Action Of Ethanol Research Articles

The Role of Endogenous Beta-Endorphin and Enkephalins in the Crosstalk Between Ethanol and Morphine.

Background: There is clinical concern about the combined use of alcohol and opiates. Several lines of evidence support an interaction between alcohol and the endogenous opioid system. Thus, we hypothesized that ethanol, by causing the release of opioid peptides, may sensitize the system to the action of exogenous opioids such as morphine. Objectives: In this study, using the place conditioning paradigm, a model of reward, we determined whether a morphine challenge would alter the pre-established preference induced by ethanol conditioning in mice, and whether this response was mediated by the mu opioid receptor (MOP). Given that ethanol exposure stimulates the release of opioid peptides, we also assessed the role of beta-endorphin (β-END) and enkephalins (ENKs) in this response. Methods: Mice lacking MOPs, β-END, and/or ENKs, and their respective wild-type controls were tested for preconditioning place preference on day 1. Mice were then conditioned with ethanol (2 g/kg) versus saline on days 2 to 4 and then tested under a drug-free state for postconditioning place preference on day 5. On day 8, mice received a single injection of morphine (5 mg/kg) and were tested for place preference. On the test days, mice were placed in the central chamber and allowed to explore the chambers. The amount of time that mice spent in the drug-paired chamber was recorded. Results: We found that a challenge dose of morphine given on day 8 enhanced the conditioned place preference (CPP) response in mice previously conditioned with ethanol. This response was abolished in MOP-null mice, confirming the role of MOPs in this response. Although this enhanced response was not altered in mice lacking either β-END or ENKs compared to their wild-type littermates/controls, it was completely blunted in mice lacking both β-END and enkephalins. Conclusions: Together, these results suggest that these opioid peptides jointly mediate the crosstalk between the rewarding actions of morphine and ethanol.

Exploration of bioactive molecules from Sesbania grandiflora (L.): identification of squalene as an effective compound against the two-spotted spider mite, Tetranychus urticae Koch, through molecular docking.

Two-spotted spider mite (TSSM), Tetranychus urticae Koch is a devastating polyphagous mite causing considerable economic loss. Acaricides are showered in crops to manage this pest. The pest is known for developing resistance to several classical acaricides. The study was aimed at the exploration of botanical acaricide for the management of TSSM, T. urticae. Adulticidal action of ethyl acetate, ethanol and water extracts of leaves of Sesbania grandiflora (Fabaceae) were tested on T. urticae. The results showed that ethyl acetate extract showed the maximum mite mortality of 94.44 per cent, followed by ethanol extract at 87.78 per cent at 5 per cent concentration. LC50 of ethyl acetate and ethanol extracts were 1.00 and 4.19 per cent, respectively. The aqueous extract gave 94.44 per cent mortality at a very high concentration of 15% with LC50 of 8.57%. Molecules from the GC-MS analysis of S. grandiflora ethyl acetate leaf extract were subjected to molecular docking using acetylcholine esterase as the target molecule. The major phytomolecules identified in the ethyl acetate leaf extract of S. grandiflora were stigmasterol (15.45%), phytol (13.60%), beta-amyrone (8.72%), and squalene (7.51%). Squalene, a biomolecule with the lowest binding energy was selected from the docking result. The toxicity of squalene was evident from the fact that it caused 81.11, 85.55 and 87.78 per cent mortality at 1800, 2000 and 2200 ppm, respectively at 48h after treatment. After, 72h, 100 per cent mortality was recorded at 1800 ppm. This study reveals that squalene can be formulated and used as the best alternative to tackle T. urticae.

The effect of alcohol on brain structures involved in the formation of addiction

Annotation. The process of forming alcohol addiction leads to the occurrence of irreversible changes in the human body, which can be fatal. Neurons of the brain are among the most sensitive structures to the effects of ethanol. Brain neurons are one of the most sensitive structures to the action of ethanol. Understanding the mechanism of formation of alcohol dependence can help in the treatment of patients with this disorder. Therefore, goal is a detailed study of the areas of the brain that are responsible for the formation of this disorder. For this, was analyzed the PubMed database. Articles were selected that discussed the areas of the brain involved in the formation of this disorder, changes in dopaminergic and GABAergic neurons, increased or decreased expression of proteins that regulate neuroplasticity of these areas during chronic ethanol consumption. For the convenience of searching, articles are grouped by publication years: 2000-2010, 2011-2018, and 2019-2023. According to the results of this study, we believe that the hippocampus, prefrontal cortex (PFC), nucleus accumbens, the amygdala and the ventral tegmental area (VTA) are key brain structures involved in the formation of addiction; these areas are part of the mesocorticolimbic reward pathway; the hippocampus is responsible for the formation of pleasant memories, it can decrease under the influence of ethanol, which leads to the loss of episodic memory; the PFC has an influence on decision-making that is based on experience, alcohol suppresses PFC activity; the adjacent nucleus stimulates a person through dopamine connections to relapse, because plasticity changes under the influence of ethanol; the amygdala - is the center of formation of positive and negative emotions, and alcohol withdrawal reduces the activity of this structure and causes stress, while chronic use of ethanol, on the contrary, activates the amygdala; The VTA has connections with all structures of the mesocorticolimbic pathway, it can both facilitate alcohol use and stimulate aversion to it. Conclusion: in our opinion, these structures are the most important in the process of forming addiction. The perspective of the research, in our opinion, is the study of the molecular mechanisms of addiction.

Stress factors and cytotoxic and genotoxic action of ethanol in Saccharomyces cerevisiae

In industrial fermentation, Saccharomyces cerevisiae are exposed to different stress conditions. In this sense, the aim of this study was to evaluate the toxic action of ethanolic stress on Saccharomyces cerevisiae. Exploratory research was carried out on the stress factors that cause injuries in yeast. Fermentation tests were conducted with the Fleischmann® and Pedra-2 strains, cultivated in sugarcane juice at 22 ºBrix and pH 5.0, adding concentrations of 5, 10, and 15% of ethyl alcohol, and incubated at 30°C at 250 rpm for 10 hours. For the cytotoxic tests, 100 µl of samples were collected for evaluation of cell growth by spectrophotometric measurements at 570 nm, and 5 µl were dripped into Petri dishes containing 2% YPD solid medium and incubated at 30ºC for 72 hours for colony growth. For the genotoxicity test, the comet test was used with 0.5 µl of the samples added to slides previously prepared and subjected to electrophoretic running and subsequently stained in a 0.1% silver nitrate solution. 100 random nucleotides were evaluated, evaluating five DNA damage classes (0, 1, 2, 3, and 4) according to the intensity and pattern of genetic material entrainment. The results show that stress factors interfere with yeast performance. Fleischmann® showed sensitivity to ethanolic stress.

Investigating the efficacy of mirtazapine-embedded invasomal gel nanocarriers via I-optimal design for management of atopic dermatitis

The objective of the present study was to optimize a novel invasomal gel (inva-gel) formulation enriched with terpene for upgrading the therapeutic action of anti-depressant mirtazapine on atopic dermatitis as an off-label use. Various factors were studied by I-optimal design to propose an optimized invasome with desirable characteristics. Its incorporation into different hydrogel bases was targeted to suggest a desirable inva-gel formulation, inspect its ex-vivo performance, and conduct in-vivo pre- and post-sacrifice assessments on atopic dermatitis-induced rats. Results revealed positive ethanol action on increasing entrapment efficiency (up to 77.88%) and decreasing size of invasomal vesicles (from 390.30 nm to 190.60 nm). Increased terpene amounts provided more space for mirtazapine incorporation with enhanced solubility and encapsulation inside invasomes. Terpene's molecular weight and lipophilicity significantly affected physicochemical characteristics of invasomes. More cross-linkages would occur by raising gel:liquid invasome ratio (from 0.5:1 to 2.5:1) and using carbopol other than hydroxylpropyl methyl cellulose (HPMC), therefore increasing rheological properties of inva-gels. Synergistic effects of phospholipid, ethanol, limonene, and carbopol to enhance mirtazapine permeation through skin were observed. Throughout the pre-sacrifice assessments, optimized inva-gel demonstrated a significant decrease in dermatitis severity score (from 8.33 to 3.00) and scratching behavior (from 184.32 s to 37.42 s) in disease-induced rats, hence showing favorable skin profile. Concerning the post-sacrifice assessments, optimized inva-gel significantly alleviated inflammation and pruritus symptoms by minimizing epidermal thickening (from 92.32 μm to 50.17 μm), down-regulating various inflammatory mediators, and decreasing infiltration of inflammatory mast cells. Besides, the ear swelling and spleen index values were markedly decreased (from 77.37 mg to 22.76 mg and from 0.56% to 0.35%, respectively). In conclusion, novel anti-depressant mirtazapine-embedded inva-gel displayed successful transdermal drug permeation offering valuable merits in atopic dermatitis management.

Alcohol and the dopamine system.

The mesolimbic dopamine pathway plays a major role in drug reinforcement and is likely involved also in the development of drug addiction. Ethanol, like most addictive drugs, acutely activates the mesolimbic dopamine system and releases dopamine, and ethanol-associated stimuli also appear to trigger dopamine release. In addition, chronic exposure to ethanol reduces the baseline function of the mesolimbic dopamine system. The molecular mechanisms underlying ethanol´s interaction with this system remain, however, to be unveiled. Here research on the actions of ethanol in the mesolimbic dopamine system, focusing on the involvement of cystein-loop ligand-gated ion channels, opiate receptors, gastric peptides and acetaldehyde is briefly reviewed. In summary, a great complexity as regards ethanol´s mechanism(s) of action along the mesolimbic dopamine system has been revealed. Consequently, several new targets and possibilities for pharmacotherapies for alcohol use disorder have emerged.

Adolescent binge ethanol impacts H3K9me3-occupancy at synaptic genes and the regulation of oligodendrocyte development.

Binge drinking in adolescence can disrupt myelination and cause brain structural changes that persist into adulthood. Alcohol consumption at a younger age increases the susceptibility of these changes. Animal models to understand ethanol's actions on myelin and white matter show that adolescent binge ethanol can alter the developmental trajectory of oligodendrocytes, myelin structure, and myelin fiber density. Oligodendrocyte differentiation is epigenetically regulated by H3K9 trimethylation (H3K9me3). Prior studies have shown that adolescent binge ethanol dysregulates H3K9 methylation and decreases H3K9-related gene expression in the PFC. Here, we assessed ethanol-induced changes to H3K9me3 occupancy at genomic loci in the developing adolescent PFC. We further assessed ethanol-induced changes at the transcription level with qPCR time course approaches in oligodendrocyte-enriched cells to assess changes in oligodendrocyte progenitor and oligodendrocytes specifically. Adolescent binge ethanol altered H3K9me3 regulation of synaptic-related genes and genes specific for glutamate and potassium channels in a sex-specific manner. In PFC tissue, we found an early change in gene expression in transcription factors associated with oligodendrocyte differentiation that may lead to the later significant decrease in myelin-related gene expression. This effect appeared stronger in males. Further exploration in oligodendrocyte cell enrichment time course and dose response studies could suggest lasting dysregulation of oligodendrocyte maturation at the transcriptional level. Overall, these studies suggest that binge ethanol may impede oligodendrocyte differentiation required for ongoing myelin development in the PFC by altering H3K9me3 occupancy at synaptic-related genes. We identify potential genes that may be contributing to adolescent binge ethanol-related myelin loss.

Ninein, a candidate gene for ethanol anxiolysis, shows complex exon-specific expression and alternative splicing differences between C57BL/6J and DBA/2J mice.

Ethanol's anxiolytic actions contribute to increased consumption and the development of Alcohol Use Disorder (AUD). Our laboratory previously identified genetic loci contributing to the anxiolytic-like properties of ethanol in BXD recombinant inbred mice, derived from C57BL/6J (B6) and DBA/2J (D2) progenitor strains. That work identified Ninein (Nin) as a candidate gene underlying ethanol's acute anxiolytic-like properties in BXD mice. Nin has a complex exonic content with known alternative splicing events that alter cellular distribution of the NIN protein. We hypothesize that strain-specific differences in Nin alternative splicing contribute to changes in Nin gene expression and B6/D2 strain differences in ethanol anxiolysis. Using quantitative reverse-transcriptase PCR to target specific Nin splice variants, we identified isoform-specific exon expression differences between B6 and D2 mice in prefrontal cortex, nucleus accumbens and amygdala. We extended this analysis using deep RNA sequencing in B6 and D2 nucleus accumbens samples and found that total Nin expression was significantly higher in D2 mice. Furthermore, exon utilization and alternative splicing analyses identified eight differentially utilized exons and significant exon-skipping events between the strains, including three novel splicing events in the 3' end of the Nin gene that were specific to the D2 strain. Additionally, we document multiple single nucleotide polymorphisms in D2 Nin exons that are predicted to have deleterious effects on protein function. Our studies provide the first in-depth analysis of Nin alternative splicing in brain and identify a potential genetic mechanism altering Nin expression and function between B6 and D2 mice, thus possibly contributing to differences in the anxiolytic-like properties of ethanol between these strains. This work adds novel information to our understanding of genetic differences modulating ethanol actions on anxiety that may contribute to the risk for alcohol use disorder.

Ethanol’s interaction with BK channel α subunit residue K361 does not mediate behavioral responses to alcohol in mice

Large conductance potassium (BK) channels are among the most sensitive molecular targets of ethanol and genetic variations in the channel-forming α subunit have been nominally associated with alcohol use disorders. However, whether the action of ethanol at BK α influences the motivation to drink alcohol remains to be determined. To address this question, we first tested the effect of systemically administered BK channel modulators on voluntary alcohol consumption in C57BL/6J males. Penitrem A (blocker) exerted dose-dependent effects on moderate alcohol intake, while paxilline (blocker) and BMS-204352 (opener) were ineffective. Because pharmacological manipulations are inherently limited by non-specific effects, we then sought to investigate the behavioral relevance of ethanol’s direct interaction with BK α by introducing in the mouse genome a point mutation known to render BK channels insensitive to ethanol while preserving their physiological function. The BK α K361N substitution prevented ethanol from reducing spike threshold in medial habenula neurons. However, it did not alter acute responses to ethanol in vivo, including ataxia, sedation, hypothermia, analgesia, and conditioned place preference. Furthermore, the mutation did not have reproducible effects on alcohol consumption in limited, continuous, or intermittent access home cage two-bottle choice paradigms conducted in both males and females. Notably, in contrast to previous observations made in mice missing BK channel auxiliary β subunits, the BK α K361N substitution had no significant impact on ethanol intake escalation induced by chronic intermittent alcohol vapor inhalation. It also did not affect the metabolic and locomotor consequences of chronic alcohol exposure. Altogether, these data suggest that the direct interaction of ethanol with BK α does not mediate the alcohol-related phenotypes examined here in mice.

The ameliorative effects of choline on ethanol-induced cell death in the neural tube of susceptible BXD strains of mice.

Fetal alcohol spectrum disorders (FASD) are the leading preventable cause of intellectual disability, providing the impetus for evaluating various potential treatments to ameliorate ethanol's teratogenic effects, particularly in the nervous system. One treatment is the dietary supplement choline which has been shown to mitigate at least some of ethanol's teratogenic effects. The present study was designed to investigate the effects of genetics on choline's efficacy in ameliorating cell death in the developing neural tube. Previously, we examined BXD recombinant inbred mice, and their parental C57BL/6 J (B6) and DBA/2 J strains, and identified strains that were sensitive to ethanol's teratogenic actions. Thus, we used these strains to identify response to choline treatment. Timed pregnant mice from 4 strains (B6, BXD51, BXD73, BXD2) were given either ethanol or isocaloric maltose-dextrin (5.8 g/kg in two administrations separated by 2 h) with choline at one of 3 doses: 0, 100 or 250 mg/kg. Subjects were exposed via intragastric gavage on embryonic day 9 and embryos were collected 7 h after the initial ethanol administrations. Cell death was analyzed using TUNEL staining in the developing forebrain and brainstem. Choline ameliorated the ethanol-induced cell death across all 4 strains without causing enhanced cell death in control mice. Choline was effective in both the developing telencephalon and in the brainstem. Both doses diminished cell death, with some differences across strains and brain regions, although the 100 mg/kg dose was most consistent in mitigating ethanol-related cell death. Comparisons across strains showed that there was an effect of strain, particularly in the forebrain at the higher dose. These results show that choline is effective in ameliorating ethanol-induced cell death at this early stage of nervous system development. However, there were some strain differences in its efficacy, especially at the high dose, providing further evidence of the importance of genetics in influencing the ability of choline to protect against prenatal alcohol exposure.

Alcohol and pregnenolone interaction on cerebral arteries through targeting of vascular smooth muscle - and voltage-gated K+ channels of big conductance.

Despite the significant number of people who may be taking pregnenolone supplements while drinking alcohol (ethanol), the widely documented cerebrovascular actions of pregnenolone and ethanol, and the critical dependence of cerebrovascular function on cerebral artery diameter, there are no studies addressing the effect of pregnenolone + ethanol in combination on cerebral artery diameter. We investigated this by evaluating the effect of this combination on middle cerebral artery diameter in male and female C57BL/6J mice, both in vivo and in vitro. The use of de-endothelialized, in vitro pressurized middle cerebral artery segments allowed us to conduct a concentration-response study of constriction induced by pregnenolone ± ethanol, in which drug action could be evaluated independently of circulating and endothelial factors. In both male and female animals, pregnenolone at lower concentrations (≤1 μM) was found to synergize with 50 mM ethanol to cause vasoconstriction. In both sexes, this synergism was lost as one or both vasoconstrictors approached their maximally effective concentrations (75 mM and 10 μM for ethanol and pregnenolone, respectively), whether this was evaluated in vitro or in vivo using a cranial window. Vasoconstriction by pregnenolone + ethanol was abolished by 1 μM paxilline, indicating BK channel involvement. Moreover, cell-free recordings of BK channel activity in cerebral artery myocyte membranes showed that 10 μM pregnenolone and pregnenolone +50 mM ethanol reduced channel activity to an identical extent, suggesting that these drugs inhibit cerebrovascular BK channels via a common mechanism or mechanisms. Indeed, pregnenolone was found to disrupt allosteric coupling to -driven gating, as previously reported for ethanol.

Experimental evaluation of the influence of electromagnetic radiation and acute alcohol intoxication on the indicators of mineral metabolism and antioxidant protection in erythrocytes and blood plasma of rats

The aim of the research was a comparative analysis of the effect of electromagnetic radiation and acute alcohol intoxication on the parameters of mineral metabolism and antioxidant protection in erythrocytes and blood plasma of rats. Materials and methods. The research was performed on 128 white non-linear rats. The study was conducted on five experimental models: acute ethanol poisoning, acute ethanol poisoning against the background of preliminary alcoholization, exposure to electromagnetic radiation for 1, 2 and 3 months. Spectrophotometrically determined the content of iron, copper, transferrin, ceruloplasmin and the activity of gamma-glutamyl transpeptidase in the blood plasma of rats, the content of glutathione in blood erythrocytes. Results and discussion. A unidirectional nature of changes in the indicators of antioxidant protection and mineral metabolism in acute alcohol intoxication and electromagnetic irradiation was established, which consists in a decrease in the content of iron, transferrin, an increase in the content of ceruloplasmin, glutathione, and gamma-glutamyl transpeptidase activity. At the same time, a decrease in the iron content and a change in the parameters of antioxidant protection in the blood plasma are more pronounced in acute ethanol poisoning than in electromagnetic irradiation. Conclusions. Ceruloplasmin, transferrin, glutathione and gamma-glutamyl transpeptidase are targets for the action of electromagnetic radiation and ethanol. Determination of the activity of gamma-glutamyl transpeptidase in blood plasma has a prognostic value for determining the degree of liver damage not only with alcohol intoxication, but also with electromagnetic irradiation of the decimeter range.

The rostromedial tegmental nucleus RMTg is not a critical site for ethanol-induced motor activation in rats.

Opioid drugs indirectly activate dopamine (DA) neurons in the ventral tegmental area (VTA) through a disinhibition mechanism mediated by mu opioid receptors (MORs) present both on the GABA projection neurons located in the medial tegmental nucleus/tail of the VTA (RMTg/tVTA) and on the VTA GABA interneurons. It is well demonstrated that ethanol, like opioid drugs, provokes VTA DA neuron disinhibition by interacting (through its secondary metabolite, salsolinol) with MORs present in VTA GABA interneurons, but it is not known whether ethanol could disinhibit VTA DA neurons through the MORs present in the RMTg/tVTA. The objective of the present study was to determine whether ethanol, directly microinjected into the tVTA/RMTg, is also able to induce VTA DA neurons disinhibition. Disinhibition of VTA DA neurons was indirectly assessed through the analysis of the motor activity of rats. Cannulae were placed into the tVTA/RMTg to perform microinjections of DAMGO (0.13 nmol), ethanol (150 or 300 nmol) or acetaldehyde (250 nmol) in animals pre-treated with either aCSF or the irreversible antagonist of MORs, beta-funaltrexamine (beta-FNA; 2.5 nmol). After injections, spontaneous activity was monitored for 30 min. Neither ethanol nor acetaldehyde directly administered into the RMTg/tVTA were able to increase the locomotor activity of rats at doses that, in previous studies performed in the posterior VTA, were effective in increasing motor activities. However, microinjections of 0.13 nmol of DAMGO into the tVTA/RMTg significantly increased the locomotor activity of rats. These activating effects were reduced by local pre-treatment of rats with beta-FNA (2.5 nmol). The tVTA/RMTg does not appear to be a key brain region for the disinhibiting action of ethanol on VTA DA neurons. The absence of dopamine in the tVTA/RMTg extracellular medium, the lack of local ethanol metabolism or both could explain the present results.

Unveiling Unconventional Luminescence Behavior of Multicolor Carbon Dots Derived from Phenylenediamine.

Fluorescence regulation of carbon dots (CDs) during their preparation has become a hot research topic. In this work, multicolor fluorescent CDs with unconventional luminescence behavior are prepared by using o-, m-, or p-phenylenediamine (o-PD, m-PD, or p-PD, respectively) and 2,3-dihydroxynaphthalene with rich hydroxyl groups as reaction precursors. Tunable multicolor fluorescent CDs with bright blue, yellow, and red colors can be obtained by a solvothermal method under the joint action of ethanol and hydrochloric acid. The fluorescence emission of the synthesized CDs follows a rule of o-PD to m-PD to p-PD from blue to red, which is contrary to most previously reported results (the luminescence from blue to red following an order of m-PD to o-PD to p-PD). Our results reveal that the differences in the polymerization, surface states, functional groups, and graphite N content of CDs might be the main reasons for the unconventional luminescence behavior. In addition, these multicolor CDs have good applications in the fields of light-emitting diode lighting and anticounterfeiting.

Implication of the PTN/RPTPβ/ζ Signaling Pathway in Acute Ethanol Neuroinflammation in Both Sexes: A Comparative Study with LPS.

Binge drinking during adolescence increases the risk of alcohol use disorder, possibly by involving alterations of neuroimmune responses. Pleiotrophin (PTN) is a cytokine that inhibits Receptor Protein Tyrosine Phosphatase (RPTP) β/ζ. PTN and MY10, an RPTPβ/ζ pharmacological inhibitor, modulate ethanol behavioral and microglial responses in adult mice. Now, to study the contribution of endogenous PTN and the implication of its receptor RPTPβ/ζ in the neuroinflammatory response in the prefrontal cortex (PFC) after acute ethanol exposure in adolescence, we used MY10 (60 mg/kg) treatment and mice with transgenic PTN overexpression in the brain. Cytokine levels by X-MAP technology and gene expression of neuroinflammatory markers were determined 18 h after ethanol administration (6 g/kg) and compared with determinations performed 18 h after LPS administration (5 g/kg). Our data indicate that Ccl2, Il6, and Tnfa play important roles as mediators of PTN modulatory actions on the effects of ethanol in the adolescent PFC. The data suggest PTN and RPTPβ/ζ as targets to differentially modulate neuroinflammation in different contexts. In this regard, we identified for the first time important sex differences that affect the ability of the PTN/RPTPβ/ζ signaling pathway to modulate ethanol and LPS actions in the adolescent mouse brain.

ЭКСПЕРИМЕНТАЛЬНО КЛИНИЧЕСКОЕ СОПОСТАВЛЕНИЕ АЛКОГОЛЬ-ИНДУЦИРОВАННЫХ ИЗМЕНЕНИЙ ВАСКУЛЯРНО-ЭНДОТЕЛИАЛЬНОГО ФАКТОРА РОСТА

Aim: to comparatively estimate the nature and direction of alcohol-induced changes of vascular endothelial growth factor in the experiment and in the clinic. Materials and methods. The experimental part of the research was performed on 50 outbred mature rats (15 females and 15 males exposed to alcohol intoxication for 30 days, and 10 females and 10 males formed a control group). The average age of males was 38 (37.25–39) weeks, females - 40.5 (40-42.5) weeks. The body weight of females was 340 (329.5–345.5) g, males – 469 (464.5–474.25) g. After fixation, the control group animals were injected with intragastrically sterile 0.9% aqueous sodium chloride solution, the rest of the animals – 40% ethanol daily at the rate of 10 ml / kg, so that the animals reached a mild degree of intoxication. Clinical part of the research included 60 young patients: 30 males and 30 females, mean age was 35,97 (34,00-40,00) in females and 37,5 (34,00-41,00) in males, who were admitted to the narcological hospital for treatment of intoxication with diagnosed alcohol use disorder. The serum concentration of VEGF-A was evaluated in the blood serum of the studied patients and animals. Results. Alcohol intoxication caused an increase of serum concentration of VEGF-A in both animals and patients in comparison with control groups. The changes were unidirectional with no significant gender differences. Conclusion. The analysis of the experimental-clinical comparison of alcohol-induced changes in the serum content of VEGF-A indicates the unidirectional nature of the biological (angiogenic) effect in the form of VEGF-A expression under the action of ethanol. In the clinical interpretation of the physiological or pathological expression of angiogenesis, accompanied by an increase in the serum concentration of VEGF-A, it is necessary to take into account the specifics of the pathological process.

Animal models for studies of alcohol effects on the trajectory of age-related cognitive decline.

There is growing interest in understanding how ethanol use interacts with advancing age to influence the brain and cognition. Animal models are employed to investigate the cellular and molecular mechanisms of brain aging and age-related neurodegenerative diseases that underlie cognitive decline. However, all too often research on problems and diseases of the elderly are conducted in healthy young animals, providing little clinical relevance. The validity of animal models is discussed, and confounds due to age-related differences in anxiety, sensory-motor function, and procedural learning are highlighted in order to enhance the successful translation of preclinical results into clinical settings. The mechanism of action of ethanol on brain aging will depend on the dose, acute or chronic treatment, or withdrawal from treatment and the age examined. Due to the fact that humans experience alcohol use throughout life, important questions concern the effects of the dose and duration of ethanol treatment on the trajectory of cognitive function. Central to this research will be questions of the specificity of alcohol effects on cognitive functions and related brain regions that decline with age, as well as the interaction of alcohol with mechanisms or biomarkers of brain aging. Alternatively, moderate alcohol use may provide a source of reserve and resilience against brain aging. Longitudinal studies have the advantage of being sensitive to detecting the effects of treatment on the emergence of cognitive impairment in middle age and can minimize effects of stress/anxiety associated with the novelty of alcohol exposure and behavioral testing, which disproportionately influence aged animals. Finally, the effect of alcohol on senescent neurophysiology and biomarkers of brain aging are discussed. In particular, the interaction of age and effects of alcohol on inflammation, oxidative stress, N-methyl-d-aspartate receptor function, and the balance of excitatory and inhibitory synaptic transmission are highlighted.

Aging in nucleus accumbens and its impact on alcohol use disorders.

Ethanol is one of the most widely consumed drugs in the world and prolonged excessive ethanol intake might lead to alcohol use disorders (AUDs), which are characterized by neuroadaptations in different brain regions, such as in the reward circuitry. In addition, the global population is aging, and it appears that they are increasing their ethanol consumption. Although research involving the effects of alcohol in aging subjects is limited, differential effects have been described. For example, studies in human subjects show that older adults perform worse in tests assessing working memory, attention, and cognition as compared to younger adults. Interestingly, in the field of the neurobiological basis of ethanol actions, there is a significant dichotomy between what we know about the effects of ethanol on neurochemical targets in young animals and how it might affect them in the aging brain. To be able to understand the distinct effects of ethanol in the aging brain, the following questions need to be answered: (1) How does physiological aging impact the function of an ethanol-relevant region (e.g., the nucleus accumbens)? and (2) How does ethanol affect these neurobiological systems in the aged brain? This review discusses the available data to try to understand how aging affects the nucleus accumbens (nAc) and its neurochemical response to alcohol. The data show that there is little information on the effects of ethanol in aged mice and rats, and that many studies had considered 2-3-month-old mice as adults, which needs to be reconsidered since more recent literature defines 6 months as young adults and >18 months as an older mouse. Considering the actual relevance of an aged worldwide population and that this segment is drinking more frequently, it appears at least reasonable to explore how ethanol affects the brain in adult and aged models.

Interspecies and regional variability of alcohol action on large cerebral arteries: regulation by KCNMB1 proteins.

Alcohol intake leading to blood ethanol concentrations (BEC) ≥ legal intoxication modifies brain blood flow with increases in some regions and decreases in others. Brain regions receive blood from the Willis' circle branches: anterior, middle (MCA) and posterior cerebral (PCA), and basilar (BA) arteries. Rats and mice have been used to identify the targets mediating ethanol-induced effects on cerebral arteries, with conclusions being freely interchanged, albeit data were obtained in different species/arterial branches. We tested whether ethanol action on cerebral arteries differed between male rat and mouse and/or across different brain regions and identified the targets of alcohol action. In both species and all Willis' circle branches, ethanol evoked reversible and concentration-dependent constriction (EC50s ≈ 37-86 mM; below lethal BEC in alcohol-naïve humans). Although showing similar constriction to depolarization, both species displayed differential responses to ethanol: in mice, MCA constriction was highly sensitive to the presence/absence of the endothelium, whereas in rat PCA was significantly more sensitive to ethanol than its mouse counterpart. In the rat, but not the mouse, BA was more ethanol sensitive than other branches. Both interspecies and regional variability were ameliorated by endothelium. Selective large conductance (BK) channel block in de-endothelialized vessels demonstrated that these channels were the effectors of alcohol-induced cerebral artery constriction across regions and species. Variabilities in alcohol actions did not fully matched KCNMB1 expression across vessels. However, immunofluorescence data from KCNMB1-/- mouse arteries electroporated with KCNMB1-coding cDNA demonstrate that KCNMB1 proteins, which regulate smooth muscle (SM) BK channel function and vasodilation, regulate interspecies and regional variability of brain artery responses to alcohol.

Molecular Imaging Studies of Alcohol Use Disorder.

Alcohol use disorder (AUD) is a serious public health problem in many countries, bringing a gamut of health risks and impairments to individuals and a great burden to society. Despite the prevalence of a disease model of AUD, the current pharmacopeia does not present reliable treatments for AUD; approved treatments are confined to a narrow spectrum of medications engaging inhibitory γ-aminobutyric acid (GABA) neurotransmission and possibly excitatory N-methyl-D-aspartate (NMDA) receptors, and opioid receptor antagonists. Molecular imaging with positron emission tomography (PET) and single-photon emission computed tomography (SPECT) can open a window into the living brain and has provided diverse insights into the pathology of AUD. In this narrative review, we summarize the state of molecular imaging findings on the pharmacological action of ethanol and the neuropathological changes associated with AUD. Laboratory and preclinical imaging results highlight the interactions between ethanol and GABA A-type receptors (GABAAR), but the interpretation of such results is complicated by subtype specificity. An abundance of studies with the glucose metabolism tracer fluorodeoxyglucose (FDG) concur in showing cerebral hypometabolism after ethanol challenge, but there is relatively little data on long-term changes in AUD. Alcohol toxicity evokes neuroinflammation, which can be tracked using PET with ligands for the microglial marker translocator protein (TSPO). Several PET studies show reversible increases in TSPO binding in AUD individuals, and preclinical results suggest that opioid-antagonists can rescue from these inflammatory responses. There are numerous PET/SPECT studies showing changes in dopaminergic markers, generally consistent with an impairment in dopamine synthesis and release among AUD patients, as seen in a number of other addictions; this may reflect the composite of an underlying deficiency in reward mechanisms that predisposes to AUD, in conjunction with acquired alterations in dopamine signaling. There is little evidence for altered serotonin markers in AUD, but studies with opioid receptor ligands suggest a specific up-regulation of the μ-opioid receptorsubtype. Considerable heterogeneity in drinking patterns, gender differences, and the variable contributions of genetics and pre-existing vulnerability traits present great challenges for charting the landscape of molecular imaging in AUD.