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The literature on the interaction of ethanol and stress is reviewed. Stress has amethystic properties in both experimental animals and human subjects when analgesia or various behavioral parameters were evaluated. In addition studies have shown that ethanol counteracts some effects of stress in non-alcoholic subjects. Improvement in performance and in the effective state of humans and reversal of some behavioral and pathological concomitants of stress in experimental animals have been reported. Although there is indication that ethanol improves the affective state in humans, reduction of anxiety has not been a universal finding. Recent studies have pointed out a number of variables (the drinking environment, cognitive set, mood and personality of subjects, prior experience with ethanol, sex, dose and type of beverage) which can significantly alter the effects of alcohol in human subjects. These may account for the variability in results in the literature. Although some studies have shown that alcohol ingestion increases under stressful conditions, others have failed to do so in both experimental animals and in humans. In alcoholics ethanol ingestion, in general, does not appear to relieve anxiety. In fact anxiety usually increases with time during a drinking binge. Therefore more research needs to be done to assess the validity of the anxiety-reducing theory for alcohol abuse. Possible mechanisms for the interaction of stress and alcohol are discussed.

The effects of L-lysine, L-arginine, L-ornithine, and glycine on acute ethanol intoxication, and the degree of ethanol-induced CNS depression, were investigated. Amino acid treatment was shown to prolong the onset of ataxia, reduce the duration of sleeping time, and decrease the number of rats losing the righting reflex, but it did not alter the LD50 values in response to ethanol. The protective actions of the amino acids are attributed to the formation of an amino acid-acetaldehyde complex, although other possible interactions are discussed.

This article reviews data on ethanol and neurosteroid interactions in the CNS. We discuss how GABAergic neurosteroids, including 3alpha,5alpha-TH PROG and 3alpha,5alpha-TH DOC, produced in response to systemic ethanol administration contribute to several of the effects of ethanol associated with modulation of GABA(A) receptors in rodents. There is an essential correlation between the time course of ethanol-induced 3alpha,5alpha-TH PROG production in the brain and specific behavioral and neural effects of ethanol. Furthermore, the anticonvulsant and inhibitory effects of ethanol on spontaneous neural activity were completely prevented by a key inhibitor of steroid biosynthesis. 3alpha,5alpha-TH PROG influences cognitive processing, spatial learning and memory and alters drinking behaviors in rats. Furthermore, ethanol induction of 3alpha,5alpha-TH PROG is diminished in tolerant and dependent animals. These effects are associated with increases in the sensitivity of GABA(A) receptors to neurosteroids and suggest an important role in ethanol withdrawal. Together, we suggest that 3alpha,5alpha-TH PROG and 3alpha,5alpha-TH DOC contribute to ethanol action and this interaction may represent a new mechanism of ethanol action. The identification of neurosteroid intermediaries involved in ethanol action may lead to important advances in the field and the development of novel therapeutics for alcoholism.

High-level alcohol consumption causes neuroplastic changes in the brain that promote pathological drinking behavior. Some of these changes have been characterized in defined brain circuits and cell types, but unbiased approaches are needed to explore broader patterns of adaptations.We used whole-brain c-Fos mapping and network analysis to assess patterns of neuronal activity during alcohol withdrawal and following reaccess in a well-characterized model of alcohol dependence. Mice underwent 4 cycles of chronic intermittent ethanol to increase voluntary alcohol consumption, and a subset underwent forced swim stress to further escalate consumption. Brains were collected either 24 hours (withdrawal) or immediately following a 1-hour period of alcohol reaccess. c-fos counts were obtained for 110 brain regions using iDISCO and ClearMap. Then, we classified mice as high or low drinkers and used graph theory to identify changes in network properties associated with high-drinking behavior.During withdrawal, chronic intermittent ethanol mice displayed widespread increased c-Fos expression relative to air-exposed mice, independent of forced swim stress. Reaccess drinking reversed this increase. Network modularity, a measure of segregation into communities, was increased in high-drinking mice after alcohol reaccess relative to withdrawal. The cortical amygdala showed increased cross-community coactivation during withdrawal in high-drinking mice, and cortical amygdala silencing in chronic intermittent ethanol mice reduced voluntary drinking.Alcohol withdrawal in dependent mice causes changes in brain network organization that are attenuated by reaccess drinking. Olfactory brain regions, including the cortical amygdala, drive some of these changes and may play an important but underappreciated role in alcohol dependence.

Substance use disorders are a leading cause of morbidity and mortality, and available pharmacological treatments are of modest efficacy. Histamine is a biogenic amine with four types of receptors. The histamine H3 receptor (H3R) is an autoreceptor and also an heteroreceptor. H3Rs are highly expressed in the basal ganglia, hippocampus and cortex, and regulate a number of neurotransmitters including acetylcholine, norepinephrine, GABA and dopamine. Its function and localization suggest that the H3R may be relevant to a number of psychiatric disorders and could represent a potential therapeutic target for substance use disorders. The purpose of the present review is to summarize preclinical studies investigating the effects of H3R agonists and antagonists on animal models of alcohol, nicotine and psychostimulant use. At present, the effects of H3R antagonists such as thioperamide, pitolisant or ciproxifan have been investigated in drug-induced locomotion, conditioned place preference, drug self-administration, reinstatement, sensitization and drug discrimination. For alcohol and nicotine, the effects of H3R ligands on two-bottle choice and memory tasks, respectively, have also been investigated. The results of these studies are inconsistent. For alcohol, H3R antagonists generally decreased the reward-related properties of ethanol, which suggests that H3R antagonists may be effective as a treatment option for alcohol use disorder. However, the effects of H3R antagonists on nicotine and psychostimulant motivation and reward are less clear. H3R antagonists potentiated the abuse-related properties of nicotine, but only a handful of studies have been conducted. For psychostimulants, evidence is mixed and suggests that more research is needed to establish whether H3R antagonists are a viable therapeutic option. The fact that different drugs of abuse have different brain targets may explain the differential effects of H3R ligands.

Cytokines are multifunctional proteins that play a critical role in cellular communication and activation. Cytokines have been classified as being proinflammatory (T helper 1, Th1) or anti‐inflammatory (T helper 2, Th2) depending on their effects on the immune system. However, cytokines impact a variety of tissues in a complex manner that regulates inflammation, cell death, and cell proliferation and migration as well as healing mechanisms. Ethanol (alcohol) is known to alter cytokine levels in a variety of tissues including plasma, lung, liver, and brain. Studies on human monocyte responses to pathogens reveal ethanol disruption of cytokine production depending upon the pathogen and duration of alcohol consumption, with multiple pathogens and chronic ethanol promoting inflammatory cytokine production. In lung, cytokine production is disrupted by ethanol exacerbating respiratory distress syndrome with greatly increased expression of transforming growth factor β (TGFβ). Alcoholic liver disease involves an inflammatory hepatitis and an exaggerated Th1 response with increases in tumor necrosis factor α (TNFα). Recent studies suggest that the transition from Th1 to Th2 cytokines contribute to hepatic fibrosis and cirrhosis. Cytokines affect the brain and likely contribute to changes in the central nervous system that contribute to long‐term changes in behavior and neurodegeneration. Together these studies suggest that ethanol disruption of cytokines and inflammation contribute in multiple ways to a diversity of alcoholic pathologies.

The effect of acute (2.0 g/kg, intragastrically) and chronic (8.0-11.0 g/kg/day for 10 days, intragastrically) ethanol exposure on beta-endorphin levels in plasma, hypothalamus and pituitary were examined in rats. Hypothalamic and plasma catecholamines and plasma corticosterone were also measured in these animals. Plasma beta-endorphin, norepinephrine (NE) and corticosterone levels were significantly increased and dopamine (DA) was unchanged in acute and chronic ethanol-treated rats. Compared to controls, plasma epinephrine (E) levels were increased in acute ethanol-treated rats but no significant change was observed in chronic ethanol-treated rats. Plasma dopamine were significantly decreased following chronic ethanol treatment while no significant change was observed after acute treatment. In the hypothalamus, beta-endorphin and dopamine contents were increased and norepinephrine levels were reduced in response to ethanol exposure. Beta-endorphin levels were decreased significantly in the anterior pituitary and the neurointermediate lobe of the pituitary in ethanol-treated animals except in the neurointermediate lobe of the chronic ethanol-treated animals. These findings together suggest that there is an interaction between beta-endorphin, catecholamines, corticosterone and ethanol in response to acute and chronic ethanol exposure in rats.

Interoception refers to the perception of the internal state of the body and is increasingly being recognized as an important factor in mental health disorders. Drugs of abuse produce powerful interoceptive states that are upstream of behaviors that drive and influence drug intake, and addiction pathology is impacted by interoceptive processes. The goal of the present review is to discuss interoceptive processes related to alcohol. We will cover physiological responses to alcohol, how interoceptive states can impact drinking, and the recruitment of brain networks as informed by clinical research. We also review the molecular and brain circuitry mechanisms of alcohol interoceptive effects as informed by preclinical studies. Finally, we will discuss emerging treatments with consideration of interoception processes. As our understanding of the role of interoception in drug and alcohol use grows, we suggest that the convergence of information provided by clinical and preclinical studies will be increasingly important. Given the complexity of interoceptive processing and the multitude of brain regions involved, an overarching network-based framework can provide context for how focused manipulations modulate interoceptive processing as a whole. In turn, preclinical studies can systematically determine the roles of individual nodes and their molecular underpinnings in a given network, potentially suggesting new therapeutic targets and directions. As interoceptive processing drives and influences motivation, emotion, and subsequent behavior, consideration of interoception is important for our understanding of processes that drive ongoing drinking and relapse.