Chronic Neurologic Effects of Alcohol.

Chronic alcohol use induces silent changes in the structure and function of the central and peripheral nervous systems that eventually result in irreversible, debilitating repercussions. Once identified, nutritional supplementation and cessation measures are critical in preventing further neurologic damage. The proposed mechanisms of neuronal injury in chronic alcohol abuse include direct toxic effects of alcohol and indirect effects, including those resulting from hepatic dysfunction, nutritional deficiencies, and neuroinflammation. Clinical manifestations include cerebellar ataxia, peripheral neuropathy and Wernicke-Korsakoff encephalopathy. Continued exploration of the pathophysiologic mechanisms may lead to the discovery of early interventions that can prevent permanent neurologic injury.

Early-stage Alcoholic Cerebellar Degeneration: Diagnostic Imaging Clues

No abstract available.

Binge-like ethanol consumption increases corticosterone levels and neurodegneration whereas occupancy of type II glucocorticoid receptors with mifepristone is neuroprotective.

Excessive ethanol (EtOH) use leads to impaired memory and cognition. Using a rat model of binge-like intoxication, we tested whether elevated corticosterone (Cort) levels contribute to the neurotoxic consequences of EtOH exposure. Rats were adrenalectomized (Adx) and implanted with cholesterol pellets, or cholesterol pellets containing Cort in order to achieve basal, medium, or high blood concentrations of Cort. Intragastric EtOH or an isocaloric control solution was given three times daily for 4 days to achieve blood alcohol levels ranging between 200 and 350 mg/dl. Mean 24-hour plasma levels of Cort were ∼110 and ∼40 ng/ml in intact EtOH-treated and intact control animals, respectively. Basal Cort replacement concentrations in EtOH-treated Adx animals did not exacerbate alcohol-induced neurodegeneration in the hippocampal dentate gyrus (DG) or the entorhinal cortex (EC) as observed by amino-cupric silver staining. In contrast, Cort replacement pellets resulting in plasma Cort levels twofold higher (medium) than normal, or greater than twofold higher (high) in Adx-Cort-EtOH animals increased neurodegeneration. In separate experiments, pharmacological blockade of the Type II glucocorticoid (GC) receptor was initiated with mifepristone (RU38486; 0, 5, 15 mg/kg/day, i.p.). At the higher dose, mifepristone decreased the number of degenerating hippocampal DG cells in binge-EtOH-treated intact animals, whereas, only a trend for reduction was observed in 15 mg/kg/day mifepristone-treated animals in the EC, as determined by fluoro-jade B staining. These results suggest that elevated circulating Cort in part mediates EtOH-induced neurotoxicity in the brain through activation of Type II GC receptors.

Region-specific depression of striatal activity in Wistar rat by modest ethanol consumption over a ten-month period.

The nucleus accumbens (nAc) is the primary target for the mesolimbic dopamine system and a key brain region for the reinforcing effects displayed by drugs of abuse, including ethanol. During the transition from recreational to compulsive consumption of reinforcing drugs, however, the dorsal striatum seems to be recruited. Understanding how synaptic activity is altered in a sub-region specific manner in the striatum during the course of long-term drug consumption thus could be essential for understanding the long-lasting changes produced by addictive substances, including ethanol. Here we evaluated synaptic activity in the dorsolateral striatum (DLS) and ventral striatum (nucleus accumbens, nAc) of single-housed Wistar rats consuming water, or water and ethanol, for up to 10 months. Even though ethanol intake was moderate, it was sufficient to decrease input/output function in response to stimulation intensity in the DLS, while recorded population spike (PS) amplitudes in the nAc were unaffected. Striatal disinhibition induced by the GABAA receptor antagonist bicuculline had a slower onset in rats that had consumed ethanol for 2 months, and was significantly depressed in slices from rats that had consumed ethanol for 4 months. Bicuculline-induced disinhibition in the nAc, on the other hand, was not significantly altered by long-term ethanol intake. Changes in PS amplitude induced by taurine or the glycine receptor antagonist strychnine were not significantly altered by ethanol in any brain region. Even though input/output function was not significantly affected by age, there was a significant decline in antagonist-induced disinhibition in brain slices from aged rats. The data presented here suggest that even modest consumption of ethanol is sufficient to alter neurotransmission in the striatum, while synaptic activity appears to be relatively well-preserved in the nAc during the course of long-term ethanol consumption.

Impact of thiamine supplementation in the reversal of ethanol induced toxicity in rats.

One of the molecular mechanisms of alcohol induced toxicities is mediated by oxidative stress. Hence our studies were focused on the effect of thiamine (antioxidant) in the reversal of alcohol induced toxicity and comparison of the reversal with abstinence. Administration of ethanol at a dose of 4 g/kg body wt/day for 90 days to Sprague Dawley rats manifested chronic alcohol induced toxicity evidenced by decreased body weight, an increase in liver-body weight ratio, increase in activities of serum and liver aspartate transaminase (AST), alanine transaminase (ALT), gamma-glutamyl transpeptidase (GGT); decrease in the activities of superoxide dismutase, catalase, glutathione peroxidase and glutathione reductase in the liver and brain. The levels of inflammatory markers, fibrosis markers and DNA fragmentation were also elevated in the serum, liver and brain. After ethanol administration for 90 days, the reversal of the alcohol induced toxicity was studied by supplementing thiamine at a dose of 25 mg/100 g body wt/day. Duration of the reversal study was 30 days. The activities of AST, ALT, GGT, scavenging enzymes as well as markers of inflammation and fibrosis in serum, liver and brain were reversed to a certain extent by thiamine. Changes in neurotransmitter levels in brain were also reversed by thiamine supplementation. DNA damage was decreased and DNA content increased in thiamine supplemented group compared to abstinence group showing a faster regeneration. In short, histopathological and biochemical evaluations indicate that thiamine supplemented abstinent rats made a faster recovery of hepatic and neuronal damage than in the abstinence group.

[Features of psychopharmacotherapeutic correction of alcohol dependence in the elderly].

The article is devoted to the actual in modern medicine problem as the study of the prevalence of alcohol dependence and its psyhofarmacological correction in the elderly. It is shown that elderly and old age as a result of reduction of the reserve capacity of the organism for clinical pathology becomes addictive specific psychopathological features that affect the course of disease and maintenance of preventive treatment. On the basis of empirical evidence the authors prove that at the border severity of alcohol withdrawal syndrome the drug "Cytoflavin" has a fairly pronounced psyhofarmacological activity for older people with alcohol dependence.

Alcohol, insulin resistance and the liver-brain axis.

Chronic alcohol exposure inhibits insulin and insulin-like growth factor signaling in the liver and brain by impairing the signaling cascade at multiple levels. These alterations produced by alcohol cause severe hepatic and central nervous system insulin resistance as the cells fail to adequately transmit signals downstream through Erk/mitogen-activated protein kinase (MAPK), which is needed for DNA synthesis and liver regeneration, and phosphatidylinositol 3-kinase (PI3K), which promotes growth, survival, cell motility, glucose utilization, plasticity, and energy metabolism. The robust inhibition of insulin signaling in liver and brain is augmented by additional factors involving the activation of phosphatases such as phosphatase and tensin homologue (PTEN), which further impairs insulin signaling through PI3K/Akt. Thus, intact insulin signaling is important for neuronal survival. Chronic alcohol consumption produces steatohepatitis, which also promotes hepatic insulin resistance, oxidative stress and injury, with the attendant increased generation of "toxic lipids" such as ceramides that increase insulin resistance. The PI3K/Akt signaling cascade is altered by direct interaction with ceramides as well as through PTEN upregulation as a downstream target gene of enhanced p53 transcriptional activity. Cytotoxic ceramides transferred from the liver to the blood can enter the brain due to their lipid-soluble nature, and thereby exert neurodegenerative effects via a liver-brain axis. We postulate that the neurotoxic and neurodegenerative effects of liver-derived ceramides activate pro-inflammatory cytokines and increase lipid adducts and insulin resistance in the brain to impair cognitive and motor function. These observations are discussed in the context of insulin sensitizers as potential cytoprotective agents against liver and brain injury induced by alcohol.

The occurrence of neurological symptoms in currently abstinent misusers of alcohol.

BACKGROUND: Significant neurological symptoms may be overlooked because of the traditional view that the non-Korsakoff's psychosis, middle aged alcoholic misuser is neurologically preserved. AIMS: In this study, we wanted to investigate the presence of neurological symptoms in individuals with misuse or dependence on alcohol who were abstinent for at least 1 month. METHOD: We used two scales from the Minnesota Multiphasic Personality Inventory-2 (MMPI-2) to ascertain the presence of both neurological symptoms (HEA-2) and symptoms of general health concern (HEA-3) in 70 individuals who had a diagnosis of alcohol misuse or dependence, who were abstinent for greater than 1 month. RESULTS: Individuals reported significantly more neurological symptoms than general health difficulties (p < 0.001). We detected neurological symptoms, unlike general health difficulties in individuals who were abstinent from alcohol for 12 months. When we examined diagnostic subgroups, general health difficulties were most present in individuals with anxiety disorders; however, neurological difficulties were present across diagnostic groups. CONCLUSION: Neurological symptoms persist to a greater extent than general health concerns in individuals who previously were dependent or misused alcohol.

Glucocorticoid and polyamine interactions in the plasticity of glutamatergic synapses that contribute to ethanol-associated dependence and neuronal injury.

Stress contributes to the development of ethanol dependence and is also a consequence of dependence. However, the complexity of physiological interactions between activation of the hypothalamic-pituitary-adrenal (HPA) axis and ethanol itself is not well delineated. Emerging evidence derived from examination of corticotropin-releasing factor systems and glucocorticoid receptor systems in ethanol dependence suggests a role for pharmacological manipulation of the HPA axis in attenuating ethanol intake, though it is not clear how activation of the HPA axis may promote ethanol dependence or contribute to the neuroadaptative changes that accompany the development of dependence and the severity of ethanol withdrawal. This review examines the role that glucocorticoids, in particular, have in promoting ethanol-associated plasticity of glutamatergic synapses by influencing expression of endogenous linear polyamines and polyamine-sensitive polypeptide subunits of N-methyl-D-aspartate (NMDA)-type glutamate receptors. We provide evidence that interactions among glucocorticoid systems, polyamines and NMDA receptors are highly relevant to both the development of ethanol dependence and to behavioral and neuropathological sequelae associated with ethanol withdrawal. Examination of these issues is likely to be of critical importance not only in further elucidating the neurobiology of HPA axis dysregulation in ethanol dependence, but also with regard to identification of novel therapeutic targets that may be exploited in the treatment of ethanol dependence.

Age- and sex-related differences in the acquisition and reinstatement of ethanol CPP in mice.

Many people begin to experiment with alcohol during adolescence, an important developmental period during which sex differences in the effects of ethanol appear. In the present study we evaluated the effect of ethanol (0, 0.625, 1.25 or 2.5 g/kg) on the acquisition of a conditioned place preference (CPP) in early and late adolescent male and female mice. In addition, we assessed the capacity of ethanol to induce reinstatement of the CPP after its extinction. CPP was induced in early and late adolescent females with 2.5 g/kg, and in early adolescent males with 1.25 or 2.5 g/kg of ethanol. No CPP was observed in late adolescent males. Priming with ethanol reinstated the CPP induced by the highest dose in early adolescent male and early and late adolescent female mice. Our data suggest that early adolescents of both sex and late adolescent females are particularly vulnerable to the effects of ethanol.

Stress and alcohol cues exert conjoint effects on go and stop signal responding in male problem drinkers.

Stress, cues, and pharmacological priming are linked with relapse to addictive behavior. Increased salience and decreased inhibitory control are thought to mediate the effects of relapse-related stimuli. However, the functional relationship between these two processes is unclear. To address this issue, a modified Stop Signal Task was employed, which used Alcohol, Neutral, and Non-Words as Go stimuli, and lexical decision as the Go response. Subjects were 38 male problem drinkers (mean Alcohol Dependence Scale (ADS) score: 18.0). Uncontrollable noise (∼ 10 min at 110 dB) was the stressor; nonalcoholic placebo beer (P-Beer) was the cue manipulation, and alcohol (0.7 g/kg), the pharmacological prime. Half the sample received alcohol, and half P-Beer. Stress and beverage (test drink vs soft drink) were manipulated within subjects on two sessions, with half the sample receiving active manipulations together and half receiving them separately. Go response time (RT) and Stop Signal RT (SSRT) were slower to Alcohol than Neutral words. Stress augmented this bias. Alcohol and P-Beer impaired overall SSRT. Stress impaired neither overall SSRT nor Go RT. SSRT to Neutral words and Non-Words correlated inversely with Go RT to Alcohol and Neutral words, and Non-Words. ADS correlated directly with SSRT to Alcohol words. A resource allocation account was proposed, whereby diversion of limited resources to salient cues effectively yoked otherwise independent Go and Stop processes. Disturbances of prefrontal norepinephrine and dopamine were cited as possibly accounting for these effects. Treatments that optimize prefrontal catecholamine transmission may deter relapse by reducing disinhibitory effects of salient eliciting stimuli.

Disulfiram: an old therapeutic with new applications.

Disulfiram treatment, despite its limitations, remains a viable option as a treatment for alcohol dependence and has shown recent promise in treating (1) those with co-morbid alcohol dependence and post-traumatic stress disorder, (2) those with co-morbid cocaine- and alcohol-dependence, and (3) those with cocaine-dependence alone. Although disulfiram's mechanism of action in alcohol dependence was long thought to be its effects as a psychological deterrent, more recent studies have uncovered potential anti-craving effects as well as direct effects of disulfiram on cocaine abuse, highlighting a few of the many potential and unique benefits disulfiram may have through its inhibition of dopamine beta-hydroxylase. This article will review the major clinical trials of disulfiram spanning nearly 60 years. We will discuss the pharmacodynamics and pharmacokinetics of disulfiram, indications and limitations of its use, suggestions for appropriate patient populations, and monitoring for compliance and adverse effects. We will also review recent literature on newer potential applications for disulfiram use via its unique action on dopamine beta-hydroxylase.

Mechanisms involved in the neurotoxic, cognitive, and neurobehavioral effects of alcohol consumption during adolescence.

Studies over the last decade demonstrate that adolescence is a brain maturation period from childhood to adulthood. Plastic and dynamic processes drive adolescent brain development, creating flexibility that allows the brain to refine itself, specialize, and sharpen its functions for specific demands. Maturing connections enable increased communication among brain regions, allowing greater integration and complexity. Compelling evidence has shown that the developing brain is vulnerable to the damaging effects of ethanol. It is possible to infer, therefore, that alcohol exposure during the critical adolescent developmental stages could disrupt the brain plasticity and maturation processes, resulting in behavioral and cognitive deficits. Recent neuroimaging studies have provided evidence of the impact of human adolescent drinking in brain structure and functions. Findings in experimental animals have also given new insight into the potential mechanisms of the toxic effects of ethanol on both adolescent brain maturation and the short- and long-term cognitive consequences of adolescent drinking. Adolescence is also characterized by the rapid maturation of brain systems mediating reward and by changes in the secretion of stress-related hormones, events that might participate in the increasing in anxiety and the initiation pattern of alcohol and drug consumption. Studies in human adolescents demonstrate that drinking at early ages can enhance the likelihood of developing alcohol-related problems. Experimental evidence suggests that early exposure to alcohol sensitizes the neurocircuitry of addiction and affects chromatin remodeling, events that could induce abnormal plasticity in reward-related learning processes that contribute to adolescents' vulnerability to drug addiction. In this article, we review the potential mechanisms by which ethanol impacts brain development and lead to brain impairments and cognitive and behavioral dysfunctions as well as the neurobiological and neurochemical processes underlying the adolescent-specific vulnerability to drug addiction.

Adolescent ethanol exposure: does it produce long-lasting electrophysiological effects?

This review discusses evidence for long-lasting neurophysiological changes that may occur following exposure to ethanol during adolescent development in animal models. Adolescence is the time that most individuals first experience ethanol exposure, and binge drinking is not uncommon during adolescence. If alcohol exposure is neurotoxic to the developing brain during adolescence, not unlike it is during fetal development, then understanding how ethanol affects the developing adolescent brain becomes a major public health issue. Adolescence is a critical time period when cognitive, emotional, and social maturation occurs and it is likely that ethanol exposure may affect these complex processes. To study the effects of ethanol on adolescent brain, animal models where the dose and time of exposure can be carefully controlled that closely mimic the human condition are needed. The studies reviewed provide evidence that demonstrates that relatively brief exposure to high levels of ethanol, via ethanol vapors, during a period corresponding to parts of adolescence in the rat is sufficient to cause long-lasting changes in functional brain activity. Disturbances in waking electroencephalogram and a reduction in the P3 component of the event-related potential (ERP) have been demonstrated in adult rats that were exposed to ethanol vapor during adolescence. Adolescent ethanol exposure was also found to produce long-lasting reductions in the mean duration of slow-wave sleep (SWS) episodes and the total amount of time spent in SWS, a finding consistent with a premature aging of sleep. Further studies are necessary to confirm these findings, in a range of strains, and to link those findings to the neuroanatomical and neurochemical mechanisms potentially underlying the lasting effects of adolescent ethanol exposure.

Roles of neural stem cells and adult neurogenesis in adolescent alcohol use disorders.

This review discusses the contributions of a newly considered form of plasticity, the ongoing production of new neurons from neural stem cells, or adult neurogenesis, within the context of neuropathologies that occur with excessive alcohol intake in the adolescents. Neural stem cells and adult neurogenesis are now thought to contribute to the structural integrity of the hippocampus, a limbic system region involved in learning, memory, behavioral control, and mood. In adolescents with alcohol use disorders (AUDs), the hippocampus appears to be particularly vulnerable to the neurodegenerative effects of alcohol, but the role of neural stem cells and adult neurogenesis in alcoholic neuropathology has only recently been considered. This review encompasses a brief overview of neural stem cells and the processes involved in adult neurogenesis, how neural stem cells are affected by alcohol, and possible differences in the neurogenic niche between adults and adolescents. Specifically, what is known about developmental differences in adult neurogenesis between the adult and adolescent is gleaned from the literature, as well as how alcohol affects this process differently among the age groups. Finally, this review suggests differences that may exist in the neurogenic niche between adults and adolescents and how these differences may contribute to the susceptibility of the adolescent hippocampus to damage. However, many more studies are needed to discern whether these developmental differences contribute to the vulnerability of the adolescent to developing an AUD.

Research on alcohol and adolescent brain development: opportunities and future directions.

In the past 15 years, both human and animal studies have advanced our understanding of the effects of adolescent alcohol exposure on behavioral and neural development, particularly in the areas of the ontogeny of initial sensitivity and tolerance to alcohol, the consequences of adolescent alcohol exposure on subsequent drinking patterns, as well as cognitive and neural function. Despite these advances, there are still substantial gaps in our understanding of whether heavy adolescent drinking interferes with normal brain development at the cellular and molecular level, and if so, how these changes may translate into patterns of brain connectivity that result in the emergence of alcohol use disorders. This article discusses our current knowledge of the cellular and molecular brain changes that stem from heavy alcohol exposure, including binge patterns, during adolescence. Progress has been made in linking the behavioral effects of adolescent drinking to underlying cellular and molecular mechanisms. However, it is suggested that future research on the etiology and consequences of adolescent drinking use an integrative approach to this problem by combining multiple levels, including genetic, cellular and molecular, systems (neuroimaging), and behavioral, with an emphasis on integrating the different levels of analysis.

Altered water-maze search behavior in adult guinea pigs following chronic prenatal ethanol exposure: lack of mitigation by postnatal fluoxetine treatment.

Ingestion of ethanol during pregnancy can result in teratogenic effects in humans, including significant and long-lasting neurobehavioral deficits. Similar results are seen in guinea pigs with chronic prenatal ethanol exposure (CPEE) via maternal ethanol administration, which produces deficits in Morris water-maze performance and impaired hippocampal functioning (e.g., decreased long-term potentiation, LTP). In this study, we tested whether postnatal treatment with fluoxetine, a selective serotonin reuptake inhibitor, decreases some of the neurobehavioral impairments produced by CPEE. Timed, pregnant guinea pigs received oral administration of ethanol (4g/kg maternal body weight) or isocaloric sucrose pair feeding (control) for 5 days/week throughout gestation. Offspring of the CPEE and control groups were randomly assigned to receive either fluoxetine (10mg/kg body weight/day) or saline intraperitoneally from postnatal day 10 to 48. Subsequent behavioral tests in the Morris water-maze revealed a significant increase in thigmotaxic swimming in CPEE offspring without apparent signs of impairment in spatial mapping of the hidden escape platform. Measures of hippocampal short- and long-term plasticity (paired-pulse facilitation, frequency facilitation, and LTP) were unaffected by CPEE, consistent with the behavioral data indicating normal hippocampal functioning. Postnatal fluoxetine administration resulted in a significant loss of body weight, but did not affect the increased thigmotaxic swimming following CPEE. These results indicate that changes in search strategies in the water-maze might be a highly sensitive index of CPEE-induced neurobehavioral toxicity that can occur in the absence of significant hippocampal dysfunction. Further, these data demonstrate that fluoxetine, at the selected treatment regime, does not mitigate the thigmotaxic swimming response to CPEE in the guinea pig.