic effects, such as the increase in physical and cognitive performance. In parallel, mixed consumption of energy drinks and ethanol, under a binge drinking modality, under a binge drinking modality, has similarly grown among adolescents. However, little is known whether the combined consumption of these drinks, during adolescence, may have long-term effects on central function, raising the question of the risks of this habit on brain maturation. Our study was designed to evaluate, by behavioral, electrophysiological and molecular approaches, the long-term effects on hippocampal plasticity of ethanol (EtOH), energy drinks (EDs), or alcohol mixed with energy drinks (AMED) in a rat model of binge-like drinking adolescent administration. The results show that AMED binge-like administration produces adaptive hippocampal changes at the molecular level, associated with electrophysiological and behavioral alterations, which develop during the adolescence and are still detectable in adult animals. Overall, the study indicates that binge-like drinking AMED adolescent exposure represents a habit that may affect permanently hippocampal plasticity.

Astrogliosis and compensatory neurogenesis after the first ethanol binge drinking-like exposure in the adolescent rat.

BACKGROUND: Multiple ethanol binge drinking-like exposures during adolescence in the rat induce neuroinflammation, loss of neurogenesis, and cognitive deficits in adulthood. Interestingly, the first ethanol binge drinking-like exposure during adolescence also induces short- term impairments in cognition and synaptic plasticity in the hippocampus though the cellular mechanisms of these effects are unclear. Here, we sought to determine which of the cellular effects of ethanol might play a role in the disturbances in cognition and synaptic plasticity observed in the adolescent male rat after two binge-like ethanol exposures. METHODS: Using immunochemistry, we measured neurogenesis, neuronal loss, astrogliosis, neuroinflammation, and synaptogenesis in the hippocampus of adolescent rats 48 h after two binge-like ethanol exposures (3 g/kg, i.p., 9 h apart). We used flow cytometry to analyze activated microglia and identify the TLR4-expressing cell types. RESULTS: We detected increased hippocampal doublecortin immunoreactivity in the subgranular zone (SGZ) of the dentate gyrus (DG), astrogliosis in the SGZ, and a reduced number of mature neurons in the DG and in CA3, suggesting compensatory neurogenesis. Synaptic density decreased in the stratum oriens of CA1 revealing structural plasticity. There was no change in microglial TLR4 expression or in the number of activated microglia, suggesting a lack of neuroinflammatory processes, although neuronal TLR4 was decreased in CA1 and DG. CONCLUSIONS: Our findings demonstrate that the cognitive deficits associated with hippocampal synaptic plasticity alterations that we previously characterized 48 h after the first binge-like ethanol exposures are associated with hippocampal structural plasticity, astrogliosis, and decreased neuronal TLR4 expression, but not with microglia reactivity.

Comparing behavior following binge ethanol in adolescent and adult DBA/2 J mice.

The adolescent brain undergoes maturation in areas critically involved in reward, addiction, and memory. Adolescents consume alcohol more than any other drug, typically in a binge-like manner. While adults also binge on alcohol, the adolescent brain is more susceptible to ethanol-related damages due to its ongoing development, which may result in persistent behavioral and physical changes, including differences in myelination in the frontal cortex. Sex also impacts ethanol metabolism and addiction progression, suggesting females are more sensitive than males. This study addressed memory, sociability, ethanol sensitivity, and myelin gene expression changes due to binge ethanol, sex, and age. DBA/2 J males and females were exposed to intermittent binge ethanol (4 g/kg, i.g.) from postnatal day (PND) 29-42 or as adults from PND 64-77. Age groups were tested for behaviors at the early phase (24 h - 7 days) and late phase (starting 3 weeks) after the last dose. Adult prefrontal cortex was collected at both phases. Adolescent ethanol impaired late phase memory while adult ethanol showed no impairment. Meanwhile, adolescent males showed early phase tolerance to ethanol-induced locomotor activation, while adult females showed tolerance at both phases. Adult-treated mice displayed reductions in social interaction. Adult ethanol decreased Mal expression, a gene involved in myelin integrity, at the early phase. No differences in myelin gene expression were observed at the late phase. Thus, adolescent binge ethanol more severely impacts memory and myelin gene expression compared to adult exposure, while adult mice display ethanol-induced reductions in social interaction and tolerance to ethanol's locomotor activation.

The persistent impact of adolescent binge alcohol on adult brain structural, cellular, and behavioral pathology: A role for the neuroimmune system and epigenetics.

Adolescence is a critical neurodevelopmental window for maturation of brain structure, neurocircuitry, and glia. This development is sculpted by an individual's unique experiences and genetic background to establish adult level cognitive function and behavioral makeup. Alcohol abuse during adolescence is associated with an increased lifetime risk for developing an alcohol use disorder (AUD). Adolescents participate in heavy, episodic binge drinking that causes persistent changes in neurocircuitry and behavior. These changes may underlie the increased risk for AUD and might also promote cognitive deficits later in life. In this chapter, we have examined research on the persistent effects of adolescent binge-drinking both in humans and in rodent models. These studies implicate roles for neuroimmune signaling as well as epigenetic reprogramming of neurons and glia, which create a vulnerable neuroenvironment. Some of these changes are reversible, giving hope for future treatments to prevent many of the long-term consequences of adolescent alcohol abuse.

Chronic binge alcohol and ovariectomy-mediated impaired insulin responsiveness in SIV-infected female rhesus macaques.

Aging people living with HIV (PLWH), especially postmenopausal women may be at higher risk of comorbidities associated with HIV, antiretroviral therapy (ART), hypogonadism, and at-risk alcohol use. Our studies in simian immunodeficiency virus (SIV)-infected male macaques demonstrated that chronic binge alcohol (CBA) reduced acute insulin response to glucose (AIRG), and at-risk alcohol use decreased HOMA-ß in PLWH. The objective of this study was to examine the impact of ovariectomy (OVX) on glucose-insulin dynamics and integrity of pancreatic endocrine function in CBA/SIV-infected female macaques. Female macaques were administered CBA (12-15 g/kg/wk) or isovolumetric water (VEH) intragastrically. Three months after initiation of CBA/VEH administration, all macaques were infected with SIVmac251, and initiated on antiretroviral therapy (ART) 2.5 mo postinfection. After 1 mo of ART, macaques were randomized to OVX or sham surgeries (n = 7 or 8/group), and euthanized 8 mo post-OVX (study endpoint). Frequently sampled intravenous glucose tolerance tests (FSIVGTT) were performed at selected time points. Pancreatic gene expression and islet morphology were determined at study endpoint. There was a main effect of CBA to decrease AIRG at Pre-SIV and study endpoint. There were no statistically significant OVX effects on AIRG (P = 0.06). CBA and OVX decreased the expression of pancreatic markers of insulin docking and release. OVX increased endoplasmic stress markers. CBA but not OVX impaired glucose-insulin expression dynamics in SIV-infected female macaques. Both CBA and OVX altered integrity of pancreatic endocrine function. These findings suggest increased vulnerability of PLWH to overt metabolic dysfunction that may be exacerbated by alcohol use and ovarian hormone loss.

Activation of locus coeruleus to rostromedial tegmental nucleus (RMTg) noradrenergic pathway blunts binge-like ethanol drinking and induces aversive responses in mice.

There is strong evidence that ethanol entails aversive effects that can act as a deterrent to overconsumption. We have found that in doses that support the development of a conditioned taste aversion ethanol increases the activity of tyrosine hydroxylase (TH) positive neurons in the locus coeruleus (LC), a primary source of norepinephrine (NE). Using cre-inducible AAV8-ChR2 viruses in TH-ires-cre mice we found that the LC provides NE projections that innervate the rostromedial tegmental nucleus (RMTg), a brain region that has been implicated in the aversive properties of drugs. Because the neurocircuitry underlying the aversive effects of ethanol is poorly understood, we characterized the role of the LC to RMTg circuit in modulating aversive unconditioned responses and binge-like ethanol intake. Here, both male and female TH-ires-cre mice were cannulated in the RMTg and injected in the LC with rAVV viruses that encode for a Gq-expressing designer receptor exclusively activated by designer drugs (DREADDs) virus, or its control virus, to directly control the activity of NE neurons. A Latin Square paradigm was used to analyze both 20% ethanol and 3% sucrose consumption using the "drinking-in-the-dark" (DID) paradigm. Chemogenetic activation of the LC to RMTg pathway significantly blunted the binge-ethanol drinking, with no effect on the sucrose consumption, increased the emission of mid-frequency vocalizations and induced malaise-like behaviors in mice. The present findings indicate an important involvement of the LC to RMTg pathway in reducing ethanol consumption, and characterize unconditioned aversive reactions induced by activation of this noradrenergic pathway.

Lateral hypothalamus-projecting noradrenergic locus coeruleus pathway modulates binge-like ethanol drinking in male and female TH-ires-cre mice.

A growing body of literature implicates noradrenergic (NE) signaling in the modulation of ethanol consumption. However, relatively few studies have detailed specific brain pathways that mediate NE-associated binge-like ethanol consumption. To begin to fill this gap in the literature, male and female C57BL6/J and TH-ires-cre mice underwent pharmacological and chemogenetic testing, respectively, in combination with "drinking in the dark" procedures to model binge-like consumption of ethanol or sucrose solutions. First, we showed that intraperitoneal administration of the NE reuptake inhibitor, reboxetine, blunted binge-like ethanol intake in C57BL6/J mice. Chemogenetic activation of locus coeruleus (LC) tyrosine hydroxylase (TH)-expressing neurons blunted binge-like ethanol intake regardless of sex. Chemogenetic activation of LC projections to the lateral hypothalamus (LH), a region implicated in ethanol consumption, blunted binge-like ethanol drinking without altering sucrose intake in ethanol-experienced or ethanol-naïve mice. In C57BL/6 J mice, LH-targeted microinfusion of an α1-adrenergic receptor (AR) agonist blunted binge-like ethanol intake across both sexes, while LH infusion of a ß-AR agonist blunted binge-like ethanol intake in females exclusively. Finally, in mice with high baseline ethanol intake both an α1- AR agonist and an α-2 AR antagonist blunted binge-like ethanol intake. The present results provide novel evidence that increased NE tone in a circuit arising from the LC and projecting to the LH reduces binge-like ethanol drinking in mice, and may represent a novel approach to treating binge or heavy drinking prior to the development of dependence. This article is part of the special Issue on "Neurocircuitry Modulating Drug and Alcohol Abuse".

Chronic binge alcohol and ovariectomy dysregulate omental adipose tissue metaboproteome in simian immunodeficiency virus-infected female macaques.

Effective antiretroviral therapy (ART) has significantly reduced mortality of people living with HIV (PLWH), and the prevalence of at-risk alcohol use is higher among PLWH. Increased survival and aging of PLWH is associated with increased prevalence of metabolic comorbidities especially among menopausal women, and adipose tissue metabolic dysregulation may be a significant contributing factor. We examined the differential effects of chronic binge alcohol (CBA) administration and ovariectomy (OVX) on the omental adipose tissue (OmAT) proteome in a subset of simian immunodeficiency virus (SIV)-infected macaques of a longitudinal parent study. Quantitative discovery-based proteomics identified 1,429 differentially expressed proteins. Ingenuity Pathway Analysis (IPA) was used to calculate z-scores, or activation predictions, for functional pathways and diseases. Results revealed that protein changes associated with functional pathways centered around the "OmAT metaboproteome profile." Based on z-scores, CBA did not affect functional pathways of metabolic disease but dysregulated proteins involved in adenosine monophosphate-activated protein kinase (AMPK) signaling and lipid metabolism. OVX-mediated proteome changes were predicted to promote pathways involved in glucose- and lipid-associated metabolic disease. Proteins involved in apoptosis, necrosis, and reactive oxygen species (ROS) pathways were also predicted to be activated by OVX and these were predicted to be inhibited by CBA. These results provide evidence for the role of ovarian hormone loss in mediating OmAT metaboproteome dysregulation in SIV and suggest that CBA modifies OVX-associated changes. In the context of OVX, CBA administration produced larger metabolic and cellular effects, which we speculate may reflect a protective role of estrogen against CBA-mediated adipose tissue injury in female SIV-infected macaques.

Binge ethanol drinking associated with sex-dependent plasticity of neurons in the insula that project to the bed nucleus of the stria terminalis.

Modifications in brain regions that govern reward-seeking are thought to contribute to persistent behaviors that are heavily associated with alcohol-use disorder (AUD) including binge ethanol drinking. The bed nucleus of the stria terminalis (BNST) is a critical node linked to both alcohol consumption and the onset, maintenance and progression of adaptive anxiety and stress-related disorders. Differences in anatomy, connectivity and receptor subpopulations, make the BNST a sexually dimorphic region. Previous work indicates that the ventral BNST (vBNST) receives input from the insular cortex (IC), a brain region involved in processing the body's internal state. This IC-vBNST projection has also been implicated in emotional and reward-seeking processes. Therefore, we examined the functional properties of vBNST-projecting, IC neurons in male and female mice that have undergone short-term ethanol exposure and abstinence using a voluntary Drinking in the Dark paradigm (DID) paired with whole-cell slice electrophysiology. First we show that IC neurons projected predominantly to the vBNST. Next, our data show that short-term ethanol exposure and abstinence enhanced excitatory synaptic strength onto vBNST-projecting, IC neurons in both sexes. However, we observed diametrically opposing modifications in excitability across sexes. In particular, short-term ethanol exposure resulted in increased intrinsic excitability of vBNST-projecting, IC neurons in females but not in males. Furthermore, in females, abstinence decreased the excitability of these same neurons. Taken together these findings show that short-term ethanol exposure, as well as the abstinence cause sex-related adaptations in BNST-projecting, IC neurons.

Pairing Binge Drinking and a High-Fat Diet in Adolescence Modulates the Inflammatory Effects of Subsequent Alcohol Consumption in Mice.

Alcohol binge drinking (BD) and poor nutritional habits are two frequent behaviors among many adolescents that alter gut microbiota in a pro-inflammatory direction. Dysbiotic changes in the gut microbiome are observed after alcohol and high-fat diet (HFD) consumption, even before obesity onset. In this study, we investigate the neuroinflammatory response of adolescent BD when combined with a continuous or intermittent HFD and its effects on adult ethanol consumption by using a self-administration (SA) paradigm in mice. The inflammatory biomarkers IL-6 and CX3CL1 were measured in the striatum 24 h after BD, 3 weeks later and after the ethanol (EtOH) SA. Adolescent BD increased alcohol consumption in the oral SA and caused a greater motivation to seek the substance. Likewise, mice with intermittent access to HFD exhibited higher EtOH consumption, while the opposite effect was found in mice with continuous HFD access. Biochemical analyses showed that after BD and three weeks later, striatal levels of IL-6 and CX3CL1 were increased. In addition, in saline-treated mice, CX3CL1 was increased after continuous access to HFD. After oral SA procedure, striatal IL-6 was increased only in animals exposed to BD and HFD. In addition, striatal CX3CL1 levels were increased in all BD- and HFD-exposed groups. Overall, our findings show that adolescent BD and intermittent HFD increase adult alcohol intake and point to neuroinflammation as an important mechanism modulating this interaction.

Alcohol intoxication, but not hangover, differentially impairs learning and automatization of complex motor response sequences.

Behavioral automatization usually makes us more efficient and less error-prone, but may also foster dysfunctional behavior like alcohol abuse. Yet, it has remained unclear whether alcohol itself causes the shift from controlled to habitual behavior commonly observed in alcohol use disorder (AUD). We thus investigated how the acute and post-acute effects of binge drinking affect the automatization of motor response sequences and the execution of automated vs. controlled motor response sequences. N = 70 healthy young men performed a newly developed automatization paradigm once sober and once after binge drinking (half of them intoxicated and half of them hungover). While we found no significant effects of alcohol hangover, acute intoxication (~ 1.2 ‰) had two dissociable effects: Firstly, it impaired the automatization of complex motor response sequence execution. Secondly, it eliminated learning effects in response selection and pre-motor planning processes. The results suggest that alcohol hangover did not affect controlled or automated processes, and disprove the assumption that alcohol intoxication generally spares or facilitates motor response sequence automatization. As these effects could be specific to the investigated explicit learning context, acute intoxication might potentially still improve the execution of pre-existing automatisms and/or the implicit acquisition of motor response sequence automatisms.

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. Findings for binge intake and aversion-resistant, compulsion-like alcohol drinking are considered, since both are likely significant contributors to alcohol problems in humans. We also describe studies regarding mechanisms that may underlie sex differences in maladaptive alcohol drinking, with some focus on the importance of nucleus accumbens (NAcb) core and shell regions, several receptor types (dopamine, orexin, AMPA-type glutamate), and possible contributions of sex hormones. Finally, we discuss how stressors such as early life stress and anxiety-like states may interact with sex differences to contribute to alcohol drinking. Together, these findings underscore the importance and critical relevance of studying female and male mechanisms for alcohol and co-morbid conditions to gain a true and clinically useful understanding of addiction and neuropsychiatric mechanisms and treatment.

Age of onset of adolescent binge drinking is differentially associated with cortical thickness in post-9/11 adult Veterans.

BACKGROUND: Adolescence is a critical period for neural development and has been associated with high rates of alcohol abuse. This research examined potential long-term brain and behavioral effects of early versus late-onset adolescent binge drinking in an adult sample of post-9/11 Veterans. METHODS: We compared cortical thickness measures in Veterans with a history of binge drinking that began before the age of 15 (n = 50; mean age = 32.1 years) to those with a history of binge drinking with onset after the age of 15 (n = 300; mean age = 32.1 years). Data processing was conducted with FreeSurfer. A targeted neuropsychological battery (Digit Span test, Delis-Kaplan Executive Function System Color-Word Interference Test, California Verbal Learning Test-II) was used to examine the relationships between cortical thickness and attention, memory, and inhibition. A reference group of social drinkers with no history of early binge drinking (n = 31) was used to provide normative data. RESULTS: Early-onset adolescent binge drinkers (EBD) had greater cortical thickness in several regions than late-onset adolescent binge drinkers (LBD); both binge-drinking groups had greater cortical thickness than the reference group. There was a stronger negative association between cortical thickness and age in EBDs than LBDs in the (i) lateral orbitofrontal cortex, (ii) supramarginal gyrus, (iii) paracentral lobule, and (iv) anterior caudal cingulate. Poorer performance on the attention and inhibition tasks in the EBDs was also associated with thicker cortices. CONCLUSIONS: This study demonstrates greater cortical thickness across frontoparietal regions in adults who began binge drinking in early versus late adolescence. A stronger negative association between cortical thickness and age in the EBDs suggests that early-onset adolescent binge drinking may be associated with accelerated cortical thinning. Thicker cortex in these regions, which are known to mediate inhibitory control, may increase impulsive behavior and contribute to the risk of alcohol addiction.

Repeated binge ethanol drinking enhances electrical activity of central amygdala corticotropin releasing factor neurons in vivo.

Binge ethanol drinking is an increasingly problematic component of alcohol use disorder costing the United States approximately over $150 billion every year and causes progressive neuroplasticity alterations in numerous brain regions. However, the precise nature or machinery that underlies binge drinking has not yet been elucidated. Corticotropin releasing factor (CRF) neurons in the central amygdala (CeA) are thought to modulate binge drinking, but the specific circuit mechanisms remain poorly understood. Here, we combined optogenetics with in vivo electrophysiology to identify and record from CeA CRF neurons in mice during a repeated binge ethanol drinking task. First, we found that CeA CRF neurons were more active than CeA non-CRF cells during our binge drinking paradigm. We also observed that CeA CRF neurons displayed a heterogeneous spectrum of responses to a lick of ethanol including, pre-lick activated, lick-excited, lick-inhibited, and no response. Interestingly, pre-lick activated CeA CRF neurons exhibited higher frequency and burst firing during binge drinking sessions. Moreover, their overall tonic and phasic electrical activity enhances over repeated binge drinking sessions. Remarkably, CeA CRF units and pre-lick activated CeA CRF neurons did not show higher firing rate or bursting activity during water and sucrose consumption, suggesting that ethanol may "hijack" or plastically alter their intrinsic excitability. This article is part of the special issue on 'Neurocircuitry Modulating Drug and Alcohol Abuse'.

Morning sympathetic activity after evening binge alcohol consumption.

Binge alcohol consumption elicits acute and robust increases of muscle sympathetic nerve activity (MSNA), yet the impact of evening binge drinking on morning-after MSNA is unknown. The present study examined the effects of evening binge alcohol consumption on polysomnographic sleep and morning-after MSNA. We hypothesized that evening binge drinking (i.e. 4-5 drink equivalent in <2 h) would reduce sleep quality and increase morning-after blood pressure (BP) and MSNA. Following a familiarization night within the sleep laboratory, 22 participants (12 men, 10 women; 25 ± 1 yr) were examined after simulated binge drinking or fluid control (randomized, crossover design). Morning MSNA was successfully recorded across both conditions in 16 participants (8 men, 8 women) during a 10-min baseline and three Valsalva's maneuvers (VM). Binge drinking reduced rapid eye movement (REM) sleep (15 ± 1 vs. 20 ± 1%, P = 0.003), increased stage II sleep (54 ± 1 vs. 51 ± 1%, P = 0.002), and increased total urine output (2.9 ± 0.2 vs. 2.1 ± 0.1 liters, P < 0.001) but did not alter morning-after urine specific gravity. Binge drinking increased morning-after heart rate [65 (54-72) vs. 58 (51-67) beats/min, P = 0.013] but not resting BP or MSNA. Binge drinking elicited greater sympathoexcitation during VM (38 ± 3 vs. 43 ± 3 bursts/min, P = 0.036). Binge drinking augmented heart rate (P = 0.002), systolic BP (P = 0.022), and diastolic BP (P = 0.037) reactivity to VM phase IV and blunted cardiovagal baroreflex sensitivity during VM phases II (P = 0.028) and IV (P = 0.043). In conclusion, evening binge alcohol consumption disrupted REM sleep and morning-after autonomic function. These findings provide new mechanistic insight into the potential role of binge drinking on cardiovascular risk.NEW & NOTEWORTHY Chronic binge alcohol consumption is associated with future cardiovascular disease (CVD) risk in both men and women. In addition, binge alcohol consumption is known to disrupt normal sleep quality during the early morning hours, coinciding with the morning sympathetic surge. In the present study, an evening of binge alcohol consumption increased baseline morning heart rate and cardiovascular reactivity during the Valsalva maneuver (VM) strain. Specifically, muscle sympathetic nerve activity and phase IV hemodynamic responses increased during VM the morning after binge alcohol consumption. The autonomic dysfunction and increased cardiovascular reactivity during VM suggests a contributing mechanism to CVD risk present in individuals who binge drink.