Initial contact with alcohol generally occurs during adolescence, and high consumption during this period is associated with increased risk for later alcohol (AUDs) and/or substance use disorders (SUDs). Rodents selectively bred for high or low alcohol consumption are used to identify behavioral characteristics associated with a propensity for high or low voluntary alcohol intake. The multivariate concentric square field™ (MCSF) is a behavioral test developed to study rodents in a semi-naturalistic setting. Testing in the MCSF creates a comprehensive behavioral profile in a single trial. The current aim was to examine the behavioral profiles of adolescent, bidirectionally selectively bred male and female high alcohol-consuming (P and HAD1/2) and low alcohol-consuming (NP and LAD1/2) rat lines, and outbred Wistar rats. Alcohol-naïve rats were tested once in the MCSF at an age between postnatal days 30 and 35. No common behavioral profile was found for either high or low alcohol-consuming rat lines, and the effect of sex was small. The P/NP and HAD2/LAD2 lines showed within pair-dependent differences, while the HAD1/LAD1 lines were highly similar. The P rats displayed high activity and risk-associated behaviors, whereas HAD2 rats displayed low activity, high shelter-seeking behavior, and open area avoidance. The results from P rats parallel clinical findings that denser family history and risk-taking behavior are strong predictors of future AUDs, often with early onset. Contrarily, the HAD2 behavioral profile was similar to individuals experiencing negative emotionality, which also is associated with a vulnerability to develop, often with a later onset, AUDs and/or SUDs.

Alcohol Use Disorder (AUD) is a chronic, relapsing syndrome diagnosed by a heterogeneous set of behavioral signs and symptoms. There are no laboratory tests that provide direct objective evidence for diagnosis. Microarray and RNA-Seq technologies enable genome-wide transcriptome profiling at low costs and provide an opportunity to identify biomarkers to facilitate diagnosis, prognosis, and treatment of patients. However, access to brain tissue in living patients is not possible. Blood contains cellular and extracellular RNAs that provide disease-relevant information for some brain diseases. We hypothesized that blood gene expression profiles can be used to diagnose AUD. We profiled brain (prefrontal cortex, amygdala, and hypothalamus) and blood gene expression levels in C57BL/6J mice using RNA-seq one week after chronic intermittent ethanol (CIE) exposure, a mouse model of alcohol dependence. We found a high degree of preservation (rho range: [0.50, 0.67]) between blood and brain transcript levels. There was small overlap between blood and brain DEGs, and considerable overlap of gene networks perturbed after CIE related to cell-cell signaling (e.g., GABA and glutamate receptor signaling), immune responses (e.g., antigen presentation), and protein processing / mitochondrial functioning (e.g., ubiquitination, oxidative phosphorylation). Blood gene expression data were used to train classifiers (logistic regression, random forest, and partial least squares discriminant analysis), which were highly accurate at predicting alcohol dependence status (maximum AUC: 90.1%). These results suggest that gene expression profiles from peripheral blood samples contain a biological signature of alcohol dependence that can discriminate between CIE and Air subjects.

Corticotropin-releasing factor (CRF) signaling in the central nucleus of the amygdala (CeA) plays a critical role in rodent models of excessive alcohol drinking. However, the source of CRF acting in the CeA during alcohol withdrawal remains to be identified. In the present study, we hypothesized that CeA CRF interneurons may represent a behaviorally relevant source of CRF to the CeA increasing motivation for alcohol via negative reinforcement. We first observed that Crh mRNA expression in the anterior part of the mouse CeA correlates positively with alcohol intake in C57BL/6J males with a history of chronic binge drinking followed by abstinence and increases upon exposure to chronic intermittent ethanol (CIE) vapor inhalation. We then found that chemogenetic activation of CeA CRF neurons in Crh-IRES-Cre mouse brain slices increases gamma-aminobutyric acid (GABA) release in the medial CeA, in part via CRF1 receptor activation. While chemogenetic stimulation exacerbated novelty-induced feeding suppression (NSF) in alcohol-naïve mice, thereby mimicking the effect of withdrawal from CIE, it had no effect on voluntary alcohol consumption, following either acute or chronic manipulation. Furthermore, chemogenetic inhibition of CeA CRF neurons did not affect alcohol consumption or NSF in chronic alcohol drinkers exposed to air or CIE. Altogether, these findings indicate that CeA CRF neurons produce local release of GABA and CRF and promote hyponeophagia in naïve mice, but do not drive alcohol intake escalation or negative affect in CIE-withdrawn mice. The latter result contrasts with previous findings in rats and demonstrates species specificity of CRF circuit engagement in alcohol dependence.

Rationale: The nucleus accumbens (NAc) is important for regulating a number of behaviors, including alcohol and substance use. We previously found that chemogenetically manipulating neuronal activity in the NAc core regulates binge-like drinking in mice. The central amygdala (CeA) is also an important regulator of alcohol drinking, and projects to the NAc core. We tested whether neuronal projections from the CeA to the NAc core, or neuropeptides released by the CeA in the NAc core, could regulate binge drinking.

Methods: For experiment 1, mice were administered AAV2 Cre-GFP into the NAc core and a Cre-inducible DREADD [AAV2 DIO- hM3Dq, -hM4Di, or -mCherry control] into the CeA. We tested the effects of altering CeA to NAc core activity on binge-like ethanol intake (via "Drinking in the Dark", DID). For experiment 2, we bilaterally microinfused corticotropin releasing factor (CRF), neuropeptide Y (NPY), or somatostatin (SST) into the NAc core prior to DID. For experiment 3, we tested whether intra-NAc CRF antagonism prevented reductions in drinking induced by CNO/hM3Dq stimulation of CeA->NAc projections.

Results: Chemogenetically increasing activity in neurons projecting from the CeA to NAc core decreased binge-like ethanol drinking (p < 0.01). Intra-NAc core CRF mimicked chemogenetic stimulation of this pathway (p < 0.05). Binge-like drinking was unaffected by the doses of NPY and SST tested. Lastly, we found that intra-NAc CRF antagonism prevented reductions in drinking induced by chemogenetic stimulation of CeA->NAc projections. These findings demonstrate that neurons projecting from the CeA to NAc core that release CRF are capable of regulating binge-like drinking in mice.

The High Drinking in the Dark (HDID-1) line of mice has been selectively bred for achieving high blood alcohol levels (BALs) in the Drinking in the Dark task, a model of binge-like drinking. Recently, we determined that glucocorticoid receptor (GR) antagonism with either mifepristone or CORT113176 (a selective GR antagonist) reduced binge-like ethanol intake in the HDID-1 mice, but not in their founder line, HS/NPT. Here, we examined whether the selection process may have altered glucocorticoid functioning by measuring (1) plasma corticosterone levels and (2) expression of the genes encoding GR (Nr3c1) and two of its chaperone proteins FKBP51 and FKBP52 (Fkbp5 and Fkbp4) in the brains (nucleus accumbens, NAc) of HDID-1 and HS/NPT mice. We observed no genotype differences in baseline circulating corticosterone levels. However, HDID-1 mice exhibited a greater stimulated peak corticosterone response to an IP injection (of either ethanol or saline) relative to their founder line. We further observed reduced basal expression of Fkbp4 and Nr3c1 in the NAc of HDID-1 mice relative to HS/NPT mice. Finally, HDID-1 mice exhibited reduced Fkbp5 expression in the NAc relative to HS/NPT mice following an injection of 2 g/kg ethanol. Together, these data suggest that selective breeding for high BALs may have altered stress signaling in the HDID-1 mice, which may contribute to the observed selective efficacy of GR antagonism in reducing binge-like ethanol intake in HDID-1, but not HS/NPT mice. These data have important implications for the role that stress signaling plays in the genetic risk for binge drinking.

Background: Greater circulating levels of the steroid hormone 17β-estradiol (E2) are associated with higher levels of binge drinking in women. In female mice, estrogen receptors in the ventral tegmental area, a dopaminergic region of the brain involved in the motivation to consume ethanol, regulate binge-like ethanol intake. We recently developed a brain-penetrant selective estrogen receptor degrader (SERD), YL3-122, that could be used to test the behavioral role of brain estrogen receptors. We hypothesized that treating female mice with this compound would reduce binge-like ethanol drinking.

Methods: Female C57BL/6J mice were treated systemically with YL3-122 and a related SERD with low brain penetrance, XR5-27, and tested for binge-like ethanol consumption in the drinking in the dark (DID) test. Mice were also tested for sucrose and water consumption and blood ethanol clearance after treatment with the SERDs. Finally, the effect of ethanol exposure on Esr1 gene expression was measured in the ventral tegmental area (VTA), prefrontal cortex (PFC), and ventral hippocampus (vHPC) of male and female mice by quantitative real-time PCR after 4 DID sessions.

Results: YL3-122 reduced ethanol consumption when mice were in diestrus but not estrus. YL3-122 also decreased sucrose consumption but did not alter water intake or blood ethanol clearance. XR5-27 did not affect any of these measures. Binge-like ethanol drinking resulted in increased Esr1 transcript in the VTA of both sexes, male vHPC, and female PFC.

Conclusions: These results indicate that SERD treatment can decrease binge-like ethanol drinking in female mice. Thus, it could be a novel strategy to reduce binge drinking in women, with the caveat that effectiveness may depend on menstrual cycle phase. In addition, Esr1 transcript is increased by binge ethanol exposure in both sexes but in a brain region-specific manner.

GPR88 is an orphan G-protein-coupled receptor that is considered a potential target to treat neuropsychiatric disorders, including addiction. Most knowledge about GPR88 function stems from knockout mouse studies, and in vivo pharmacology is still scarce. Here we examine the effects of the novel brain-penetrant agonist RTI-13951-33 on several alcohol-related behaviours in the mouse. In the intermittent-access-two-bottle-choice paradigm, the compound reduced excessive voluntary alcohol drinking, while water drinking was intact. This was observed for C57BL/6 mice, as well as for control but not Gpr88 knockout mice, demonstrating efficacy and specificity of the drug in vivo. In the drinking-in-the-dark paradigm, RTI-13951-33 also reduced binge-like drinking behaviour for control but not Gpr88 knockout mice, confirming the alcohol consumption-reducing effect and in vivo specificity of the drug. When C57BL/6 mice were trained for alcohol self-administration, RTI-13951-33 decreased the number of nose-pokes over a 4-h session and reduced the number of licks and bursts of licks, suggesting reduced motivation to obtain alcohol. Finally, RTI-13951-33 did not induce any place preference or aversion but reduced the expression of conditioned place preference to alcohol, indicative of a reduction of alcohol-reward seeking. Altogether, data show that RTI-13951-33 limits alcohol intake under distinct conditions that require consummatory behaviour, operant response or association with contextual cues. RTI-13951-33 therefore is a promising lead compound to evaluate GPR88 as a therapeutic target for alcohol use disorders. More broadly, RTI-13951-33 represents a unique tool to better understand GPR88 function, disentangle receptor roles in development from those in the adult and perhaps address other neuropsychiatric disorders.

The general anesthetic etomidate, which acts through γ-aminobutyric acid type A (GABA_A) receptors, impairs the formation of new memories under anesthesia. This study addresses the molecular and cellular mechanisms by which this occurs. Here, using a new line of genetically engineered mice carrying the GABA_A receptor (GABA_AR) β2-N265M mutation, we tested the roles of receptors that incorporate GABA_A receptor β2 versus β3 subunits to suppression of long-term potentiation (LTP), a cellular model of learning and memory. We found that brain slices from β2-N265M mice resisted etomidate suppression of LTP, indicating that the β2-GABA_ARs are an essential target in this model. As these receptors are most heavily expressed by interneurons in the hippocampus, this finding supports a role for interneuron modulation in etomidate control of synaptic plasticity. Nevertheless, β2 subunits are also expressed by pyramidal neurons, so they might also contribute. Therefore, using a previously established line of β3-N265M mice, we also examined the contributions of β2- versus β3-GABA_ARs to GABA_A,slow dendritic inhibition, because dendritic inhibition is particularly well suited to controlling synaptic plasticity. We also examined their roles in long-lasting suppression of population activity through feedforward and feedback inhibition. We found that both β2- and β3-GABA_ARs contribute to GABA_A,slow inhibition and that both β2- and β3-GABA_ARs contribute to feedback inhibition, whereas only β3-GABA_ARs contribute to feedforward inhibition. We conclude that modulation of β2-GABA_ARs is essential to etomidate suppression of LTP. Furthermore, to the extent that this occurs through GABA_ARs on pyramidal neurons, it is through modulation of feedback inhibition.NEW & NOTEWORTHY Etomidate exerts its anesthetic actions through GABA_A receptors. However, the mechanism remains unknown. Here, using a hippocampal brain slice model, we show that β2-GABA_ARs are essential to this effect. We also show that these receptors contribute to long-lasting dendritic inhibition in feedback but not feedforward inhibition of pyramidal neurons. These findings hold implications for understanding how anesthetics block memory formation and, more generally, how inhibitory circuits control learning and memory.

Alcohol use disorder is a complex psychiatric disorder that can be modeled in rodents using a number of drinking paradigms. Drinking-in-the-dark (DID) is widely used to model the binge/intoxication stage of addiction, and chronic intermittent ethanol vapor procedures (CIE) are used to induce dependence and model withdrawal/negative affect induced escalation of drinking. We discuss experiments showing the ventral striatum (vStr) and extended amygdala (EA) are engaged in response to ethanol in rodents through c-Fos/Fos immunoreactivity studies. We also discuss experiments in rodents that span a wide variety of techniques where the function of vStr and EA structures are changed following DID or CIE, and the role of neurotransmitter and neuropeptide systems studies in these ethanol-related outcomes. We note where signaling systems converge across regions and paradigms and where there are still gaps in the literature. Dynorphin/κ-opioid receptor (KOR) signaling, as well as corticotropin releasing factor (CRF)/CRF receptor signaling were found to be important regulators of drinking behaviors across brain regions and drinking paradigms. Future research will require that females and a variety of rodent strains are used in preclinical experiments in order to strengthen the generalizability of findings and improve the likelihood of success for testing potential therapeutics in human laboratory studies.

A major barrier to remission from an alcohol use disorder (AUD) is the continued risk of relapse during abstinence. Assessing the neuroadaptations after chronic alcohol and repeated abstinence is important to identify mechanisms that may contribute to relapse. In this study, we used a rhesus macaque model of long-term alcohol use and repeated abstinence, providing a platform to extend mechanistic findings from rodents to primates. The central amygdala (CeA) displays elevated GABA release following chronic alcohol in rodents and in abstinent male macaques, highlighting this neuroadaptation as a conserved mechanism that may underlie excessive alcohol consumption. Here, we determined circulating interleukin-1β (IL-1β) levels, CeA transcriptomic changes, and the effects of IL-1β and corticotropin releasing factor (CRF) signaling on CeA GABA transmission in male controls and abstinent drinkers. While no significant differences in peripheral IL-1β or the CeA transcriptome were observed, pathway analysis identified several canonical immune-related pathways. We addressed this potential dysregulation of CeA immune signaling in abstient drinkers with an electrophysiological approach. We found that IL-1β decreased CeA GABA release in controls while abstinent drinkers were less sensitive to IL-1β's effects, suggesting adaptations in the neuromodulatory role of IL-1β. In contrast, CRF enhanced CeA GABA release similarly in controls and abstinent drinkers, consistent with rodent studies. Notably, CeA CRF expression was inversely correlated with intoxication, suggesting that CRF levels during abstinence may predict future intoxication. Together, our findings highlight conserved and divergent actions of chronic alcohol on neuroimmune and stress signaling on CeA GABA transmission across rodents and macaques.

Purpose: A growing body of evidence has implicated the endocannabinoid (eCB) system in the acute, chronic, and withdrawal effects of alcohol/ethanol on synaptic function. These eCB-mediated synaptic effects may contribute to the development of alcohol use disorder (AUD). Alcohol exposure causes neurobiological alterations similar to those elicited by chronic cannabinoid (CB) exposure. Like alcohol, cannabinoids alter many central processes, such as cognition, locomotion, synaptic transmission, and neurotransmitter release. There is a strong need to elucidate the effects of ethanol on the eCB system in different brain regions to understand the role of eCB signaling in AUD.

Search methods: For the scope of this review, preclinical studies were identified through queries of the PubMed database.

Search results: This search yielded 459 articles. Clinical studies and papers irrelevant to the topic of this review were excluded.

Discussion and conclusions: The endocannabinoid system includes, but is not limited to, cannabinoid receptors 1 (CB₁), among the most abundantly expressed neuronal receptors in the brain; cannabinoid receptors 2 (CB₂); and endogenously formed CB₁ ligands, including arachidonoylethanolamide (AEA; anandamide), and 2-arachidonoylglycerol (2-AG). The development of specific CB₁ agonists, such as WIN 55,212-2 (WIN), and antagonists, such as SR 141716A (rimonabant), provide powerful pharmacological tools for eCB research. Alcohol exposure has brain region-specific effects on the eCB system, including altering the synthesis of endocannabinoids (e.g., AEA, 2-AG), the synthesis of their precursors, and the density and coupling efficacy of CB₁. These alcohol-induced alterations of the eCB system have subsequent effects on synaptic function including neuronal excitability and postsynaptic conductance. This review will provide a comprehensive evaluation of the current literature on the synaptic interactions of alcohol exposure and eCB signaling systems, with an emphasis on molecular and physiological synaptic effects of alcohol on the eCB system. A limited volume of studies has focused on the underlying interactions of alcohol and the eCB system at the synaptic level in the brain. Thus, the data on synaptic interactions are sparse, and future research addressing these interactions is much needed.

Background: Alcohol acts as an addictive substance that may lead to alcohol use disorder. In humans, magnetic resonance imaging showed diverse structural and functional brain alterations associated with this complex pathology. Single magnetic resonance imaging modalities are used mostly but are insufficient to portray and understand the broad neuroadaptations to alcohol. Here, we combined structural and functional magnetic resonance imaging and connectome mapping in mice to establish brain-wide fingerprints of alcohol effects with translatable potential.

Methods: Mice underwent a chronic intermittent alcohol drinking protocol for 6 weeks before being imaged under medetomidine anesthesia. We performed open-ended multivariate analysis of structural data and functional connectivity mapping on the same subjects.

Results: Structural analysis showed alcohol effects for the prefrontal cortex/anterior insula, hippocampus, and somatosensory cortex. Integration with microglia histology revealed distinct alcohol signatures, suggestive of advanced (prefrontal cortex/anterior insula, somatosensory cortex) and early (hippocampus) inflammation. Functional analysis showed major alterations of insula, ventral tegmental area, and retrosplenial cortex connectivity, impacting communication patterns for salience (insula), reward (ventral tegmental area), and default mode (retrosplenial cortex) networks. The insula appeared as a most sensitive brain center across structural and functional analyses.

Conclusions: This study demonstrates alcohol effects in mice, which possibly underlie lower top-down control and impaired hedonic balance documented at the behavioral level, and aligns with neuroimaging findings in humans despite the potential limitation induced by medetomidine sedation. This study paves the way to identify further biomarkers and to probe neurobiological mechanisms of alcohol effects using genetic and pharmacological manipulations in mouse models of alcohol drinking and dependence.

Binge alcohol consumption is common among adolescents and may impair normal brain development. Emerging, longitudinal studies in adolescents suggest that the effects of binge alcohol exposure on brain structure differ between sexes. To test the hypothesis that the effects of binge alcohol exposure on developmental brain growth trajectories are influenced by age of exposure and sex, adolescent and adult, male and female C57Bl/6 mice (n = 32), were exposed to a binge-like ethanol (EtOH) exposure paradigm (i.e., 5 cycles of 2 on/2 off days of 5 g/kg EtOH intraperitoneal) or served as saline controls. Longitudinal structural magnetic resonance imaging was acquired at baseline, following binge EtOH exposure, and after 2 weeks of recovery. Alcohol treatment showed interactions with age and sex in altering whole brain volume: adolescents of both sexes demonstrated inhibited whole brain growth relative to their control counterparts, although significance was only attained in female mice which showed a larger magnitude response to EtOH compared to male mice. In region of interest analyses, the somatosensory cortex and cerebellum showed inhibited growth in male and female adolescent mice exposed to EtOH, but the difference relative to controls did not reach multiple comparison-corrected statistical significance. These data suggest that in mice exposed to binge EtOH treatment, adolescent age of exposure and female sex may confer a higher risk to the detrimental effects of EtOH on brain structure and reinforce the need for direct testing of both sexes.

Extracellular vesicles (EVs) are important players in normal biological function and disease pathogenesis. Of the many biomolecules packaged into EVs, coding and noncoding RNA transcripts are of particular interest for their ability to significantly alter cellular and molecular processes. Here we investigate how chronic ethanol exposure impacts EV RNA cargo and the functional outcomes of these changes. Following chronic intermittent ethanol (CIE) vapor exposure, EVs were isolated from male and female C57BL/6J mouse brain. Total RNA from EVs was analyzed by lncRNA/mRNA microarray to survey changes in RNA cargo following vapor exposure. Differential expression analysis of microarray data revealed a number of lncRNA and mRNA differentially expressed in CIE compared to control EVs. Weighted gene co-expression network analysis identified multiple male and female specific modules related to neuroinflammation, cell death, demyelination, and synapse organization. To functionally test these changes, whole cell voltage clamp recordings was used to assess synaptic transmission. Incubation of nucleus accumbens brain slices with EVs led to a reduction in spontaneous excitatory postsynaptic current amplitude, although no changes in synaptic transmission were observed between control and CIE EV administration. These results indicate that CIE vapor exposure significantly changes the RNA cargo of brain-derived EVs, which have the ability to impact neuronal function.

Prefrontal circuits are thought to underlie aberrant emotion contributing to relapse in abstinence; however, the discrete cell-types and mechanisms remain largely unknown. Corticotropin-releasing factor and its cognate type-1 receptor, a prominent brain stress system, is implicated in anxiety and alcohol use disorder (AUD). Here, we tested the hypothesis that medial prefrontal cortex CRF1-expressing (mPFCCRF1+) neurons comprise a distinct population that exhibits neuroadaptations following withdrawal from chronic ethanol underlying AUD-related behavior. We found that mPFCCRF1+ neurons comprise a glutamatergic population with distinct electrophysiological properties and regulate anxiety and conditioned rewarding effects of ethanol. Notably, mPFCCRF1+neurons undergo unique neuroadaptations compared to neighboring neurons including a remarkable decrease in excitability and glutamatergic signaling selectively in withdrawal, which is driven in part by the basolateral amygdala. To gain mechanistic insight into these electrophysiological adaptations, we sequenced the transcriptome of mPFCCRF1+ neurons and found that withdrawal leads to an increase in colony-stimulating factor 1 (CSF1) in this population. We found that selective overexpression of CSF1 in mPFCCRF1+ neurons is sufficient to decrease glutamate transmission, heighten anxiety, and abolish ethanol reinforcement, providing mechanistic insight into the observed mPFCCRF1+ synaptic adaptations in withdrawal that drive these behavioral phenotypes. Together, these findings highlight mPFCCRF1+ neurons as a critical site of enduring adaptations that may contribute to the persistent vulnerability to ethanol misuse in abstinence, and CSF1 as a novel target for therapeutic intervention for withdrawal-related negative affect.

We have modelled genetic risk for binge-like drinking by selectively breeding High Drinking in the Dark-1 and -2 (HDID-1 and HDID-2) mice for their propensity to reach intoxicating blood alcohol levels (BALs) after binge-like drinking in a single bottle, limited access paradigm. Interestingly, in standard two-bottle choice (2BC) tests for continuously available alcohol versus water, HDID mice show modest levels of preference. This indicates some degree of independence of the genetic contributions to risk for binge-like and sustained, continuous access drinking. We had few data where the drinking in the dark (DID) tests of binge-like drinking had been repeatedly performed, so we serially offered multiple DID tests to see whether binge-like drinking escalated. It did not. We also asked whether HDID mice would escalate their voluntary intake with prolonged exposure to alcohol 2BC. They did not. Lastly, we assessed whether an alcohol deprivation effect (ADE) developed. ADE is a temporary elevation in drinking typically observed after a period of abstinence from sustained access to alcohol choice. With repetition, these periods of ADE sometimes have led to more sustained elevations in drinking. We therefore asked whether repeated ADE episodes would elevate choice drinking in HDID mice. They did not. After nearly 500 days of alcohol access, the intake of HDID mice remained stable. We conclude that a genetically-enhanced high risk for binge-like drinking is not sufficient to yield alterations in long-term alcohol intake.

This article provides an overview of recent advances in understanding the effects of alcohol use disorders (AUD) on the brain from the perspective of magnetic resonance imaging (MRI) research in preclinical models and clinical studies. As a noninvasive investigational tool permitting assessment of morphological, metabolic, and hemodynamic changes over time, MRI offers insight into the dynamic course of alcoholism beginning with initial exposure through periods of binge drinking and escalation, sobriety, and relapse and has been useful in differential diagnosis of neurological diseases associated with AUD. Structural MRI has revealed acute and chronic effects of alcohol on both white and gray matter volumes. MR Spectroscopy, able to quantify brain metabolites in vivo, has shed light on biochemical alterations associated with alcoholism. Diffusion tensor imaging permits microstructural characterization of white matter fiber tracts. Functional MRI has allowed for elucidation of hemodynamic responses at rest and during task engagement. Positron emission tomography, a non-MRI imaging tool, has led to a deeper understanding of alcohol-induced receptor and neurotransmitter changes during various stages of drinking and abstinence. Together, such in vivo imaging tools have expanded our understanding of the dynamic course of alcoholism including evidence for regional specificity of the effects of AUD, hints at mechanisms underlying the shift from casual to compulsive use of alcohol, and profound recovery with sustained abstinence.

There is compelling evidence that sex and gender have crucial roles in excessive alcohol (ethanol) consumption. Here, we review some of the data from the perspective of brain transcriptional differences between males and females, focusing on rodent animal models. A key emerging transcriptional feature is the role of neuroimmune processes. Microglia are the resident neuroimmune cells in the brain and exhibit substantial functional differences between males and females. Selective breeding for binge ethanol consumption and the impacts of chronic ethanol consumption and withdrawal from chronic ethanol exposure all demonstrate sex-dependent neuroimmune signatures. A focus is on resolving sex-dependent differences in transcriptional responses to ethanol at the neurocircuitry level. Sex-dependent transcriptional differences are found in the extended amygdala and the nucleus accumbens. Telescoping of ethanol consumption is found in some, but not all, studies to be more prevalent in females. Recent transcriptional studies suggest that some sex differences may be due to female-dependent remodeling of the primary cilium. An interesting theme appears to be developing: at least from the animal model perspective, even when males and females are phenotypically similar, they differ significantly at the level of the transcriptome.

An overarching goal of our research has been to develop a valid animal model of alcoholism with similar imaging phenotypes as those observed in humans with the ultimate objective of assessing the effectiveness of pharmacological agents. In contrast to our findings in humans with alcohol use disorders (AUD), our animal model experiments have not demonstrated enduring brain pathology despite chronic, high ethanol (EtOH) exposure protocols. Relative to healthy controls, older individuals with AUD demonstrate accelerating brain tissue loss with advanced age. Thus, this longitudinally controlled study was conducted in 4-month old (equivalent to ~16-year-old humans) and 17-month old (equivalent to ~45-year-old humans) male and female Fisher 344 rats to test the hypothesis that following equivalent alcohol exposure protocols, older relative to younger animals would exhibit more brain changes as evaluated using in vivo structural magnetic resonance imaging (MRI) and MR spectroscopy (MRS). At baseline, total brain volume as well as the volumes of each of the three constituent tissue types (i.e., cerebral spinal fluid (CSF), gray matter, white matter) were greater in old relative to young rats. Baseline metabolite levels (except for glutathione) were higher in older than younger animals. Effects of binge EtOH exposure on brain volumes and neurometabolites replicated our previous findings in Wistar rats and included ventricular enlargement and reduced MRS-derived creatine levels. Brain changes in response to binge EtOH treatment were more pronounced in young relative to older animals, negating our hypothesis. Higher baseline glutathione levels in female than male rats suggest that female rats are perhaps protected against the more pronounced changes in CSF and gray matter volumes observed in male rats due to superior metabolic homeostasis mechanisms. Additional metabolite changes including low inositol levels in response to high blood alcohol levels support a mechanism of reversible osmolarity disturbances due to temporarily altered brain energy metabolism.

The misuse of alcohol in the United States continues to take a large toll on society, resulting in the deaths of about 88,000 Americans per year. Moreover, it is estimated that nearly 14.6 million Americans currently meet diagnostic criteria for current alcohol use disorder (AUD). However, very few individuals receive treatment, with an even smaller portion receiving medications approved by the U.S. Food and Drug Administration (FDA) for the treatment of AUD, despite scientifically rigorous evidence showing the benefits of combining medication approved for treating AUD with evidence-based behavioral therapy. These benefits include higher rates of abstinence and less risk of relapse to heavy drinking, with associated improvements in medical and mental health and in quality of life. This review provides an overview of FDA-approved medications and “off-label” drugs for the treatment of AUD. The article emphasizes that AUD medical advice and prescription recommendations should come from professionals with training in the treatment of AUD and that treatment plans should consider medication in conjunction with evidence-based behavioral therapy. Finally, this review notes the limited number of medications available and the continued need for the development of new pharmacotherapies to optimize AUD recovery goals