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Alcohol-Induced Neurodegeneration: When, Where and Why?
Abstract
This manuscript reviews the proceedings of a symposium organized by Drs. Antonio Noronha and Fulton Crews presented at the 2003 Research Society on Alcoholism meeting. The purpose of the symposium was to examine recent findings on when alcohol induced brain damage occurs, e.g., during intoxication and/or during alcohol withdrawal. Further studies investigate specific brain regions (where) and the mechanisms (why) of alcoholic neurodegeneration. The presentations were (1) Characterization of Synaptic Loss in Cerebella of Mature and Senescent Rats after Lengthy Chronic Ethanol Consumption, (2) Ethanol Withdrawal Both Causes Neurotoxicity and Inhibits Neuronal Recovery Processes in Rat Organotypic Hippocampal Cultures, (3) Binge Drinking-Induced Brain Damage: Genetic and Age Related Effects, (4) Binge Ethanol-Induced Brain Damage: Involvement of Edema, Arachidonic Acid and Tissue Necrosis Factor alpha (TNFalpha), and (5) Cyclic AMP Cascade, Stem Cells and Ethanol. Taken together these studies suggest that alcoholic neurodegeneration occurs through multiple mechanisms and in multiple brain regions both during intoxication and withdrawal.
... Man geht davon aus, dass sowohl während der akuten Alkoholintoxikation als auch in der frühen Phase des Entzugs neurotoxische Prozesse stattfinden (Crews et al., 2004 (Crews & Vetreno, 2015;Zhao et al., 2013). Außerdem induziert sie die Produktion proinflammatorischer Zytokine im ZNS und führt zu einer Hochregulation der Expression der Nicotinamidadenindinucleotidphosphat (NADPH)-Oxidase, die eine Umwandlung von Sauerstoff O2 in freie Sauerstoffradikale O2katalysiert (Qin & Crews, 2012). ...
... Es wird spekuliert, dass die beschriebenen Entzündungsreaktionen im Gehirn außerdem zu einer Ödembildung führen (Wolter, 2006;Crews et al., 2004). ...
... Veränderungen der Mikroarchitektur der weißen Substanz im Balken (Corpus callosum) sowie im Marklager (Zentrum semiovale) mit einer Akkumulation intra-und extrazellulärer Flüssigkeit in Verbindung gebracht werden Wolter, 2006). Neben dem Zellverlust infolge der beschriebenen neurotoxischen Mechanismen soll auch die alkoholbedingte Störung der adulten Neurogenese einen Beitrag zur neuronalen Degeneration leisten (Wolter, 2006;Crews et al., 2004). ...
Übermäßiger Alkoholkonsum führt aufgrund der neurotoxischen Wirkung zu funktionellen und strukturellen zerebralen Schädigungen. Diese sind nach aktueller Datenlage bei Abstinenz teilweise reversibel. Wir untersuchten 63 abstinente alkoholabhängige Patienten im Intervall von zehn bis zwanzig Tagen. An diesen Messzeitpunkten führten wir mehrere neuropsychologische Testungen sowie eine MRT-Messung durch. Zudem durchliefen 49 Kontrollprobanden einmalig die neuropsychologische Testung sowie die MRT-Untersuchung. In unserem Probandenkollektiv konnten wir die in der Literatur beschriebenen Funktionseinschränkungen bei abstinenten alkoholabhängigen Patienten bestätigen. Die Patienten schnitten in allen beschriebenen neuropsychologischen Tests (mit Ausnahme einzelner untergeordneter Kategorien) zum Zeitpunkt t1 signifikant schlechter ab als die gesunden Kontrollprobanden. Unsere Ergebnisse weisen auf Funktionseinschränkungen im Bereich der Exekutiven Funktionen, wie der Aufmerksamkeitssteuerung, der kognitiven Flexibilität, der Abstraktionsfähigkeit, der Fähigkeit zu Problemlösung und der Inhibitionskontrolle hin. Zudem konnten wir eine geringere Wahrnehmungsgeschwindigkeit und ein reduziertes Konzentrationsvermögen messen. Des Weiteren fanden wir eine signifikante Steigerung der Performance der Patienten in neuropsychologischen Tests im Intervall zwischen Erst- und Zweitmessung und bestätigten die Hypothese der funktionellen Regeneration in der frühen Phase der Abstinenz. Bei einigen Kategorien der neuropsychologischen Tests führte die Verbesserung dazu, dass sich die Performance der abstinenten alkoholabhängigen Patienten zum Zeitpunkt t2 nicht mehr signifikant von der Leistung der Kontrollprobanden zum Zeitpunkt t1 unterschied. Ein Schwachpunkt unserer Studie ist die einmalige Testung der Kontrollprobanden. Wir verwendeten nur Aufgaben mit guter Test-Rest-Retest-Reliabilität. Dennoch ist ein Lerneffekt durch die fehlende Zweitmessung der Kontrollprobanden nicht sicher auszuschließen. Zusätzlich zu den neuropsychologischen Verbesserungen konnten wir einen Volumenzuwachs der grauen Substanz zwischen Erst- und Zweitmessung nachweisen. Die Zunahme der grauen Substanz zeigte sich im limbischen System, insbesondere im Gyrus cinguli sowie im Gyrus parahippocampalis, den Basalganglien (Nucleus caudatus) und im Claustrum. Auch im Gyrus temporalis superior und medius sowie im Gyrus postcentralis, Lobulus parietalis inferior und Nucleus ruber fanden wir eine signifikante Volumenzunahme der grauen Substanz. Aufgrund der in Studien beschriebenen Zuordnung der Exekutiven Funktionen zum Präfrontalen Kortex hätten wir zusätzlich einen Volumenzuwachs in diesem Bereich erwartet. Möglicherweise hat das kurze Messintervall von zwei Wochen dazu geführt, dass die Regenerationsprozesse sich noch nicht in einem Volumenzuwachs in diesem Bereich zeigten. Wir untersuchten, ob ein Zusammenhang zwischen funktioneller Verbesserung und strukturellen Volumenveränderungen nachweisbar ist. Eine Regressionsanalyse der Differenzwerte der Neuropsychologie mit den Differenzbildern der grauen Substanz ergab allerdings keine signifikanten Korrelationen. Daraufhin führten wir eine voxelbasierte Korrelationsanalyse der MRT-Bilder der grauen Substanz und unserer neuropsychologischen Ergebnisse der alkoholabhängigen Probanden zum Zeitpunkt t1 durch, um einen Zusammenhang zwischen spezifischen Lokalisationen der grauen Substanz und neuropsychologischen Funktionen zu beschreiben. Einzig die Reaktionszeit eines Untertests (der Inkongruenz-Bedingung des Stroop-Farbtests) korrelierte negativ mit dem Volumen im Bereich des Gyrus cinguli. Wir vermuten, dass kognitive Funktionen nicht allein auf einzelnen zerebralen Strukturen, sondern auf der Wechselwirkung funktionell vernetzter Nervenzellverbände in komplexen Netzwerken beruhen, was die Zuordnung einzelner Funktionen zu spezifischen zerebralen Lokalisationen erschwert. Folglich sind Untersuchungen bezüglich der Veränderungen der Aktivierung verschiedener Hirnareale bei abstinenten alkoholabhängigen Patienten im Vergleich zu gesunden Kontrollen sowie im Verlauf der Abstinenz interessant. Langzeitbetrachtungen mit Messzeitpunkten über mehrere Monate hinweg, könnten Aussagen zur Stabilität und dem Verlauf der strukturellen und funktionellen Regeneration erlauben. Ein tiefgreifendes Verständnis für alkoholbedingte zerebrale Veränderungen sowie darüber, wie sich diese im Laufe der Abstinenz verhalten, könnte wertvoll für die Suche nach Prädiktoren einer erfolgreichen Abstinenz sowie für die Weiterentwicklung der Therapiestrategien bei Suchterkrankungen sein.
... Alcohol neurodegenerative effects are observed since the first intoxications [20] and over chronic use [21]. Alcohol-induced neurodegeneration occurs in specific regions of the brain, including the PFC [22], by means of complex processes, e.g. higher levels of reactive oxygen species (ROS), edema, cell-survival transcription factor modification and activation of inflammatory pathways [23], resulting in neuronal and axonal damage. These alterations occur with or without an association with alcoholinduced nutritional deficiency [24]. ...
... + 10.05 ml; weekly mean + SEM) [t(14) = 2.57; p = 0.02]. [21][22][23][24][25][26][27] Mean alcohol consumption by the AL group throughout the treatment was 4.12 + 0.61 g/kg/24 h (weekly mean + SEM). ...
... Nevertheless, this is only a supposition and functional studies are necessary to investigate this hypothesis. It should be noted that the volume reduction of this area occurred already after four weeks of chronic alcohol ingestion by the Table 1 Stereological [21][22][23][24][25][26][27] animals. ...
Alcohol consumption has been identified as a causal factor promoting changes in different molecular and cellular mechanisms resulting in neurodegeneration. This process is specific to certain brain regions and its effects on different areas of the brain can result in a variety of deleterious consequences. The prefrontal cortex (PFC) appears to be particularly sensitive to alcohol-induced neurodegeneration; this region is quite complex, as it is responsible for high order mental processes such as decision making. Thus, it is important to have precise and unbiased data of neuronal morphology parameters to understand the real effects of alcohol on the PFC. This study aimed to investigate alcohol-induced neurodegeneration in the PFC by utilizing behavioral and stereological methods. In the first phase of the study, we utilized eighteen animals, six controls and twelve alcohol-treated, that were submitted to voluntary chronic alcohol ingestion for four or eight weeks. Their brains were analyzed by design-based stereology methods to assess number and volume parameters regarding neuronal integrity in regions of the PFC (prelimbic - PL, infralimbic - IL and anterior cingulate - ACC). In the second phase of the study, six animals were utilized as controls and eight animals were submitted to the same alcohol ingestion protocol and to a behavioral decision-making test. In conclusion, our findings indicate that chronic alcohol consumption promotes a decrease in volume in the prelimbic and in the anterior cingulate, a decrease of mean neuronal volume in the anterior cingulate cortex and a decrease of total volume of neurons in the IL area. We did not observe changes in decision-making behavior in either of the two periods of alcohol intake. This shows that morphological changes occur in specific regions of the prefrontal cortex, a noble area of cognitive functions, induced by chronic alcohol consumption.
... Alcohol causes a dysregulation of the neuroimmune system in the brain which corresponds to alcohol-induced neurodegeneration and addiction pathology [1][2][3][4]. Alcohol consumption is also correlated with a variety of negative health outcomes, including but not limited to onset of alcohol use disorders (AUD), fetal alcohol spectrum disorders, alcoholic liver disease and cancers. In particular, Toll-like receptor (TLR) signaling has been suggested to be implicated in alcohol pathology. ...
... In SH-SY5Y, ethanol did not affect cytokine expression but increased TLR3 and TLR7 expression [36]. However, we observed a significant main effect of co-culture (F [1,17] Table S2). Post-hoc analysis indicated that in BV2 alone, ethanol increases expression of IL-1β (1.9-fold, p < 0.01), which was blocked when co-cultured with SH-SY5Y (Figure 2A). ...
... There was also a significant main effect of ethanol (F [1,17] = 11.56, p < 0.01) and a significant co-culture x ethanol interaction (F [1,19] Figure 2C). There was a significant main effect of co-culture on TLR3 (F [1,17] = 8.297, p < 0.05), TLR4 (F [1,20] = 227.6, ...
Innate immune signaling molecules, such as Toll-like receptors (TLRs), cytokines and transcription factor NFκB, are increased in post-mortem human alcoholic brain and may play roles in alcohol dependence and neurodegeneration. Innate immune signaling involves microglia -neuronal signaling which while poorly understood, may impact learning and memory. To investigate mechanisms of ethanol induction of innate immune signaling within and between brain cells, we studied immortalized BV2 microglia and SH-SY5Y human neuroblastoma to model microglial and neuronal signaling. Cells were treated alone or in co-culture using a Transwell system, which allows transfer of soluble mediators. We determined immune signaling mRNA using real-time polymerase chain reaction. Ethanol induced innate immune genes in both BV2 and SH-SY5Y cultured alone, with co-culture altering gene expression at baseline and following ethanol exposure. Co-culture blunted ethanol-induced high mobility group box protein 1 (HMGB1)-TLR responses, corresponding with reduced ethanol induction of several proinflammatory NFκB target genes. In contrast, co-culture resulted in ethanol upregulation of cytokines IL-4 and IL-13 in BV2 and corresponding receptors, that is, IL-4 and IL-13 receptors, in SH-SY5Y, suggesting induction of a novel signaling pathway. Co-culture reduction in HMGB1-TLR levels occurs in parallel with reduced proinflammatory gene induction and increased IL-4 and IL-13 ligands and receptors. Findings from these immortalized and tumor-derived cell lines could provide insight into microglial-neuronal interactions via release of soluble mediators in vivo.
... After prolonged heavy drinking, the physical and the mental state can be signi cantly impaired, leading to serious damage to the occupational functions and social adaptability. The gradual growth in alcohol consumption leads to the changes in the brain structure and function, and impairments the control of behaviors, which further promote the alcohol abuse and neurodegenerative diseases [1]. ...
... Researches have reported that chronic alcohol exposure inhibited neurogenesis and after weeks of abstinence, new neurons would be ourishing in surviving, proliferating and differentiating [33] and the reversibility of brain atrophy is believed to be due to sprouting of dendrites and axons. In the clinic, we can also nd that after physical withdrawal and large supplemental doses of vitamin, especially Vitamin B1 can partly reverse cognitive disturbances, especially memory de cit [35] and control of impulse behavior [1]. Furthermore, abstinence can also increase cortical gray matter and shrink the third ventricle [36]. ...
Objective
Prolonged excessive ethanol intake impairs learning, memory and also causes brain atrophy. Brain-derived neurotrophic factor (BDNF) plays pivotal roles in the pathology of alcohol dependence. Our previous work found that chronic ethanol exposure altered the metabolism of BDNF, leading to the imbalance of proBDNF and mature BDNF (mBDNF). In this study, we hypothesized that early alcohol withdrawal would reverse the abnormal levels of proBDNF, mBDNF and their receptors.Method30 male alcohol dependence patients were recruited. Peripheral blood was sampled from all the subjects before and one week after alcohol withdrawal. The lymphocyte protein levels of proBDNF, p75NTR, sortilin and TrkB were analyzed by western blots and the serum level of mBDNF and TrkB was assayed by sandwich enzyme-linked immunosorbent assay (ELISA) at two different time points. ResultsThe levels of mBDNF and its receptor (TrkB) increased, oppositely the levels of proBDNF and its receptors (p75NTR and sortilin) decreased one week after alcohol withdrawal. Conclusions
Early alcohol withdrawal reversed the abnormal levels of proBDNF, mBDNF and their receptors. The shift levels of proBDNF and mBDNF were both taken in the pathology of alcohol withdrawal.
... Together, acute alcohol intoxication seems to result in increased Apart from acute changes in brain activity caused by alcohol intoxication, basic animal model studies have established that high blood levels of alcohol can directly induce brain damage (Crews and Nixon, 2009;Crews et al., 2004). These types of alcohol-induced alterations in the brain structure may further cause an increase in impulsivity, promote further alcohol use and neurodegeneration contributing to the severity of alcohol use disorders (for a review see Crews and Boettiger, 2009;Crews et al., 2004). ...
... Together, acute alcohol intoxication seems to result in increased Apart from acute changes in brain activity caused by alcohol intoxication, basic animal model studies have established that high blood levels of alcohol can directly induce brain damage (Crews and Nixon, 2009;Crews et al., 2004). These types of alcohol-induced alterations in the brain structure may further cause an increase in impulsivity, promote further alcohol use and neurodegeneration contributing to the severity of alcohol use disorders (for a review see Crews and Boettiger, 2009;Crews et al., 2004). ...
Alcohol misuse is a major public concern. Impulsivity has been recognised as a significant risk factor predisposing for the initiation of alcohol use, continuation and excessive alcohol use. Evidence suggests that impulsivity is also a result of both acute alcohol intoxication and long-term alcohol abuse. The multifaceted character of impulsivity and the various ways of assessing it in humans and animal models, hampers the full understanding of how impulsivity relates to alcohol use and misuse. Therefore, in this review we evaluate recent developments in the field, trying to disentangle the contribution of different impulsivity subtypes as causes and effects of alcohol use. Moreover, we review a growing body of evidence, including brain imaging, suggesting the importance of emotional states in engaging in alcohol consumption, particularly in highly impulsive individuals. We also present recent insights into how emotional processing is manifested in alcoholism and binge drinking and suggest novel approaches to treatment and prevention opportunities which target emotional-regulation as well as emotional perception and insight.
... However, this review highlights the contribution of inflammatory processes in alcohol-mediated tissue damage specifically in the context of cardiac and CNS damage whose injury mechanisms are not yet fully understood. Postmortem studies of both human alcoholic brains and basic animal models have demonstrated that heavy alcohol use is associated with an increased incidence of myopathy and neuropathy suggesting heart and brain changes (Crews et al., 2004;Liu et al., 2004Liu et al., , 2006Remick, 2013; Fernandez-Sola and Planavila Porta, 2016). Interestingly heavy alcoholism is also associated with increased cytokine secretion and inflammation in these organs, reinforcing the possibility that cytokines play a pivotal role in alcohol-related brain and heart damages (Tables 1-2). ...
Alcohol is one of the most commonly abused substances in the United States. Chronic consumption of ethanol has been responsible for numerous chronic diseases and conditions globally. The underlying mechanism of liver injury has been studied in depth, however, far fewer studies have examined other organs especially the heart and the central nervous system (CNS). The authors conducted a narrative review on the relationship of alcohol with heart disease and dementia. With that in mind, a complex relationship between inflammation and cardiovascular disease and dementia has been long proposed but inflammatory biomarkers have gained more attention lately. In this review we examine some of the consequences of the altered cytokine regulation that occurs in alcoholics in organs other than the liver. The article reviews the potential role of inflammatory markers such as TNF-α in predicting dementia and/or cardiovascular disease. It was found that TNF-α could promote and accelerate local inflammation and damage through autocrine/paracrine mechanisms. Unraveling the mechanisms linking chronic alcohol consumption with proinflammatory cytokine production and subsequent inflammatory signaling pathways activation in the heart and CNS, is essential to improve our understanding of the disease and hopefully facilitate the development of new remedies.
... Alcoholism causes multiple system damages, especially inducing the irreversible damage of brain central nervous systems, which were related to several neurodegenerative disease processes [1][2][3][4]. Alcohol has nice permeability to the blood-brain barrier, thus resulting in higher damage potentials to the central nervous system [5][6][7]. It was reported that alcohol exposure could affect the development of the central nervous system, especially of the hippocampus [8][9][10]. ...
... Heavy drinking during adolescence is associated with damage to the prefrontal cortex and hippocampal area, and with neurocognitive dysfunctions as well as in visuospatial, verbal, and attention functions [94,95]. Pascual et al. showed that, during adolescence, intermittent ethanol intake induces inflammation and cell death in the neocortex, hippocampus, and cerebellum, and cognitive impairment, supporting the role of inflammation in ethanol-induced brain damage [96]. Overall, alcohol may support the generation and sustenance of AD pathology via neuroinflammation. ...
Background:
Alzheimer's disease (AD), the most threatening neurodegenerative disease, is characterized by the loss of memory and language function, an unbalanced perception of space, and other cognitive and physical manifestations. The pathology of AD is characterized by neuronal loss and the extensive distribution of senile plaques and neurofibrillary tangles (NFTs). The role of environment and the diet in AD is being actively studied, and nutrition is one of the main factors playing a prominent role in the prevention of neurodegenerative diseases. In this context, the relationship between dementia and wine use/abuse has received increased research interest, with varying and often conflicting results. Scope and Approach: With this review, we aimed to critically summarize the main relevant studies to clarify the relationship between wine drinking and AD, as well as how frequency and/or amount of drinking may influence the effects. Key Findings and Conclusions: Overall, based on the interpretation of various studies, no definitive results highlight if light to moderate alcohol drinking is detrimental to cognition and dementia, or if alcohol intake could reduce risk of developing AD.
... Alcoholism causes multiple system damages, especially inducing the irreversible damage of brain central nervous systems, which were related to several neurodegenerative disease processes [1][2][3][4]. Alcohol has nice permeability to the blood-brain barrier, thus resulting in higher damage potentials to the central nervous system [5][6][7]. It was reported that alcohol exposure could affect the development of the central nervous system, especially of the hippocampus [8][9][10]. ...
Excessive alcohol intake can significantly reduce cognitive function and cause irreversible learning and memory disorders. The brain is particularly vulnerable to alcohol-induced ROS damage; the hippocampus is one of the most sensitive areas of the brain for alcohol neurotoxicity. In the present study, we observed significant increasing of intracellular ROS accumulations in Peroxiredoxin II (Prx II) knockdown HT22 cells, which were induced by alcohol treatments. We also found that the level of ROS in mitochondrial was also increased, resulting in a decrease in the mitochondrial membrane potential. The phosphorylation of GSK3β (Ser9) and anti-apoptotic protein Bcl2 expression levels were significantly downregulated in Prx II knockdown HT22 cells, which suggests that Prx II knockdown HT22 cells were more susceptible to alcohol-induced apoptosis. Scavenging the alcohol-induced ROS with NAC significantly decreased the intracellular ROS levels, as well as the phosphorylation level of GSK3β in Prx II knockdown HT22 cells. Moreover, NAC treatment also dramatically restored the mitochondrial membrane potential and the cellular apoptosis in Prx II knockdown HT22 cells. Our findings suggest that Prx II plays a crucial role in alcohol-induced neuronal cell apoptosis by regulating the cellular ROS levels, especially through regulating the ROS-dependent mitochondrial membrane potential. Consequently, Prx II may be a therapeutic target molecule for alcohol-induced neuronal cell death, which is closely related to ROS-dependent mitochondria dysfunction.
... Heavy drinking during adolescence is associated with damage to the prefrontal cortex and hippocampal area, and with neurocognitive dysfunctions as well as in visuospatial, verbal, and attention functions [94,95]. Pascual et al. showed that, during adolescence, intermittent ethanol intake induces inflammation and cell death in the neocortex, hippocampus, and cerebellum, and cognitive impairment, supporting the role of inflammation in ethanol-induced brain damage [96]. Overall, alcohol may support the generation and sustenance of AD pathology via neuroinflammation. ...
Background: Alzheimer’s disease (AD), the most threatening neurodegenerative diseases, is characterized by the loss of memory and language function, an unbalanced perception of space and other cognitive and physical manifestations. Pathology of the AD is characterized by neuronal loss, and the extensive distribution of senile plaques and neurofibrillary tangles (NFTs). The role of environment and the diet in the AD is being studied actively, and nutrition is certainly one of the main factors playing a prominent role in the prevention of neurodegenerative diseases. In this context, the relationship between dementia and wine use/abuse has received increased research interest in recent times, with varying and often conflicting results. Scope and approach: This review aims to critically summarize the most recent studies conducted to clarify the relationship between wine drinking and AD, as well as whether effects are influenced by quantity and/or frequency of drinking. Key findings and Conclusion: Overall, based on the interpretation of various studies, it can be concluded that there is no indication that light to moderate alcohol drinking is detrimental to cognition and dementia, and it is not possible to define whether alcohol could be used as a means to reduce risk of developing AD.
... Reduced hippocampal volume is associated with both AUD and sub-clinical problematic alcohol use, such as binge drinking (Wilson, Bair, Thomas, & Iacono, 2017). The hippocampus plays a key role in learning and memory and alcohol-related damage to this area can cause deficits in learning, memory, and spatial navigation (Beatty, Hames, Blanco, Nixon, & Tivis, 1996;Crews et al., 2004;Pitel et al., 2009;Townshend & Duka, 2005). Although the hippocampus is an area particularly vulnerable to alcohol toxicity, it also is a highly plastic region that is capable of recovery from alcohol-induced damage. ...
There are vast literatures on the neural effects of alcohol and the neural effects of exercise. Simply put, exercise is associated with brain health, alcohol is not, and the mechanisms by which exercise benefits the brain directly counteract the mechanisms by which alcohol damages it. Although a degree of brain recovery naturally occurs upon cessation of alcohol consumption, effective treatments for alcohol-induced brain damage are badly needed, and exercise is an excellent candidate from a mechanistic standpoint. In this chapter, we cover the small but growing literature on the interactive neural effects of alcohol and exercise, and the capacity of exercise to repair alcohol-induced brain damage. Increasingly, exercise is being used as a component of treatment for alcohol use disorders (AUD), not because it reverses alcohol-induced brain damage, but because it represents a rewarding, alcohol-free activity that could reduce alcohol cravings and improve comorbid conditions such as anxiety and depression. It is important to bear in mind, however, that multiple studies attest to a counterintuitive positive relationship between alcohol intake and exercise. We therefore conclude with cautionary notes regarding the use of exercise to repair the brain after alcohol damage.
... Marked individual differences in age-related cognitive changes exist; hence, identification of risk factors-in particular modifiable factors-is fundamental to facilitate interventions to prevent or postpone cognitive decline. Alcohol consumption is a modifiable and plausible risk factor as excessive alcohol consumption is linked with both acute neurotoxic and long-term neurodegenerative effects (Crews et al., 2004;Rao and Draper, 2015). However, longitudinal studies on the association of alcohol consumption with cognitive decline show mixed results (Richards et al., 2005;Stampfer et al., 2005;Sabia et al., 2014;Topiwala et al., 2017;Piumatti et al., 2018). ...
Aims:
Alcohol consumption is a modifiable and plausible risk factor for age-related cognitive decline but more longitudinal studies investigating the association are needed. Our aims were to estimate associations of adult-life alcohol consumption and consumption patterns with age-related cognitive decline.
Methods:
We investigated the associations of self-reported adult-life weekly alcohol consumption and weekly extreme binge drinking (≥10 units on the same occasion) with changes in test scores on an identical validated test of intelligence completed in early adulthood and late midlife in 2498 Danish men from the Lifestyle and Cognition Follow-up study 2015. Analyses were adjusted for year of birth, retest interval, baseline IQ, education and smoking.
Results:
Men with adult-life alcohol consumption of more than 28 units/week had a larger decline in IQ scores from early adulthood to late midlife than men consuming 1-14 units/week (B29-35units/week = -3.6; P < 0.001). Likewise, a 1-year increase in weekly extreme binge drinking was associated with a 0.12-point decline in IQ scores (P < 0.001). Weekly extreme binge drinking explained more variance in IQ changes than average weekly consumption. In analyses including mutual adjustment of weekly extreme binge drinking and average weekly alcohol consumption, the estimated IQ decline associated with extreme binge drinking was largely unaffected, whereas the association with weekly alcohol consumption became non-significant.
Conclusions:
Adult-life heavy alcohol consumption and extreme binge drinking appear to be associated with larger cognitive decline in men. Moreover, extreme binge drinking may be more important than weekly alcohol consumption in relation to cognitive decline.
... Memory blackouts can have devastating personal and societal effects, particularly among adolescents and young adults, and may predict further cognitive difficulties with ongoing alcohol use (White, 2003;Parada et al., 2011). There is also evidence that adverse brain effects of acute binge alcohol consumption (Crews et al., 2004), including defects in short-term memory, can persist in the alcohol hangover period when BAC levels have dropped to zero (Contreras et al., 2019;Gunn et al., 2018;Silvestre de Ferron et al., 2015;West et al. 2018). This latter state may be akin to the persisting adverse effects of ethanol on LTP that we observe after ethanol washout. ...
Ethanol intoxication can produce marked changes in cognitive function including states in which the ability to learn and remember new information is completely disrupted. These defects likely reflect changes in the synaptic plasticity thought to underlie memory formation. We have studied mechanisms contributing to the adverse effects of ethanol on hippocampal long-term potentiation (LTP) and provided evidence that ethanol-mediated LTP inhibition involves a form of metaplasticity resulting from local metabolism of ethanol to acetaldehyde and untimely activation of N-methyl-d-aspartate receptors (NMDARs), both of which are neuronal stressors. In the present studies, we sought to understand the role of cellular stress in LTP defects, and demonstrate that ethanol's effects on LTP in the CA1 hippocampal region are overcome by agents that inhibit cellular stress responses, including ISRIB, a specific inhibitor of integrated stress responses, and GW3965, an agonist that acts at liver X receptors (LXRs) and dampens cellular stress. The agents that alter LTP inhibition also prevent the adverse effects of acute ethanol on one trial inhibitory avoidance learning. Unexpectedly, we found that the LXR agonist but not ISRIB overcomes effects of ethanol on synaptic responses mediated by N-methyl-d-aspartate receptors (NMDARs). These results have implications for understanding the adverse effects of ethanol and possibly for identifying novel paths to treatments that can prevent or overcome ethanol-induced cognitive dysfunction.
... It has been accepted that factors such as oxidative stress, inflammatory cytokines, and thiamine deficiency are major contributors to reductions in brain structures due to chronic alcohol consumption. It has also been considered that certain portions of the brain experience different rates of degeneration in chronic exposure to alcohol depending on how each structure reacts to loss of nutrition and to inhibition of neuroregeneration (12). ...
Changes in brain morphometry have been extensively reported in various studies examining the effects of chronic alcohol use in alcohol-dependent patients. Such studies were able to confirm the association between chronic alcohol use and volumetric reductions in subcortical structures using FSL (FMRIB software library). However, each study that utilized FSL had different sets of subcortical structures that showed significant volumetric reduction. First, we aimed to investigate the reproducibility of using FSL to assess volumetric differences of subcortical structures between alcohol-dependent patients and control subjects. Second, we aimed to use Vertex analysis, a less utilized program, to visually inspect 3D meshes of subcortical structures and observe significant shape abnormalities that occurred in each subcortical structure. Vertex analysis results from the hippocampus and thalamus were overlaid on top of their respective subregional atlases to further pinpoint the subregional locations where shape abnormalities occurred. We analyzed the volumes of 14 subcortical structures (bilateral thalamus, caudate, putamen, globus pallidus, hippocampus, amygdala, nucleus accumbens) in 21 alcohol-dependent subjects and 21 healthy controls using images acquired with 3T MRI. The images were run through various programs found in FSL, such as SIENAX, FIRST, and Vertex analysis. We found that in alcohol-dependent patients, the bilateral thalamus (left: p < 0.01, right: p = 0.01), bilateral putamen (left: p = 0.02, right: p < 0.01), right globus pallidus (p < 0.01), bilateral hippocampus (left: p = 0.05, right: p = 0.03) and bilateral nucleus accumbens (left: p = 0.05, right: p = 0.03) were significantly reduced compared to the corresponding subcortical structures of healthy controls. With vertex analysis, we observed surface reductions of the following hippocampal subfields: Presubiculum, hippocampal tail, hippocampal molecular layer, hippocampal fissure, fimbria, and CA3. We reproduced the assessment made in previous studies that reductions in subcortical volume were negatively associated with alcohol dependence by using the FMRIB Software Library. In addition, we identified the subfields of the thalamus and hippocampus that showed volumetric reduction.
... The neurodegenerative effects of excessive alcohol consumption are well documented. [1][2][3][4] Alzheimer's disease and dementia have replaced ischaemic heart disease as the leading cause of death in England and Wales, 5 and death rates for neurological disease are increasing worldwide. [6][7][8] A limited number of studies suggest a J-or U-shaped relationship between the volume of alcohol consumed and the long-term cognitive decline, [9][10][11] suggesting light to moderate alcohol consumption is a positive predictor of health status in older adults, 12 protects cognition and may reduce the risk of dementia [13][14][15] in later life. ...
Background. Using UK Biobank data, this study sought to explain the causal relationship between alcohol intake and cognitive decline in middle and older aged populations. Methods. Data from 13,342 men and women, aged between 40 and 73 years were used in regression analysis that tested the functional relationship and impact of alcohol on cognitive performance. Performance was measured using mean reaction time and intra-individual variation in reaction time, collected in response to a perceptual matching task. Covariates included body mass index, physical activity, tobacco use, socioeconomic status, education and baseline cognitive function. Results. A restricted cubic spline regression with three knots showed how the linear (β1=-0.048, 95% CI -0.105 to -0.030) and non-linear effects (β2=0.035, 95% CI 0.007 to 0.059) of alcohol use on mean reaction time and intra-individual variation in reaction time (β1=-0.055, 95% CI -0.125 to -0.034; β2=0.034, 95% CI 0.002 to 0.064) were significant adjusting for covariates. Cognitive function declined as alcohol use increased beyond 10g/day. Decline was more apparent as age increased. Conclusions. The relationship between alcohol use and cognitive function is non-linear. Consuming more than one UK standard unit of alcohol per day is detrimental to cognitive performance and is more pronounced in older populations.
... This is in agreement with the results of Lohren et al. [46] which proved the inorganic Hg cytotoxicity in astrocytes and neurons, even though the occurrence of apoptotic processes was not observed. Another factor associated with this reduction of neuronal cells may be a notable reduction in their replacement due to the reduction of neurogenesis and gliogenesis [54]. ...
Mercury (Hg) is a highly toxic metal, which can be found in its inorganic form in the environment. This form presents lower liposolubility and lower absorption in the body. In order to elucidate the possible toxicity of inorganic Hg in the hippocampus, we investigated the potential of low doses of mercury chloride (HgCl 2 ) to promote hippocampal dysfunction by employing a chronic exposure model. For this, 56 rats were exposed to HgCl 2 (0.375 mg/kg/day) via the oral route for 45 days. After the exposure period, the animals were submitted to the cognitive test of fear memory. The hippocampus was collected for the measurement of total Hg levels, analysis of oxidative stress, and evaluation of cytotoxicity, apoptosis, and tissue injury. It was observed that chronic exposure to inorganic Hg promotes an increase in mercury levels in this region and damage to short- and long-term memory. Furthermore, we found that this exposure model provoked oxidative stress, which led to cytotoxicity and cell death by apoptosis, affecting astrocytes and neurons in the hippocampus. Our study demonstrated that inorganic Hg, even with its low liposolubility, is able to produce deleterious effects in the central nervous system, resulting in cognitive impairment and hippocampal damage when administered for a long time at low doses in rats.
... Accumulating evidence reveals that AIE treatment causes a persistent upregulation of multiple neuroimmune signaling molecules throughout the adult brain [32,33,35,[46][47][48] and induction of neuroimmune signaling has been linked to ethanol-induced neurodegeneration [49,50]. NF-κB is a transcription factor known to induce neuroimmune genes [36]. ...
Basal forebrain cholinergic neurons mature in adolescence coinciding with development of adult cognitive function. Preclinical studies using the rodent model of adolescent intermittent ethanol (AIE; 5.0 g/kg, i.g., 2-days on/2-days off from postnatal day [P]25 to P55) reveal persistent increases of brain neuroimmune genes that are associated with cognitive dysfunction. Adolescent intermittent ethanol exposure also reduces basal forebrain expression of choline acetyltransferase (ChAT), an enzyme critical for acetylcholine synthesis in cholinergic neurons similar to findings in the post-mortem human alcoholic basal forebrain. We report here that AIE decreases basal forebrain ChAT+IR neurons in both adult female and male Wistar rats following early or late adolescent ethanol exposure. In addition, we find reductions in ChAT+IR somal size as well as the expression of the high-affinity nerve growth factor (NGF) receptor tropomyosin receptor kinase A (TrkA) and the low-affinity NGF receptor p75NTR, both of which are expressed on cholinergic neurons. The decrease in cholinergic neuron marker expression was accompanied by increased phosphorylation of NF-κB p65 (pNF-κB p65) consistent with increased neuroimmune signaling. Voluntary wheel running from P24 to P80 prevented AIE-induced cholinergic neuron shrinkage and loss of cholinergic neuron markers (i.e., ChAT, TrkA, and p75NTR) as well as the increase of pNF-κB p65 in the adult basal forebrain. Administration of the anti-inflammatory drug indomethacin (4.0 mg/kg, i.p prior to each ethanol exposure) during AIE also prevented the loss of basal forebrain cholinergic markers and the concomitant increase of pNF-κB p65. In contrast, treatment with the proinflammatory immune activator lipopolysaccharide (1.0 mg/kg, i.p. on P70) caused a loss of cholinergic neuron markers that was paralleled by increased pNF-κB p65 in the basal forebrain. These novel findings are consistent with AIE causing lasting activation of the neuroimmune system that contributes to the persistent loss of basal forebrain cholinergic neurons in adulthood.
... The loss of cortical gray matter (GM) in prefrontal, motor, and temporal cortices, insula, and anterior cingulum in alcoholism (Cardenas et al., 2007;Makris et al., 2008;Fein et al., 2009) has been a consistent finding in alcohol use disorder (AUD) (Pfefferbaum et al., 1992;Hommer et al., 2001;Chanraud et al., 2007;Demirakca et al., 2011;Le Berre et al., 2014). This cortical GM loss in people with AUD likely reflects reversible neurodegeneration (Crews et al., 2004;Bartsch et al., 2007), although there is also evidence of long-lasting neuropathology particularly in frontal regions (Volkow et al., 1997). Few studies have evaluated GM atrophy and brain glucose metabolism in the same AUD participants. ...
Background:
Excessive alcohol consumption is associated with reduced cortical thickness (CT) and lower cerebral metabolic rate of glucose (CMRGlu), but the correlation between these 2 measures has not been investigated.
Methods:
We tested the association between CT and cerebral CMRGlu in 19 participants with alcohol use disorder (AUD) and 20 healthy controls. Participants underwent 2-Deoxy-2-[18F]fluoroglucose positron emission tomography to map CMRGlu and magnetic resonance imaging to assess CT.
Results:
Although performance accuracy on a broad range of cognitive domains did not differ significantly between AUD and HC, AUD had widespread decreases in CT and CMRGlu. CMRGlu, normalized to cerebellum (rCMRGlu), showed significant correlation with CT across participants. Although there were large group differences in CMRGlu (>17%) and CT (>6%) in medial orbitofrontal and BA 47, the superior parietal cortex showed large reductions in CMRGlu (~17%) and minimal CT differences (~2.2%). Though total lifetime alcohol (TLA) was associated with CT and rCMRGlu, the causal mediation analysis revealed significant direct effects of TLA on rCMRGlu but not on CT, and there were no significant mediation effects of TLA, CT, and rCMRGlu.
Conclusions:
The significant correlation between decrements in CT and CMRGlu across AUD participants is suggestive of alcohol-induced neurotoxicity, whereas the findings that the most metabolically affected regions in AUD had minimal atrophy and vice versa indicates that changes in CT and CMRGlu reflect distinct responses to alcohol across brain regions.
... Control animals performed very well on this task, reaching maximum performance by the second block of trials on day 1 (Fig. 3B). As with any spatial working memory task, the entire fronto-hippocampal circuit is involved, including the hippocampus, which plays a key role in spatial working memory, and damage to it can negatively affect performance on learning, memory and spatial navigation tasks [56][57][58][59]. All spatial working memory tasks likely rely on the use of the hippocampus and mPFC working in conjunction, however, and consistent with this, alcohol-induced damage to the prefrontal cortex has previously been associated with impairments in this spatial working memory task [29]. ...
Excessive alcohol intake is associated with a multitude of health risks, especially for women. Recent studies in animal models indicate that the female brain is more negatively affected by alcohol, compared to the male brain. Among other regions, excessive alcohol consumption damages the frontal cortex, an area important for many functions and decision making of daily life. The objective of the present study was to determine whether the medial prefrontal cortex (mPFC) in female rats is selectively vulnerable to alcohol-induced damage. In humans, loss of prefrontal grey matter resulting from heavy alcohol consumption has been documented, however this volume loss is not necessarily due to a decrease in the number of neurons. We therefore quantified both number and nuclear volume of mPFC neurons following binge alcohol, as well as performance and neuronal activation during a prefrontal-dependent behavioral task. Adult male and female Long-Evans rats were assigned to binge or control groups and exposed to ethanol using a well-established 4-day model of alcohol-induced neurodegeneration. Both males and females had significantly smaller average neuronal nuclei volumes than their respective control groups immediately following alcohol binge, but neither sex showed a decrease in neuron number. Binged rats of both sexes initially showed spatial working memory deficits. Although they eventually achieved control performance, binged rats of both sexes showed increased c-Fos labeling in the mPFC during rewarded alternation, suggesting decreased neural efficiency. Overall, our results substantiate prior evidence indicating that the frontal cortex is vulnerable to alcohol, but also indicate that sex-specific vulnerability to alcohol may be brain region-dependent.
... It was quite clear that NFκB was down-regulated in comparison to acute alcohol drinking. One study showed no NFκB activation in binge alcohol drinking models, when given anti-oxidants (furosemide and butylatedhydroxytoluene) to prevent neuronal degeneration [56]. ...
... The neurodegenerative effects of excessive alcohol consumption are well documented. [1][2][3][4] Alzheimer's disease and dementia have replaced ischaemic heart disease as the leading cause of death in England and Wales, 5 and death rates for neurological disease are increasing worldwide. [6][7][8] A limited number of studies suggest a J-or U-shaped relationship between the volume of alcohol consumed and the long-term cognitive decline, [9][10][11] suggesting light to moderate alcohol consumption is a positive predictor of health status in older adults, 12 protects cognition and may reduce the risk of dementia [13][14][15] in later life. ...
Background. Using UK Biobank data, this study sought to explain the causal relationship between alcohol intake and cognitive decline in middle and older aged populations.
Methods. Data from 13 342 men and women, aged between 40 and 73 years were used in regression analysis that tested the functional relationship and impact of alcohol on cognitive performance. Performance was measured using mean reaction time (RT) and intra-individual variation (IIV) in RT, collected in response to a perceptual matching task. Covariates included body mass index, physical activity, tobacco use, socioeconomic status, education and baseline cognitive function.
Results. A restricted cubic spline regression with three knots showed how the linear (β1 = −0.048, 95% CI: −0.105 to −0.030) and non-linear effects (β2 = 0.035, 95% CI: 0.007–0.059) of alcohol use on mean RT and IIV in RT (β1 = −0.055, 95% CI: −0.125 to −0.034; β2 = 0.034, 95% CI: 0.002–0.064) were significant adjusting for covariates. Cognitive function declined as alcohol use increased beyond 10 g/day. Decline was more apparent as age increased.
Conclusions. The relationship between alcohol use and cognitive function is non-linear. Consuming more than one UK standard unit of alcohol per day is detrimental to cognitive performance and is more pronounced in older populations.
... Here, we report equivalent BECs between male and female groups each week confirming that both groups received similar alcohol treatments regardless of weight and consistent with our prior findings showing similar BEC between the sexes [41]. Moreover, the BEC are substantial (mean 176 mg/dL) and consistent with those linked to brain damage and neurodegeneration [74]. The heavy consumption of alcohol has been shown to alter the levels of the stress hormone, corticosterone. ...
Binge alcohol consumption and alcohol use disorders (AUD) are prevalent, and there is comorbidity with depression and anxiety. Potential underlying mechanisms include neurophysiological, genetic, and metabolic changes resulting from alcohol exposure. Mood and anxiety disorders are more common among women, but whether females are more susceptible to binge-induced oxidative stress and co-occurring anxiety and depression-like behaviors remains unknown. Here, we used a repeated, weekly binge alcohol paradigm in male and female rats to investigate sex differences in despair and anxiety-like behaviors and brain oxidative stress parameters. A single binge alcohol exposure significantly elevated glutathione (GSH) levels in prefrontal cortex (PFC) of both male and female animals. This was accompanied by increased lipid peroxidation in PFC of both sexes. Repeated (once weekly) binge exposure induced changes in anxiety- and depression-like behaviors in both males and females and increased GSH level in the PFC without detectable oxidative damage. Our findings suggest that repeated binge alcohol exposure influences affect regardless of sex and in the absence of membrane damage.
... E THANOL (ETOH) CONSUMPTION causes increased proinflammatory signaling in brain that is linked with neurodegeneration (Collins et al., 1996;Crews et al., 2004Crews et al., , 2006Qin et al., 2008;Reynolds et al., 2015), alcoholism Vetreno et al., 2013), fetal alcohol syndrome disorder (Drew and Kane, 2014), and drinking behavior (Agrawal et al., 2011;Blednov et al., 2005Blednov et al., , 2012. EtOH treatment in mice increases transcription of proinflammatory cytokines such as TNF-a, IL-1b, and IL-6 in brain (Alfonso-Loeches et al., 2010;Qin and Crews, 2012a;Qin et al., 2008). ...
Background:
Ethanol (EtOH) consumption leads to an increase of proinflammatory signaling via activation of toll-like receptors (TLRs) such as TLR3 and TLR4 that leads to kinase activation (ERK1/2, p38, TBK1), transcription factor activation (NFκB, IRF3) and increased transcription of pro-inflammatory cytokines such as TNFα, IL-1β, and IL-6. This immune signaling cascade is thought to play a role in neurodegeneration and alcohol use disorders. While microglia are considered to be the primary macrophage in brain, it is unclear what if any role neurons play in ethanol-induced proinflammatory signaling METHODS: Microglia-like BV2 and retinoic acid differentiated neuron-like SH-SY5Y were treated with TLR3 agonist Poly(I:C), TLR4 agonist LPS, or EtOH for 10 or 30 minutes to examine proinflammatory immune signaling kinase and transcription factor activation using western blot, and for 24 hours to examine induction of proinflammatory gene mRNA using RT-PCR RESULTS: In BV2, both LPS and Poly(I:C) increased p-ERK1/2, p-p38, and p-NFκB by 30 minutes, whereas EtOH decreased p-ERK1/2 and increased p-IRF3. LPS, Poly(I:C), and EtOH all increased TNFα and IL-1β mRNA, and EtOH further increased TLR2,7, 8, and MD-2 mRNA in BV2. In SH-SY5Y, LPS had no effect on kinase or proinflammatory gene expression. However, Poly(I:C) increased p-p38 and p-IRF3, and increased expression of TNFα, IL-1β, and IL-6, while EtOH increased p-p38, p-IRF3, p-TBK1 and p-NFκB while decreasing p-ERK1/2 and increasing expression of TLR3,7,8, and RAGE mRNA. HMGB1, a TLR agonist, was induced by LPS in BV2 and by EtOH in both cell types. EtOH was more potent at inducing proinflammatory gene mRNA in SH-SY5Y compared to BV2 CONCLUSIONS: These results support a novel and unique mechanism of ethanol, TLR3, and TLR4 signaling in neuron-like SH-SY5Y and microglia-like BV2 that likely contributes to the complexity of brain neuroimmune signaling. This article is protected by copyright. All rights reserved.
... Although animal studies have demonstrated that alcohol use in adolescence induces neurodegeneration (Crews et al., 2000(Crews et al., , 2004Pascual et al., 2007) and inhibition of neurogenesis (Crews et al., 2006), it remains to be determined to what extent alcohol use in human adolescents relates to changes in developmental brain trajectories. Preliminary longitudinal studies demonstrated alterations in adolescent brain development due to excessive exposure to alcohol could have functional consequences throughout life (reviewed in Squeglia, Jacobus, & Tapert, 2014). ...
Alcohol consumption is commonly initiated during adolescence but the effects on human brain development remain unknown. In this multi-site study, we investigated the longitudinal associations of adolescent alcohol use and brain morphology.
Three longitudinal cohorts in the Netherlands (BrainScale n=200, BrainTime n=239, and a subsample of the Generation R study n=318) of typically developing participants aged between 8-29 years were included. Adolescent alcohol use was self-reported. Longitudinal neuroimaging data were collected for at least two time points. Processing pipelines and statistical analyses were harmonized across cohorts. Main outcomes were global and regional brain volumes, which were a priori selected. Linear mixed effect models were used to test main effects of alcohol use and interaction effects of alcohol use with age in each cohort separately.
Alcohol use was associated with adolescent’s brain morphology showing accelerated decrease in gray matter volumes, in particular in the frontal and cingulate cortex volumes, and decelerated increase in white matter volumes. No dose-response association was observed. The findings were most prominent and consistent in the older cohorts (BrainScale and BrainTime).
In summary, this longitudinal study demonstrated differences in neurodevelopmental trajectories of gray and white matter volume in adolescents who consume alcohol compared to non-users. These findings highlight the importance to further understand underlying neurobiological mechanisms when adolescents initiate alcohol consumption. Therefore, further studies need to determine to what extent this reflects the causal nature of this association, as this longitudinal observational study does not allow for causal inference.
... In recent years, circRNAs have become increasingly relevant for the study of neuropsychiatric and neurodegenerative disorders as potential regulators of the brain's complex and unique transcriptome. 49 Here, we examined the intersection between the pathological characteristics of AD (aberrant neurogenesis and accelerated neurodegeneration 50,51 ) and circRNA's predicted role in regulating neurobiological processes within the context of circRNA-miRNA-mRNA interactions. ...
Our lab and others have shown that chronic alcohol use leads to gene and miRNA expression changes across the mesocorticolimbic (MCL) system. Circular RNAs (circRNAs) are noncoding RNAs that form closed-loop structures and are reported to alter gene expression through miRNA sequestration, thus providing a potentially novel neurobiological mechanism for the development of alcohol dependence (AD). Genome-wide expression of circRNA was assessed in the nucleus accumbens (NAc) from 32 AD-matched cases/controls. Significant circRNAs (unadj. p ≤ 0.05) were identified via regression and clustered in circRNA networks via weighted gene co-expression network analysis (WGCNA). CircRNA interactions with previously generated mRNA and miRNA were detected via correlation and bioinformatic analyses. Significant circRNAs (N = 542) clustered in nine significant AD modules (FWER p ≤ 0.05), within which we identified 137 circRNA hubs. We detected 23 significant circRNA–miRNA–mRNA interactions (FDR ≤ 0.10). Among these, circRNA-406742 and miR-1200 significantly interact with the highest number of mRNA, including genes associated with neuronal functioning and alcohol addiction (HRAS, PRKCB, HOMER1, and PCLO). Finally, we integrate genotypic information that revealed 96 significant circRNA expression quantitative trait loci (eQTLs) (unadj. p ≤ 0.002) that showed significant enrichment within recent alcohol use disorder (AUD) and smoking genome-wide association study (GWAS). To our knowledge, this is the first study to examine the role of circRNA in the neuropathology of AD. We show that circRNAs impact mRNA expression by interacting with miRNA in the NAc of AD subjects. More importantly, we provide indirect evidence for the clinical importance of circRNA in the development of AUD by detecting a significant enrichment of our circRNA eQTLs among GWAS of substance abuse.
... Indeed, alcohol intoxication has been observed to induce neuroinflammation and neurodegeneration in humans and animals [8][9][10]. Recently, many neurological disorders have been associated to alcohol abuse such as Parkinson's disease, epilepsy, and many others [11][12][13][14]. ...
In recent years, alcohol abuse has dramatically grown with deleterious consequence for people’s health and, in turn, for health care costs. It has been demonstrated, in humans and animals, that alcohol intoxication induces neuroinflammation and neurodegeneration thus leading to brain impairments. Furthermore, it has been shown that alcohol consumption is able to impair the blood–brain barrier (BBB), but the molecular mechanisms underlining this detrimental effect have not been fully elucidated. For this reason, in this study we investigated the effects of alcohol exposure on a rat brain endothelial (RBE4) cell line, as an in vitro-validated model of brain microvascular endothelial cells. To assess whether alcohol caused a concentration-related response, the cells were treated at different times with increasing concentrations (10–1713 mM) of ethyl alcohol (EtOH). Microscopic and molecular techniques, such as cell viability assay, immunofluorescence and Western blotting, were used to examine the mechanisms involved in alcohol-induced brain endothelial cell alterations including tight junction distribution, apoptosis, and reactive oxygen species production. Our findings clearly demonstrate that alcohol causes the formation of gaps between cells by tight junction disassembly, triggered by the endoplasmic reticulum and oxidative stress, highlighted by GRP78 chaperone upregulation and increase in reactive oxygen species production, respectively. The results from this study shed light on the mechanisms underlying alcohol-induced blood–brain barrier dysfunction and a better understanding of these processes will allow us to take advantage of developing new therapeutic strategies in order to prevent the deleterious effects of alcohol.
... Heavy ethanol consumption has been reported to result in significant alterations of brain structure, physiology, and function. In fact, ethanol promotes brain injury and neurodegeneration in corticolimbic areas and results in memory impairment in both humans (Hildebrandt, Brokate, Eling, & Lanz, 2004; Kim, Ke, & Adkins, 2004; Ratti et al., 1999;Tedstone & Coyle, 2004) and rodents (Crews et al., 2004Crews et al., , 2006 Garcia-Moreno et al., 2002; Obernier, Bouldin, & Crews, 2002; Obernier, White, Swartzwelder, & Crews, 2002; Roberto, Nelson, Ur, & Gruol, 2002; Santucci et al., 2004). Clinical and experimental studies have shown that the adolescent brain is more vulnerable to the neurodegenerative effects of ethanol (Crews, Braun, Hoplight, Switzer, & Knapp, 2000; Dahl, 2004; Spear, 2000; White & Swartzwelder, 2004), as well as to the functional consequences resulting from this neurodegenerative process, including learning and memory impairment (Acheson, Stein, & Swartzwelder, 1998; White & Swartzwelder, 2005). ...
Adolescent brain development seems to be important for the maturation of brain structures and behavior. Intermittent binge ethanol drinking is common among adolescents, and this type of drinking can induce brain damage and cognitive deficits. In addition, emotional changes are frequently seen in alcoholics and rodents treated with ethanol. Considering the close relation between emotional arousal and cognitive responses, the present work investigates if intermittent ethanol binge exposure could differentially alter the performance of adolescent rats in aversive and non-aversive motivated tests. Male adolescent rats were submitted to ethanol treatment (2.5 or 5.0 g/Kg, o.a.) at 48-h intervals over postnatal day (PND) 30 to 60. Control animals were exposed to a similar administration protocol with saline administration. At PND61-PND63 animals were submitted to one-trial object recognition or contextual and tone fear conditioning paradigms. Binge ethanol drinking (at both 2.5 and 5.0 g/Kg) did not change freezing response in the contextual and tone fear conditioning. However, all doses impaired recognition rates 24h after training in object recognition test. In addition, despite a diminution of horizontal locomotion in the open field (only for the 5.0 g/Kg dose), no difference was detected regarding time in immobility, time in grooming and number of rearing in this paradigm. The present results show that the cognitive impairment resulting from intermittent binge ethanol exposure has a negative correlation with learning-associated emotional arousal.
... Rodent models replicate the pattern of brain damage seen in AUD (Collins et al. 1996;Obernier et al. 2002a, b;Crews and Nixon 2009), and provide a means by which to systematically evaluate sex differences in extent of damage as well as underlying mechanisms. One goal of the present study was to evaluate sex differences in binge alcoholinduced brain damage and cognitive dysfunction using a well-established model (Majchrowicz 1975;Collins et al. 1996) that reproduces the level of intoxication and neurodegeneration seen in human AUD (Collins et al. 1996;Corso et al. 1998;Obernier et al. 2002b;Crews et al. 2004;Hamelink et al. 2005). Using this model, we have previously shown a significant decrease in granule neurons in the hippocampal dentate gyrus (DG) of female rats (Leasure and Nixon 2010; Maynard and Leasure 2013), but whether the male hippocampus is similarly affected remains unknown. ...
Compared to men, women disproportionally experience alcohol-related organ damage, including brain damage, and while men remain more likely to drink and to drink heavily, there is cause for concern because women are beginning to narrow the gender gap in alcohol use disorders. The hippocampus is a brain region that is particularly vulnerable to alcohol damage, due to cell loss and decreased neurogenesis. In the present study, we examined sex differences in hippocampal damage following binge alcohol. Consistent with our prior findings, we found a significant binge-induced decrement in dentate gyrus (DG) granule neurons in the female DG. However, in the present study, we found no significant decrement in granule neurons in the male DG. We show that the decrease in granule neurons in females is associated with both spatial navigation impairments and decreased expression of trophic support molecules. Finally, we show that post-binge exercise is associated with an increase in trophic support and repopulation of the granule neuron layer in the female hippocampus. We conclude that sex differences in alcohol-induced hippocampal damage are due in part to a paucity of trophic support and plasticity-related signaling in females.
... Recognition memory is the ability to recognize previously encountered events, objects, or people, and this memory depends on the integrity of the medial temporal lobe regions (Squire et al. 2007), which include the hippocampus and perirhinal cortex (Squire and Zola-Morgan 1991). As demonstrated before (Crews et al. 2004), these brain structures are very susceptible to ethanol-induced neurodegeneration. The perirhinal cortex is a crucial region for recognition memory performance (Brown et al. 1987;Zhu et al. 1995;Brown and Xiang 1998), but the role of the hippocampus in object recognition is still under debate (Mumby et al. 2002;Langston and Wood 2010;Clark et al. 2000;Broadbent et al. 2009;Cohen et al. 2013;Yi et al. 2016). ...
Glutamate is essential for learning and memory processes, and acute and chronic exposures to ethanol (or protracted abstinence) alter glutamatergic transmission. In the current study, we investigated the effects of VU-29, positive allosteric modulator of metabotropic glutamate 5 (mGlu5) receptor, on the acute ethanol- and ethanol withdrawal-induced impairment of novel object recognition (NOR) task in rats. The influence of VU-29 (30 mg/kg) on memory retrieval was measured (a) at 4-h delay after acute ethanol administration, as well as (b) after acute withdrawal (24 and 48 h) of repeated (2.0 g/kg, once daily for 7 days) ethanol administration. Additionally, the effects of VU-29 on expression of mGlu5 and mGlu2 receptor proteins in the hippocampus, prefrontal cortex, and striatum were determined 48 h after ethanol withdrawal. Our results indicated that VU-29, given before acute ethanol administration, prevented the ethanol-induced impairments in spatial memory retrieval. Furthermore, VU-29 given before the testing session on the first day of abstinence facilitated NOR performance in ethanol-withdrawn rats at 4- and 24-h delay after administration. Our ELISA results show that VU-29 normalized ethanol withdrawal induced increase in expression of mGlu5 receptor protein in the hippocampus, prefrontal cortex, and striatum, as well as expression of mGlu2 receptor protein in the hippocampus. Thus, results from our study indicate that positive modulation of mGlu5 receptor prevented and reversed ethanol-induced memory impairment. Moreover, mGlu5 (hippocampus, prefrontal cortex, and striatum) and mGlu2 (hippocampus) receptors play an important role in the ethanol-induced recognition memory impairment induced by ethanol withdrawal.
... Substantial damage to the substantia nigra, an area of the brain associated with PD, has been observed in chronic alcoholics, including necrosis, and increased melanin and iron deposition in the perivascular spaces [88]. Alcohol-induced brain damage occurs via multiple mechanisms and in multiple brain regions, including the hippocampus, cerebellum and limbic cortex, with varying effects depending on intoxication or withdrawal [89]. Some of the effects of alcohol include increased oxidative stress, increases in pro-inflammatory cytokines, reduction in synapses, glutamate excitotoxicity, and effects on neural stem cells and neural cell proliferation [90]. ...
Alpha-synuclein (α-Syn) is a 140-amino acid (aa) protein encoded by the Synuclein alpha SNCA gene. It is the synaptic protein associated with Parkinson’s disease (PD) and is the most highly expressed protein in the Lewy bodies associated with PD and other alpha synucleopathies, including Lewy body dementia (LBD) and multiple system atrophy (MSA). Iron deposits are present in the core of Lewy bodies, and there are reports suggesting that divalent metal ions including Cu2+ and Fe2+ enhance the aggregation of α-Syn. Differential expression of α-Syn is associated with alcohol use disorder (AUD), and specific genetic variants contribute to the risk for alcoholism, including alcohol craving. Spliced variants of α-Syn, leading to the expression of several shorter forms which are more prone to aggregation, are associated with both PD and AUD, and common transcript variants may be able to predict at-risk populations for some movement disorders or subtypes of PD, including secondary Parkinsonism. Both PD and AUD are associated with liver and brain iron dyshomeostasis. Research over the past decade has shown that α-Syn has iron import functions with an ability to oxidize the Fe3+ form of iron to Fe2+ to facilitate its entry into cells. Our prior research has identified an iron-responsive element (IRE) in the 5’ untranslated region (5’UTR) of α-Syn mRNA, and we have used the α-Syn 5’UTR to screen for small molecules that modulate its expression in the H4 neuronal cell line. These screens have led us to identify several interesting small molecules capable of both decreasing and increasing α-Syn expression and that may have the potential, together with the recently described mesenchymal stem cell therapies, to normalize α-Syn expression in different regions of the alcoholic and PD brain.
... Nearly 100,000 patients die each year because of AUD [1], which induces organ injury throughout the body, including in the liver and in the brain. In both humans and mice, alcohol intoxication leads to central nervous system (CNS) inflammation and neurodegeneration [2][3][4]. Recent studies using animal models have shown that inflammatory signaling not only contributes to neurodegeneration but also to alcohol addiction [5][6][7], making targeting of neuroinflammation a critical approach in the treatment of AUD. ...
Background:
Chronic alcohol consumption is associated with neuroinflammation, neuronal damage, and behavioral alterations including addiction. Alcohol-induced neuroinflammation is characterized by increased expression of proinflammatory cytokines (including TNFα, IL-1β, and CCL2) and microglial activation. We hypothesized chronic alcohol consumption results in peripheral immune cell infiltration to the CNS. Since chemotaxis through the CCL2-CCR2 signaling axis is critical for macrophage recruitment peripherally and centrally, we further hypothesized that blockade of CCL2 signaling using the dual CCR2/5 inhibitor cenicriviroc (CVC) would prevent alcohol-induced CNS infiltration of peripheral macrophages and alter the neuroinflammatory state in the brain after chronic alcohol consumption.
Methods:
C57BL/6J female mice were fed an isocaloric or 5% (v/v) ethanol Lieber DeCarli diet for 6 weeks. Some mice received daily injections of CVC. Microglia and infiltrating macrophages were characterized and quantified by flow cytometry and visualized using CX3CR1eGFP/+ CCR2RFP/+ reporter mice. The effect of ethanol and CVC treatment on the expression of inflammatory genes was evaluated in various regions of the brain, using a Nanostring nCounter inflammation panel. Microglia activation was analyzed by immunofluorescence. CVC-treated and untreated mice were presented with the two-bottle choice test.
Results:
Chronic alcohol consumption induced microglia activation and peripheral macrophage infiltration in the CNS, particularly in the hippocampus. Treatment with CVC abrogated ethanol-induced recruitment of peripheral macrophages and partially reversed microglia activation. Furthermore, the expression of proinflammatory markers was upregulated by chronic alcohol consumption in various regions of the brain, including the cortex, hippocampus, and cerebellum. Inhibition of CCR2/5 decreased alcohol-mediated expression of inflammatory markers. Finally, microglia function was impaired by chronic alcohol consumption and restored by CVC treatment. CVC treatment did not change the ethanol consumption or preference of mice in the two-bottle choice test.
Conclusions:
Together, our data establish that chronic alcohol consumption promotes the recruitment of peripheral macrophages into the CNS and microglia alterations through the CCR2/5 axis. Therefore, further exploration of the CCR2/5 axis as a modulator of neuroinflammation may offer a potential therapeutic approach for the treatment of alcohol-associated neuroinflammation.
... At present, alcohol intoxication is one of the consistently associated factors with alcohol-induced brain damage in animal models (Crews and Nixon, 2009). Binge intake (8.3 -9.7 g/kg/day; serum ethanol level: 250-400 mg%) (Crews et al., 2004;Tajuddin et al., 2014), chronic intermittent access to alcohol (20% v/v in tap water for 26 weeks, 5-6 g/kg intake per session) (Charlton et al., 2019) have been associated with alcohol-induced neurodegeneration. Equally, in humans, consumption of beverages with high ethanol content such as hard liquor was associated with higher rate of cognitive decline (Heymann et al., 2016) and PD risk . ...
Alcohol use disorder (AUD) has been associated with neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease. Prolonged excessive alcohol intake contributes to increased production of reactive oxygen species that triggers neuroimmune response and cellular apoptosis and necrosis via lipid peroxidation, mitochondrial, protein or DNA damage. Long term binge alcohol consumption also upregulates glutamate receptors, glucocorticoids and reduces reuptake of glutamate in the central nervous system, resulting in glutamate excitotoxicity, and eventually mitochondrial injury and cell death. In this review, we delineate the following principles in alcohol-induced neurodegeneration: (1) alcohol-induced oxidative stress, (2) neuroimmune response toward increased oxidants and lipopolysaccharide, (3) glutamate excitotoxicity and cell injury, and (4) interplay between oxidative stress, neuroimmune response and excitotoxicity leading to neurodegeneration and (5) potential chronic alcohol intake-induced development of neurodegenerative diseases, including Alzheimer’s and Parkinson’s disease.
... Cognitive and emotional processing alterations in heavy alcohol users have been associated with alcohol-induced grey-and white matter abnormalities within several brain regions including frontal lobe and limbic systems, basal forebrain, and cerebellum (Crews et al., 2004;Sullivan & Pfefferbaum, 2005;Crews & Nixon, 2009). Emerging evidence suggests that chronic alcohol use affects the relationship between these regions at the level of functional connectivity (FC). ...
Binge drinking is associated with increased impulsivity and altered emotional processing. The current study investigated, in a group of university students who differed in their level of binge drinking, whether the ability to inhibit a pre‐potent response and to delay gratification is disrupted in the presence of emotional context. We further tested whether functional connectivity within intrinsic resting‐state networks was associated with alcohol use. Higher incidence of binge drinking was associated with enhanced activation of the lateral occipital cortex, angular gyrus, the left frontal pole during successful response inhibition irrespective of emotional context. This observation suggests a compensatory mechanism. However, higher binge drinking attenuated frontal and parietal activation during successful response inhibition within a fearful context, indicating the selective emotional facilitation of inhibitory control. Similarly, higher binge drinking was associated with attenuated frontopolar activation when choosing a delayed reward over an immediate reward within the fearful, relative to the neutral, context. Resting‐state functional data analysis revealed that binge drinking decreased coupling between right supramarginal gyrus and Ventral Attention Network, indicating alcohol‐associated disruption of functional connectivity within brain substrates directing attention. Together, our results suggest that binge drinking makes response inhibition more effortful, yet emotional (more arousing) contexts may mitigate this; disrupted functional connectivity between regions underlying adaptive attentional control, is a likely mechanism underlying these response inhibition effects associated with binge drinking.
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The effects of chronic EtOH consumption, associated or not with thiamine deficiency (TD), on cognitive impairment, oxidative damage, and β-amyloid (Aβ) peptide accumulation in the brain were investigated in male C57BL/6 mice. We established an alcoholic mouse model by feeding an EtOH liquid diet, a TD mouse model by feeding a thiamine-depleted liquid diet, and an EtOH treatment associated with TD mouse model by feeding a thiamine-depleted EtOH liquid diet for 7 weeks. The learning and memory functions of the mice were detected through the Y-maze test. Biochemical parameters were measured using corresponding commercial kits. The Aβ expression in the hippocampus was observed by immunohistochemical staining. Several results were obtained. First, EtOH significantly reduced cognitive function by significantly decreasing the Glu content in the hippocampus; increasing the AChE activity in the cortex; and reducing the thiamine level, and superoxide dismutase (SOD), glutathione peroxidase (GPx), and choline acetyltransferase (ChAT) activities in both the hippocampus and cortex. The treatment also increased the levels of malondialdehyde (MDA), protein carbonyl, 8-hydroxydeoxyguanosine (8-OHdG), and nitric oxide (NO) and the activities of total nitric oxide synthase (tNOS), inducible nitric oxide synthase (iNOS), and monoamine oxidase B (MAO-B). Furthermore, EtOH enhanced the expression levels of Aβ1–42 and Aβ1–40 in the hippocampus. Second, TD induced the same dysfunctions caused by EtOH in the biochemical parameters, except for learning ability, 8-OHdG content, and GPx, tNOS, and AChE activities in the cortex. Third, the modification of MDA, protein carbonyl and NO levels, and GPx, iNOS, ChAT, and MAO-B activities in the brain induced by chronic EtOH treatment associated with TD was greater than that induced by EtOH or TD alone. The synergistic effects of EtOH and TD on Aβ1–40 and Glu release, as well as on SOD activity, depended on their actions on the hippocampus or cortex. These findings suggest that chronic EtOH consumption can induce TD, cognitive impairment, Aβ accumulation, oxidative stress injury, and neurotransmitter metabolic abnormalities. Furthermore, the association of chronic EtOH consumption with TD causes dramatic brain dysfunctions with a severe effect on the brain.
Immer mehr ältere Menschen sind von problematischem Substanzkonsum betroffen. Da insbesondere Suchterkrankungen sehr schambehaftet sind, geschieht dieses häufig im Verborgenen oder wird von Angehörigen stillschweigend hingenommen. Oft wird auch nicht erkannt, welche Folgen der anhaltende Substanzkonsum für den Betroffenen hat und Folgeschäden werden fälschlicherweise dem zunehmenden Alter zugeschrieben. Besonders hervorzuheben ist der Konsum von Alkohol und der Gebrauch von Medikamenten. Im Falle eines Medikamentenmissbrauchs ist dieser vielen älteren Menschen gar nicht bewusst und sie reagieren häufig empört auf das Thema. Therapeutische Interventionen haben sich auch bei älteren Menschen als wirksam erwiesen und können helfen die Lebensqualität des Einzelnen zu erhöhen.
The prefrontal cortex undergoes functional and structural changes due to binge or chronic alcohol consumption. This study examines alcohol-induced cerebral cortex damage and the association with oxidative stress in an animal model. Twenty-four Wistar rats (12 males and 12 females) weighing 150g to 250g were divided into four groups, A, B, C and D according to their weights. The rats in groups B, C and D were administered with 2mls of 52.5%, 16.5% and 4.3% v/v aqueous alcoholic solution respectively for 21 days. While rats in group A (control group) were given distilled water only, for the same period. The brain of each rat was excised, weighed and fixed in 10% formal saline for histological analysis while others were immersed in ice cold 30% sucrose solution, homogenized and analyzed for superoxide dismutase, malondialdehyde and acetylcholinesterase activity. Results indicate chromatolysis of Nissl bodies, cortical necrosis, and uneven neuronal loss with varying range of vacuolations in the prefrontal cortices of the alcohol treated rats in a dose- dependent manner when compared with the control group. Cerebral cortex damage due to acute oral alcohol intake is associated with oxidative stress.
Jasmonic acid (JA), cytokinins (CK), gibberellins (GA), abscisic acid (ABA), ethylene (ET), and salicylic acid (SA) are potent plant stress hormones (phytohormones/PTH). Methyl jasmonate (MeJA), a volatile ester of JA, is derived from the petals of Jasminum grandiflorum (jasmine). The MeJA has been meticulously confirmed for its food, agricultural, and therapeutic uses in the treatment of a range of serious illnesses. Several scientific articles have studied and reported on the role of free radicals in the development of life-threatening clinical illnesses. The inflammatory signaling pathway is triggered by a weak or interfering endogenous antioxidant system, or the elaborated production of free radicals, which causes damage to key cellular components. The current chapter focused on and demonstrated MeJA’s multifunctional role in antioxidant and anti-inflammatory signaling mechanisms such as inhibition of NF-B (nuclear factor kappa-light-chain-enhancer of activated B cells), mitogen-activated protein kinase (MAPK or MAP kinase) pathway inhibition/down-regulation of pro-inflammatory mediators (IL, TNF-), cyclo-oxygenase (COX), and (LOX). The antioxidant effect of MeJA’s interaction with miRNA, transcription of nuclear factor erythroid 2-related 2 (Nfr2), activation of sirtuins (SIRTs), antioxidant and redox signaling pathway were also discussed in the chapter.
Background
Differences in regional brain volumes as a function of family history (FH) of alcohol use disorder (AUD) have been reported, and it has been suggested that these differences might index genetic risk for AUD. However, results have been inconsistent. The aims of the current study were 1) to provide an updated descriptive review of the existing literature; and 2) to examine the association of FH with indices of subcortical volumes and cortical thickness in a sample of youth recruited based on FH status.
Methods
To address aim 1, a literature search located fifteen published studies comprising 1735 participants. Studies were characterized according to population, analytic methods, regions of interest (ROIs), and primary findings. To address the second aim, we examined volumetric and cortical thickness in a sample of 69 youth (mean age = 19.71 years, SD = 0.79) recruited based on FH status and matched on drinking variables. Associations of sex and alcohol use with volumetric outcomes were also examined.
Results
Our descriptive review revealed an inconsistent pattern of results with respect to the presence, direction, and regional specificity of volumetric differences across FH groups. The most consistent finding, significantly smaller amygdala volumes in FH+ participants, was not replicated in all studies. In the current sample of youth, measures of subcortical volumes and cortical thickness did not significantly differ as a function of FH, sex, or their interaction.
Conclusions
Evidence for FH group differences in regional brain volumes is inconsistent, and the current study failed to detect any group differences. Further research is needed to confirm the reproducibility of FH group differences and implications for AUD risk.
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The neurodegeneration and neurobehavioral consequences of alcohol are serious and offering therapeutic approaches for management of these types of neurodegeneration is one of the main concerns of researchers in this manner. Alcohol-stimulated oxidative stress, apoptosis and inflammation, with modulation of involved signaling pathway in neuroprotection, was reported previously. Neuroprotective strategy for management of alcohol induced neurodegeneration through a new generation neuroprotective agent and based on modulation of some neuroprotective signaling pathway such as CREB/BDNF and Akt/GSK has always been superior to any other therapeutic interventions. Therefore, the introduction and development of potential new neuroprotective properties and clarification of their effects on major cell signaling such as CREB/BDNF and Akt/GSK is necessitated. During recent years, using new neuroprotective compounds with therapeutic probability for treatment of alcohol induced neuro-biochemical and neuro-behavioral malicious effects have been amazingly increased. Many previous studies have reported the neuroprotective roles of crocin (major active component of saffron) in multiple neurodegenerative events and diseases in animal model. But the role of crocin neuroprotective effects against alcohol induced neurodegeneration and neurobehavioral sequels and also role of CREB/BDNF and Akt/GSK in this manner remain unclear. Hence we hypothesized that by using crocin in alcohol dependent subject it would provide neuroprotection against alcohol induced neurodegeneration and neurobehavioral and probably can manage sequels of alcohol abuses. Also we hypothesized that crocin, via intonation of CREB/BDNF and Akt/GSK signaling pathway, can inhibit alcohol induced neurodegeneration. In this article, we tried to discuss our hypothesis regarding the possible role of crocin, as a potent neuroprotective agent, and also role of Akt/GSK and CREB/BDNF signaling pathway in treatment of alcohol induced neurodegeneration and neurobehavioral through its anti-inflammatory, anti-apoptotic, anti-oxidative stress and cognitive enhancer.
This review describes interactions between compounds, primarily dihydropyridines, that block L-type calcium channels and drugs that cause dependence, and the potential importance of these interactions. The main dependence-inducing drugs covered are alcohol, psychostimulants, opioids, and nicotine. In preclinical studies, L-type calcium channel blockers prevent or reduce important components of dependence on these drugs, particularly their reinforcing actions and the withdrawal syndromes. The channel blockers also reduce the development of tolerance and/or sensitization, and they have no intrinsic dependence liability. In some instances, their effects include reversal of brain changes established during drug dependence. Prolonged treatment with alcohol, opioids, psychostimulant drugs, or nicotine causes upregulation of dihydropyridine binding sites. Few clinical studies have been carried out so far, and reports are conflicting, although there is some evidence of effectiveness of L-channel blockers in opioid withdrawal. However, the doses of L-type channel blockers used clinically so far have necessarily been limited by potential cardiovascular problems and may not have provided sufficient central levels of the drugs to affect neuronal dihydropyridine binding sites. New L-type calcium channel blocking compounds are being developed with more selective actions on subtypes of L-channel. The preclinical evidence suggests that L-type calcium channels may play a crucial role in the development of dependence to different types of drugs. Mechanisms for this are proposed, including changes in the activity of mesolimbic dopamine neurons, genomic effects, and alterations in synaptic plasticity. Newly developed, more selective L-type calcium channel blockers could be of considerable value in the treatment of drug dependence. SIGNIFICANCE STATEMENT: Dependence on drugs is a very serious health problem with little effective treatment. Preclinical evidence shows drugs that block particular calcium channels, the L-type, reduce dependence-related effects of alcohol, opioids, psychostimulants, and nicotine. Clinical studies have been restricted by potential cardiovascular side effects, but new, more selective L-channel blockers are becoming available. L-channel blockers have no intrinsic dependence liability, and laboratory evidence suggests they reverse previously developed effects of dependence-inducing drugs. They could provide a novel approach to addiction treatment.
Additions define neurobehavioral disorders in which the brain circuits responsible for pleasure, motivation, stress and decision-making are structurally and functionally disturbed. In this section we will talk about how people become addicted and how the activation of the reward system of the brain by alcohol and drugs not only generates rewarding sensations associated with these substances, but also triggers changes in the way a person responds to associated stimuli.
Die Antwort der Gesellschaft auf die alte Frage – was einen Suchtkranken dazu verleitet Alkohol, Tabak oder Drogen (erneu) zu konsumieren – auch nachdem ihr Leben bereits signifikant von diesen geschädigt wurde – führt oft zu einer allzu simplen Antwort: Schwacher Wille!
Historically, most alcohol neurotoxicity studies were conducted in young adult males and focused on chronic intake. There has been a shift towards studying the effects of alcohol on the adolescent brain, due to alcohol consumption during this formative period disrupting the brain’s developmental trajectory. Because the most typical pattern of adolescent alcohol intake is heavy episodic (binge) drinking, there has also been a shift towards the study of binge alcohol-induced neurobehavioral toxicity. It has thus become apparent that binge alcohol damages the adolescent brain and there is increasing attention to sex-dependent effects. Significant knowledge gaps remain in our understanding of the effects of binge alcohol on the female brain, however. Moreover, it is unsettling that population-level studies indicate that the prevalence of binge drinking is increasing among American women, particularly those in older age groups. Therefore, although study of adolescents has made it apparent that binge alcohol disrupts ongoing brain maturational processes, we know almost nothing about how it impacts the aging brain, as studies of its effects on the aged brain are relatively scarce, and the study of sex-dependent effects is just beginning. Given the rapidly increasing population of older Americans, it is crucial that studies address age-dependent effects of binge alcohol, and given the increase in binge drinking in older women who are at higher risk for cognitive decline relative to men, studies must encompass both sexes. Because adolescence and older age are both characterized by age-typical brain changes, and because binge drinking is the most common pattern of alcohol intake in both age groups, the knowledge that we have amassed on binge alcohol effects on the adolescent brain can inform our study of its effects on the aging brain. In this review, we therefore cover the current state of knowledge of sex and age-dependent effects of binge alcohol, as well as statistical and methodological considerations for studies aimed at addressing them.
Efficacious pharmacotherapies for the treatment of substance use disorders need to be expanded and improved. Non-neuronal cells, particularly astrocytes and microglia, have emerged as therapeutic targets for the development of pharmacotherapies to treat dependence and relapse that accompanies chronic drug use. Cytokines and chemokines are neuroimmune factors expressed in neurons, astrocytes, and microglia that demonstrate promising clinical utility as therapeutic targets for substance use disorders. In this review, we describe a role for cytokines and chemokines in the rewarding and reinforcing effects of alcohol, opioids, and psychostimulants. We also discuss emerging cytokine- and chemokine-based therapeutic strategies that differ from conventional strategies directed toward transporters and receptors within the dopamine, glutamate, GABA, serotonin, and GABA systems.
Ethanol is a non-competitive inhibitor of N-methyl-D-aspartate receptors (NMDARs) and acutely disrupts hippocampal synaptic plasticity and learning. In the present study, we examined the effects of oxysterol positive allosteric modulators (PAMs) of NMDARs on ethanol-mediated inhibition of NMDARs, block of long-term potentiation (LTP) and long-term depression (LTD) in rat hippocampal slices, and defects in one-trial learning in vivo We found that 24S-hydroxycholesterol (24S-HC) and a synthetic oxysterol analogue overcame effects of ethanol on NMDAR-mediated synaptic responses in the CA1 region but did not alter acute effects of ethanol on LTD; the synthetic oxysterol, however, overcame acute inhibition of LTP. In addition, both oxysterols overcame persistent metaplastic effects of ethanol on LTP in vitro, and the synthetic analogue reversed defects in one-trial inhibitory avoidance learning in vivo These results indicate that effects of ethanol on both LTP and LTD arise by complex mechanisms beyond NMDAR antagonism and that oxysterol NMDAR PAMs may represent a novel approach for preventing and reversing acute ethanol-mediated changes in cognition. Significance Statement Ethanol acutely inhibits hippocampal NMDARs, LTP and learning. In this study, we found that certain oxysterols that are NMDAR positive allosteric modulators can overcome the acute effects of ethanol on NMDARs, LTP and learning. Oxysterols differ in their effects from agents that inhibit integrated cellular stress responses.
Alcohol is an important public health issue worldwide. A major cause of its toxicity is
the production of reactive oxygen species generated during its metabolism. The aim of the
present study was to compare the effect of binge drinking-like alcohol exposure on a panel of
genes involved in oxidative mechanisms in adolescent and adult mice. In adolescent animals,
alcohol decreased the expression of genes involved in the repair of DNA damage and
increased the expression of proapoptotic genes. In contrast, in the adult brain, genes activated
by alcohol were associated with protective mechanisms. In adolescent mice, multiple binge
ethanol exposure substantially reduced neurogenesis in the hippocampus and impaired shortterm
memory. Taken together, our results indicate that alcohol causes deleterious effects in
the adolescent brain which are distinct from those observed in adults. These data contribute to
explain the greater sensitivity of the adolescent brain to alcohol toxicity. PACAP is a
neuropeptide which has been shown to exert various neuroprotective roles. Adolescent and
adult wild type and PACAP KO mice were treated with a single binge episode. Biochemical
analyses revealed that alcohol administration induced an increase of oxidative stress and
apoptosis in PACAP KO mice only. A microarray analysis was performed to characterize the
mechanisms underlying the sensitivity of PACAP KO mice. Interestingly, in adolescent and
adult PACAP KO mice, the set of genes regulated were different but both seemed to inhibit
network associated with DNA repair and cell cycle. These data imply that alcohol induces
serious DNA damages and cell cycle alteration in PACAP KO mice. This was in accordance
with the reduced number of proliferating cells in adolescent and adult PACAP KO mice
treated with alcohol. To conclude, endogenous PACAP protects the brain from alcohol
toxicity but acts through different sets of genes according to brain maturation.
The prefrontal cortex undergoes functional and structural changes due to binge or chronic alcohol consumption. This study examines alcohol-induced cerebral cortex damage and the association with oxidative stress in an animal model. Twenty-four Wistar rats (12 males and 12 females) weighing 150g to 250g were divided into four groups, A, B, C and D according to their weights. The rats in groups B, C and D were administered with 2mls of 52.5%, 16.5% and 4.3% v/v aqueous alcoholic solution respectively for 21 days. While rats in group A (control group) were given distilled water only, for the same period. The brain of each rat was excised, weighed and fixed in 10% formal saline for histological analysis while others were immersed in ice cold 30% sucrose solution, homogenized and analyzed for superoxide dismutase, malondialdehyde and acetylcholinesterase activity. Results indicate chromatolysis of Nissl bodies, cortical necrosis, and uneven neuronal loss with varying range of vacuolations in the prefrontal cortices of the alcohol treated rats in a dosedependent manner when compared with the control group. Cerebral cortex damage due to acute oral alcohol intake is associated with oxidative stress.Keywords: Brain, cerebral cortex, alcohol, Wistar rats, oxidative stress
Ethanol withdrawal commonly leads to anxiety-related disorder, a central factor toward negative reinforcement leading to relapse. The lateral habenula (LHb), an epithalamic nucleus, has emerged to be critical for both reward and aversion processing. Recent studies have also implicated the hyperactivity of LHb, adding to the emergence of negative emotional states during withdrawal from addictive drugs. Herein, we have studied the effects of glutamate transporter inhibitor (PDC), GluN2B-containing NMDAR antagonist (Ro25-6981), and intracellular calcium chelator (BAPTA-AM) injection in LHb on ethanol withdrawal symptoms. We found that ethanol 4 g/kg 20% w/v intragastric (i.g.) for 10 days followed by 24 hr of withdrawal showed a significant increase in somatic signs characterized by vocalization, shaking, and scratching. It also increased locomotor activity and anxiety-like behavior, collectively showing expression of ethanol withdrawal symptoms. The intra-LHb administration of PDC (0.5 ng) worsened the effect of ethanol withdrawal, whereas Ro25-6981 (2 and 4 ng) and BAPTA-AM (6.5 and 13 ng) significantly reversed ethanol withdrawal-induced behavior evident by a decrease in somatic signs, locomotor activity, and anxiety-like behavior. Further, pretreatment of Ro25-6981 and BAPTA-AM reduced the neuronal loss, whereas PDC increased it compared to the vehicle-treated group, as evidenced by NeuN staining. Altogether, our results suggest that increased glutamate, GluN2B activation, and likely calcium increase indicative of glutamate excitotoxicity-induced neuronal loss in LHb possibly endorse the emergence of ethanol withdrawal symptoms, while their inhibition might help in alleviating the ethanol withdrawal symptoms.
The central nervous system (CNS) is strongly affected by ethanol (EtOH) toxicity and there are many mechanisms involved in the damage process. Histological changes in nervous tissues are commonly observed in experimental models of EtOH exposure. Among these impairments are included neuron death and reduction of glial cell populations. In this chapter, we approach the mechanisms involved in tissue changes in CNS, exploring biochemical and cellular processes.
Alcohol can be neurotoxic. Recent studies have indicated that the prefrontal cortex is particularly sensitive to the neurotoxic actions of alcohol, as are specific groups of neurons that project throughout the brain including the frontal cortex, biogenic amine, and peptidergic neurons. Alcohol-induced brain damage is a significant problem that leads to permanent changes in brain function, although abstinence does allow partial recovery of function. The relationship between alcohol-induced brain damage and the development of alcohol dependence requires additional experimentation, but it presents the possibility that treatments for neurodegeneration and improved cognitive performance could contribute to improved recovery from alcohol dependence.
It has long been thought that neuronal production ceases after birth and regeneration of the nervous system was impossible. However repeated studies have shown that neurogenesis does occur within certain sites in the adult nervous system. This review provides information on details of neurogenic sites in mammalian central nervous system that is reported in literature. Advancement in cellular techniques have enabled scientists to isolate neural stem cells from the subventricular zone, dentate gyrus, septum and striatum, third ventricle, spinal cord, substantia nigra and amygdala from various mammals. Even areas thought to be non neurogenic in nature such as the neocortex, subcortical white matter, the olfactory bulb and rostral extension and the dorsal vagal complex yielded multipotent stem cells. The subventircular zone and the dentate gyrus remain the two most active neurogenic regions while the neurogenic properties of some regions such as the substantia nigra are still under controversy although most reported sites exhibit a substantial amount of neurogenesis. In South Africa, no animal model seems to have been used to investigate adult neurogenesis.
The role of the cerebellar cortex in motor learning was investigated by comparing the paramedian lobule of adult rats given difficult acrobatic training to that of rats that had been given extensive physical exercise or had been inactive. The paramedian lobule is activated during limb movements used in both acrobatic training and physical exercise. Acrobatic animals had greater numbers of synapses per Purkinje cell than animals from the exercise or inactive groups. No significant difference in synapse number or size between the exercised and inactive groups was found. This indicates that motor learning required of the acrobatic animals, and not repetitive use of synapses during physical exercise, generates new synapses in cerebellar cortex. In contrast, exercise animals had a greater density of blood vessels in the molecular layer than did either the acrobatic or inactive animals, suggesting that increased synaptic activity elicited compensatory angiogenesis.
Biochemical, immunological, and molecular cloning studies have suggested the existence of multiple forms of adenylyl cyclase (EC 4.6.1.1). An adenylyl cyclase cDNA clone (type II) was isolated from a rat brain library and found to encode a protein of 1090 amino acids that was homologous to but distinct from the previously described Ca2+/calmodulin-stimulated adenylyl cyclase from bovine brain. Expression of the type II cDNA in an insect cell line resulted in an increased level of adenylyl cyclase activity that was insensitive to Ca2+/calmodulin. Addition of activated Gs alpha protein to type II-containing membranes increased enzyme activity. The mRNA encoding the type II protein was expressed at high levels in brain tissue and at low levels in olfactory epithelium and lung. The existence of multiple adenylyl cyclase enzymes may provide for complex and distinct modes of biochemical regulation of cAMP levels in the brain.
We have cloned and expressed a cDNA that encodes a widely distributed form of mammalian adenylyl cyclase (EC 4.6.1.1). Although those adenylyl cyclases described previously have a rather narrow tissue distribution, this enzyme (type IV) is apparently synthesized in a variety of peripheral tissues and in the central nervous system. The protein resembles the other adenylyl cyclases in its proposed structure. It most resembles the type II adenylyl cyclase described in the preceding paper [Feinstein, P. G., Schrader, K. A., Bakalyar, H. A., Tang, W.-J., Krupinski, J., Gilman, A. G. & Reed, R. R. (1991) Proc. Natl. Acad. Sci. USA 88, 10173-10177] in its amino acid sequence, lack of response to calmodulin, and synergistic activation by a combination of the Gs alpha subunit and the G-protein beta gamma subunit complex.
A quantitative neuropathological necropsy study of the human cerebral cortex showed that the number of cortical neurones in the superior frontal cortex in chronic alcoholic patients is significantly reduced compared with that in controls matched for age and sex. The number of neurones in the motor cortex did not differ significantly between the controls and alcoholics, but in both cortical regions there was evidence that alcoholic patients had smaller (shrunken) neurones than controls. Further studies are necessary to identify other regions of the cerebral cortex that are selectively damaged in brain damage associated with alcohol.
Phenotypic analysis of hematopoietic stem and progenitor cells (HSCs) has been an invaluable tool in defining the biology of stem cell populations. We have recently described the production of AC133, a monoclonal antibody (MoAb) that binds to a novel cell surface antigen present on a CD34bright subset of human HSCs. This antigen is a glycosylated protein with a molecular weight of 120 kD. Here, we report the molecular cloning of a cDNA encoding this antigen and show that it does not share homology with any previously described hematopoietic or other cell surface antigen(s). The AC133 polypeptide has a predicted size of 97 kD and contains five-transmembrane (5-TM) domains with an extracellular N-terminus and a cytoplasmic C-terminus. Whereas the expression of tetraspan (4-TM) and 7-TM molecules is well documented on mature and immature hematopoietic cells and leukocytes, this 5-TM type of structure containing two large (255–amino acid [aa] and 290-aa) extracellular loops is unique and does not share sequence homology with any known multi-TM family members. Expression of this protein appears limited to bone marrow in normal tissue by immunohistochemical staining; however, Northern analysis suggests that the mRNA transcript is present in a variety of tissues such as the kidney, pancreas, placenta, and fetal liver. The AC133 antigen is also expressed on subsets of CD34+ leukemias, suggesting that it may be an important early marker for HSCs, as well as the first described member of a new class of TM receptors.
Background: Biogenic amine neurons are involved in a number of mental diseases including addiction and alcohol dependence. Because chronic ethanol is known to cause supersensitivity to NMDA excitotoxicity in cortical neurons, this study sought to determine the effect of ethanol treatment on biogenic amine neurons. Methods: To determine if ethanol exposure alters the vitality of biogenic amine neurons; cultures were prepared from E14 rat brain. After 24 hr in culture, cells were divided into control or ethanol (100 mM) treatment groups, cultured an additional 48 hr, and then half of them exposed to NMDA for 25 min. The NMDA was then removed and cells cultured in fresh media for an additional 24 hr to allow for excitotoxic delayed neuronal death. Cultures were then stained with antibodies to 5-hydroxytryptamine or tyrosine hydroxylase to identify serotonin and dopamine neurons, respectively. Cultures were analyzed for cell number and neuronal morphology. Results: Ethanol treatment alone had no effect on biogenic amine cell number, soma area, number of neurites, or terminal segments, although the field area of dopamine neurons was decreased. Treatment with 30 mu M NMDA had no effect on controls, but significantly decreased dopamine neurons in ethanol-treated cultures as well as reduced soma area, field area, number of neurites and number of terminal segments. Treatment with higher concentrations of NMDA reduced dopamine and serotonin neurons in both controls and ethanol-treated groups, and ethanol treatment significantly enhanced NMDA excitotoxic effects. Treatment with Brain Derived Neurotrophic Factor (BDNF) prevented ethanol sensitization to NMDA excitotoxicity. Conclusions: These studies suggest that ethanol treatment sensitizes biogenic amine neurons to excitotoxic insults. Ethanol sensitization of biogenic amine neurons to insults could contribute to the development of mental disease.
Vertebrate cerebella occupy a position in the rostral roof of the 4th ventricle and share a common pattern in the structure of their cortex. They differ greatly in their external form, the disposition of the neurones of the cerebellar cortex and in the prominence of their afferent, intrinsic and efferent connections.
Background:
Between 1978 and 1988, 453 sons (age range, 18 to 29 years) of alcoholic and control subjects were evaluated for their level of reaction (LR) to alcohol. This article presents the results of the 8.2-year follow-up of 450 of these men. The three goals were (1) to attempt to replicate results of the follow-up of the first 223 subjects, (2) to evaluate the potential impact of the quantity and frequency of drinking at the time of the original study on the relationship between LR and alcoholic outcome (ALC), and, most importantly, (3) to test if the relationship between family history (FH) and ALC might be mediated by LR in a subset of the sample.
Methods:
Face-to-face structured follow-up interviews were carried out with the subjects and separately with an additional informant, and blood samples, as well as urine specimens, were obtained for determination of state markers of heavy drinking and drug toxicology screens.
Results:
First, the rate of development of DSM-ÍIÍ-R abuse and dependence on alcohol was 14.1% and 28.6%, respectively, for family history positive (FHP) subjects, compared with 6.6% and 10.8%, respectively, for family history negative (FHN) men. Second, neither consideration of the quantity nor the frequency of drinking at the time of the original study, nor their combination, effectively diminished the relationships between LR and ALC. Third, among men who drank and demonstrated the 15% highest and lowest scores on LR at about the age of 20 years (ie, 30% of the relevant population), the correlation between FH and ALC was greatly reduced when LR was considered, but the correlation between LR and ALC was not greatly diminished when the impact of FH was evaluated.
Conclusions:
In this sample of moderately functional white men, the development of alcoholism occurred in relationship to an FH of alcoholism, but alcohol abuse or dependence was unrelated to prior psychiatric disorders. For this group, LR at the age of 20 years was associated with future alcoholism in a manner that was independent of the drinking practices at the time of the original study. At least among those men with clearly high and low LR scores, these data are consistent with the conclusion that LR might be a mediator of the alcoholism risk.
Abstract : Tumor necrosis factor-α (TNF-α) is a cytokine that elicits cell responses by activating the mitogen-activated protein kinase (MAP kinase) cascade and transcription factors such as nuclear factor-kB (NF-kB). As these elements play a central role in the mechanisms of signaling involved in the activation of cytosolic phospholipase A2 (cPLA2) and cyclooxygenase-2 (COX-2), the effect of TNF-α on arachidonate (AA) metabolism in 1321N1 astrocytoma cells was assayed. TNF-α produced a phosphorylation of cPLA2, which was preceded by an activation of both c-Jun N-terminal kinase (JNK) and p38-MAP kinase, and this was associated with the release of [3H]AA. In contrast, TNF-α did not activate the extracellular signal-regulated kinase (MAP kinase) p42, nor did it elicit a mitogenic response. Analysis of [3H]AA metabolites by reverse-phase HPLC showed that all of the [3H]AA released during the first hour after TNF-α addition eluted as authentic AA, whereas in samples obtained at 24 h after addition of TNF-α, 25% of the [3H]AA had been converted into COX products as compared with only 9% in control cells. In keeping with these findings, TNF-α produced an increase of COX-2 expression, as judged from both RT-PCR studies and immunoblot of COX-2 protein, and a long-lasting activation of NF-kB. These data show that TNF-α produces in astrocytoma cells an early activation of both p38-MAP kinase and JNK, which is followed by the phosphorylation of cPLA2 and the release of AA. On the other hand, the activation of NF-kB may explain the induction of the expression of COX-2 and the delayed generation of prostanoids.
Prior research indicates risk for alcoholism is increased among individuals who begin to drink at an early age. We replicate and extend these findings, addressing causal and noncausal explanations for this association. Structured psychiatric interviews, including assessment of lifetime DSM-IV alcohol abuse and alcohol dependence (AD), were conducted with 8746 adult twins ascertained through a population-based twin registry. We found strong evidence for an association between early drinking onset and risk for AD, but less evidence for an association with alcohol abuse. The results of twin-pair analyses suggest that all of the association between early drinking and later AD is due to familial sources, which probably reflect both shared environmental and genetic factors. These results suggest the association between drinking onset and diagnosis is noncausal, and attempts to prevent the development of AD by delaying drinking onset are unlikely to be successful.
Prominin is the first identified member of a novel family of polytopic membrane proteins conserved throughout the animal kingdom. It has an unusual membrane topology, containing five transmembrane domains and two large glycosylated extracellular loops. In mammals, prominin is expressed in various embryonic and adult epithelial cells, as well as in nonepithelial cells, such as hematopoietic stem cells. At the subcellular level, prominin is selectively localized in microvilli and other plasma membrane protrusions, irrespective of cell type. At the molecular level, prominin specifically interacts with membrane cholesterol and is a marker of a novel type of cholesterol-based lipid ‘raft’. A frameshift mutation in the human prominin gene, which results in a truncated protein that is no longer transported to the cell surface, is associated with retinal degeneration. Given that prominin is concentrated in the plasma membrane evaginations at the base of the outer segment of rod photoreceptor cells, which are essential precursor structures in the biogenesis of photoreceptive disks, it is proposed that prominin has a role in the generation of plasma membrane protrusions, their lipid composition and organization and their membrane-to-membrane interactions.
Background: The etiological factors associated with the predisposition to develop alcohol dependence remain largely unknown. In recent years, neurophysiological anomalies have been identified in young and adult offspring of alcoholic probands. These neuroelectric features have been replicated in several laboratories across many different countries and are observed in male and female alcoholics and some of their relatives and offspring. Moreover, these electrophysiological abnormalities are heritable and predictive of future alcohol abuse or dependence.
Methods: A model is presented which hypothesizes that the genetic predisposition to develop alcoholism involves an initial state of central nervous system (CNS) disinhibition/hyperexcitability. We propose that the event-related brain potential (ERP) anomalies reflect CNS disinhibition. This homeostatic imbalance results in excess levels of CNS excitability which are temporarily alleviated by the ingestion of alcohol. It is hypothesized that this hyperexcitability is heritable, and is critically involved in the predisposition toward alcoholism and the development of dependence. A brief review of the relevant literature is presented.
Results: Neurophysiological, neurochemical, and genetic evidence support the proposed model. In addition, strikingly similar observations between animal research and the human condition are identified. Finally, it is asserted that the proposed model is primarily biological in nature, and therefore does not account for the entire clinical variance.
Conclusion: A putative CNS homeostatic imbalance is noted as a critical state of hyperexcitability. This hyperexcitability represents a parsimonious model of what is inherited in the predisposition to develop alcoholism. It is our hope that this model will have heuristic value, resulting in the elucidation of etiological factors involved in alcohol dependence.
An animal's age at the time of ethanol treatment is related to dendritic vulnerability to ethanol damage. The dendritic networks of Purkinje neurons of 5-month-old rats treated with ethanol were quantitavely similar to those of age-matched pair-fed rats, but dendritic networks of 14-month-old rats treated with ethanol were significantly reduced compared with those of their age-matched pair-fed controls.
Rats repeatedly intoxicated with alcohol (ethanol, three times daily) over a 4-day period display neuronal degeneration in the dentate gyrus; entorhinal, piriform, insular, orbital, and perirhinal cortices; and in the olfactory nerve fibers and terminals in the olfactory bulb. Postulating a role for excitotoxicity, we have attempted to prevent the degeneration using antagonists that are neuroprotective in this type of brain damage. In an initial study, continuous subcutaneous infusion of a high dose of the glutamate/NMDA receptor antagonist MK-801 (2 mg/kg/day) by itself caused extensive neuronal degeneration in several brain regions and severe behavioral intoxication that precluded survival if combined with high blood alcohol levels (approximately 300 mg/dl). Moreover, the lower, nonneurotoxic blood alcohol levels (approximately 150 mg/dl) that were compatible with survival worsened the MK-801-induced brain damage. In a subsequent experiment, daily intraperitoneal injections of a lower dose of MK-801 (1 mg/kg/day) resulted in no MK-801 toxicity and, when combined with neurotoxic levels of alcohol, no reduction in alcohol-induced neurotoxicity. Nimodipine, a voltage-gated Ca2+ channel blocker, reduced the neuronal damage in the dentate gyrus, but greatly increased it in the piriform cortex when administered intragastrically at 600 mg/kg/day; it provided no protection from alcohol-dependent degeneration when given intragastrically at 100 mg/kg/day. Continuous intracerebroventricular delivery of 0.24 to 0.29 mg/day of 6,7-dinitro-quinoxaline-2,3-dione, a glutamate/alpha-amino-3-hydroxy-5-methyl-4-isoxazole receptor antagonist, failed to diminish alcohol-dependent neuronal damage in any brain region. We conclude that brain damage from episodic "binge" alcohol intoxication is not primarily mediated by excitotoxic mechanisms, implying that other, nonexcitotoxic pathophysiological mechanisms, are involved. Furthermore, MK-801, far from protecting from the alcohol-induced damage, at high doses causes widespread neuropathology that is significantly potentiated by alcohol.
Vertebrate cerebella occupy a position in the rostral roof of the 4th ventricle and share a common pattern in the structure of their cortex. They differ greatly in their external form, the disposition of the neurons of the cerebellar cortex and in the prominence of their afferent, intrinsic and efferent connections.
This paper reports findings relative to a simple, rapid and reproducible technique for the induction of physical dependence upon ethanol in the rat. The dependence was induced by intragastric intubation of 20% (w/v) ethanol solutions at 9-15 g/kg in 3-5 fractional doses daily for 4 days, maintaining blood ethanol concentrations above a threshold level sufficient to sustain observable sedation throughout the entire period of intubation. Two phases were distinguished during the withdrawal period: 1. Prodromal detoxication, characterized by a spectrum of signs and responses of diminishing severity, related to the decline in blood ethanol concentrations (mg/dl): death, greater than 640; coma, 780-460; loss of righting reflex, 640-400; ataxia 3-1, 570-250; sedation 340-190; neutrality, 220-130; 2. Ethanol dependence, characterized by a spectrum of withdrawal signs and reactions of progressively increasing severity as blood ehtanol concentration approached 100 mg/dl: hyperactivity, tremors, akinesia, spastic rigidity, and induced and spontaneous convulsions. A rapid sucession of two diverse clusters of signs and reactions represents a reversal of the central nervous system function from the extremes of ethanol intoxication (CNS depression) to the extremes of ethanol dependence (CNS hyperexcitability) during the withdrawal period. Both extremes may terminate in death.
Magnetic resonance imaging (MRI) was used to study in vivo the brains of 49 patients with chronic alcoholism, 3 to 4 weeks post-withdrawal, and 43 normal healthy controls, all right-handed male veterans between the ages of 23 and 70 years. MRI scans were analyzed using a semi-automated procedure, which allowed the subcortical regions to be segmented into cerebrospinal fluid (CSF) and brain tissue and the cortical regions to be segmented into CSF, gray matter, and white matter. An age regression model was used to examine the effects of alcohol on brain structure, over and above that expected from the normal aging process. The alcoholics exhibited decreased tissue and increased CSF after correcting for aging. In the cortex, there was significant loss of both gray matter and white matter volume. In this sample of alcoholics, no particular cortical region was preferentially affected or spared. Furthermore, brain tissue volume loss increased with advanced age in the alcoholics. In this group of alcoholics there was no relationship between length of illness and age, i.e., the younger alcoholics had as heavy alcohol use histories as did the older alcoholics. Thus, the increased brain tissue loss with advanced age is interpreted as evidence for age-related increase in brain vulnerability to chronic alcohol abuse.
Dendritic networks of cerebellar Purkinje neurons from aging ethanol-treated Fisher 344 rats were analyzed for metric changes in terminal and internal segments of the networks. Mean lengths of three categories of dendritic segments were determined. No significant metric changes in segment lengths were detectable immediately at the termination of 24 weeks of ethanol treatment, but significant changes were apparent after 8 weeks of recovery from ethanol treatment. Return to a diet of standard laboratory chow was associated with a period of dendritic extension in networks from pair-fed control rats but not in those from the ethanol-treated rats. The resulting significant differences in mean segment length were restricted to the paired terminal segments at the peripheral tips of the bifurcating networks. Unpaired terminal segments and internal segments of the networks showed no significant changes in length during the recovery period.
The number of spines on an individual Purkinje cell in the cerebellar cortex of the rat was determined by stereological methods. Investigations were based on thin section electron micrographs, freeze fracture replicas, and horseradish peroxidase labeled cells. Purkinje cell dendritic spines in our embedded material had a mean length of 1.4 +/- 0.05 micron and mean neck and head diameters of 0.22 +/- 0.01 micron and 0.45 +/- 0.02 micron, respectively. From these dimensions, an estimate of spine volume in embedded material of 0.132 micron 3 was obtained. The density of dendritic spines in our fixed material was 8.15 x 10(8) or 7.24 x 10(8) per microliters of molecular layer from volume fraction and density per mm2, respectively. The number of spines per linear micron of Purkinje cell spiny branchlet was 17.2 from freeze fracture and 17.6 from horseradish peroxidase labeled dendrites. These all indicate that there are between 154,000 and 175,000 spines on the dendritic tree of each Purkinje cell, considerably more than previously reported for the rat.
A conditioned taste aversion (CTA) paradigm was used to determine whether aversion to the pharmacological effects of ethanol, apart from orosensory cues, can contribute to genetic differences in voluntary ethanol consumption. Four doses of ethanol, administered IP, were paired with the consumption of a 0.1% saccharin solution in rats from the alcohol-preferring (P) and alcohol-nonpreferring (NP) lines. Repeated pairing of saccharin and ethanol in a dose of 1.0 g/kg produced stronger and more prolonged aversion to saccharin in NP rats, compared with P rats, at comparable blood ethanol levels. A low dose of ethanol (0.25 g/kg) produced transient conditioned facilitation of saccharin consumption in P rats, but not in NP rats, at comparable blood ethanol levels. The results suggest that rats of the NP line find the postingestional effects of high-dose ethanol more aversive, and low-dose ethanol less reinforcing, than do rats of the P line. Genetic differences in voluntary ethanol consumption may be due, in part, to differences in aversion to the postingestional effects of ethanol.
We recently reported that selectively bred, alcohol-preferring (P) and alcohol-nonpreferring (NP) rats differ in sensitivity to a single sedative-hypnotic dose of ethanol, as measured by performance in the jump test. The present study examines the contributions of initial sensitivity and acute tolerance development to this difference. Initial sensitivity, assessed by brain alcohol content upon loss of the aerial righting reflex, was not significantly different between P and NP groups given 3 g ethanol/kg body weight intraperitoneally. Acute tolerance was indexed from blood alcohol concentrations (BAC) upon recovery of jumping performance following two successive ethanol doses. Practiced P and NP rats were required to jump 35 cm to a descending platform following the IP injection of 2.0 g ethanol/kg. The NP group took significantly longer (74 min) than the P (33 min) group whereupon BAC1 of NP rats (234 mg%) was significantly lower than that of P rats (250 mg%). A second injection (1.0 g/kg) was given immediately after the animals reached the 35 cm criterion. Again, NP rats took significantly longer (124 min) than P rats (52 min) to jump 35 cm and BAC2 of NP animals was lower (295 mg%) than that of P rats (343 mg%). The difference between BAC2 and BAC1, the measure of tolerance development, was significantly larger for P rats (90 mg%) than for NP rats (61 mg%). No significant differences in blood ethanol elimination were observed between the groups. The data indicate no difference in initial sensitivity between P and NP animals but that P rats develop acute tolerance more rapidly and/or to a greater degree than do NP rats. The results are consistent with a relationship in these selectively bred lines of rats between alcohol preference and the development of acute tolerance.
Neurons in the mammalian central nervous system are generated from progenitor cells near the lumen of the neural tube. Time-lapse microscopy of dividing cells in slices of developing cerebral cortex reveals that cleavage orientation predicts the fates of daughter cells. Vertical cleavages produce behaviorally and morphologically identical daughters that resemble precursor cells; these symmetric divisions may serve to expand or maintain the progenitor pool. In contrast, horizontally dividing cells produce basal daughters that behave like young migratory neurons and apical daughters that remain within the proliferative zone. Notch1 immunoreactivity is distributed asymmetrically in mitotic cells, with Notch1 inherited selectively by the basal (neuronal) daughter of horizontal divisions. These results provide cellular and molecular evidence that cortical neurons are generated from asymmetric divisions.
The present study proposed to determine the significance of previously reported ethanol-induced dendritic lengthening in mature cerebellar Purkinje neurons (PN). An analysis of dendritic path lengths (PL) was used to make this determination. A PL is the curvilinear length from the origin of the dendritic root segment to the free tip of a dendritic terminal. It was hypothesized that treatment-induced dendritic lengthening resulted from dendritic growth, and that growth should produce an upward shift in the value of the median PL. The PL and the segment length (SL) for each dendritic terminal were measured in PN of 24 month old male F344 rats, previously fed a liquid diet containing 35% ethanol-derived calories for 48 weeks, to test that hypothesis. Because there are large numbers of terminal dendrites in PN networks a shift in the value of their median PL is a sensitive measure of change in these networks. It was found that almost 30% of the ethanol-exposed cell sample had median PL that were shorter than expected and that the median SL in these same neurons tended to be longer than expected. At the end of the ethanol treatment, half of these rats were weaned from the ethanol diet for a subsequent 8 weeks to test for reversibility of these changes. Following the period of abstinence from dietary ethanol, the significant ethanol-related differences previously found in dendritic lengths were no longer present. A consideration of two models of dendritic regression suggested that elongation of surviving terminal dendritic segments in the ethanol-exposed neurons occurred through deletion of other terminal segments at their vertices (branch points). It was shown that deletions of entire terminal dendritic segments at their vertices would produce increases in the lengths of associated terminal segments in the absence of real growth. Deletions of dendritic segments would also entail loss of PL unique to the deleted segments, thereby causing a shift in the value of the median PL of affected networks.
Magnetic resonance imaging was used to quantify the volume of the hippocampus in 47 men with chronic alcoholism and 72 healthy male control subjects. The subjects ranged in age from 21 to 70 years, thus permitting a test of whether older alcoholics suffer greater brain tissue volume reduction than do younger ones. Comparison brain regions included temporal lobe gray matter, white matter, and cerebrospinal fluid, as well as measures of the lateral ventricles, third ventricle, and temporal horns. The results of this cross-sectional study showed that the anterior, but not the posterior, portions of the hippocampus in both hemispheres were significantly smaller in the alcoholic than the healthy control group. Furthermore, the bilateral anterior hippocampal volume loss was greater in older than younger alcoholics. Despite the hippocampal volume deficit, these alcoholics did not demonstrate an explicit memory impairment; furthermore, memory test scores did not correlate significantly with hippocampal volumes. In the alcoholics, the age-related volume loss, which was over and above that expected in normal aging, was also evident in the temporal cortex and white matter. Likewise, alcoholic ventricular enlargement was age-related. Analysis of covariance revealed that the anterior hippocampal deficit persisted after accounting for the temporal lobe gray matter volume deficit. Multiple regression analysis revealed that the age-related brain volume abnormalities observed in the alcoholics could not be attributed to duration of alcoholism or total lifetime consumption of alcohol.