Binge drinking is an increasingly important topic in alcohol research, but the field lacks empirical cohesion and definitional precision. The present review summarizes findings and viewpoints from the scientific binge-drinking literature. Epidemiological studies quantify the seriousness of alcohol-related problems arising from binge drinking, with a growing incidence reported in college-age men over the last 2 years. Experimental studies have found neurocognitive deficits for frontal lobe processing and working memory operations in binge-drinking compared with nonbinge alcohol drinkers. The findings are organized with the goals of providing a useful binge-drinking definition in the context of the empirical results. Theoretical implications are discussed on how binge drinking may alter neurophysiological and neurocognitive function.

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Binge drinking in young adults: Data, definitions, and determinants.

Centers for Disease Control and Prevention(CDC)での生活

Numerous mechanisms likely contribute to the damaging effects of prenatal alcohol exposure on the developing fetus and particularly the developing central nervous system (CNS). The coexistence of a multitude of mechanisms that may act simultaneously or consecutively and differ among various cell types poses particular challenges to researchers. To study alcohol's effects on the fetus more easily, investigators have used animal models and tissue-culture experiments. Such approaches have identified numerous potential mechanisms through which alcohol acts on the fetus, many of which result in cell death by necrosis or apoptosis. Among these mechanisms are increased oxidative stress, damage to the mitochondria, interference with the activity of growth factors, effects on glia cells, impaired development and function of chemical messenger systems involved in neuronal communication, changes in the transport and uptake of the sugar glucose, effects on cell adhesion, and changes in the regulation of gene activity during development.

Mechanisms of alcohol-induced damage to the developing nervous system

Hepatic fibrosis is a wound healing response to insults and as such affects the entire world population. In industrialized countries, the main causes of liver fibrosis include alcohol abuse, chronic hepatitis virus infection and non-alcoholic steatohepatitis. A central event in liver fibrosis is the activation of hepatic stellate cells, which is triggered by a plethora of signaling pathways. Liver fibrosis can progress into more severe stages, known as cirrhosis, when liver acini are substituted by nodules, and further to hepatocellular carcinoma. Considerable efforts are currently devoted to liver fibrosis research, not only with the goal of further elucidating the molecular mechanisms that drive this disease, but equally in view of establishing effective diagnostic and therapeutic strategies. The present paper provides a state-of-the-art overview of in vivo and in vitro models used in the field of experimental liver fibrosis research.

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Experimental models of liver fibrosis

Guidelines for the care and use of mammals in neuroscience and behavioral research

Since the identification of Fetal Alcohol Syndrome over 40 years ago, much has been learned about the detrimental effects of prenatal alcohol exposure on the developing brain. This review highlights recent neuroimaging studies, within the context of previous work. Structural magnetic resonance imaging has described morphological differences in the brain and their relationships to cognitive deficits and measures of facial dysmorphology. Diffusion tensor imaging has elaborated on the relationship between white matter microstructure and behavior. Atypical neuromaturation across childhood and adolescence has been observed in longitudinal neuroimaging studies. Functional imaging has revealed differences in neural activation patterns underlying sensory processing, cognition and behavioral deficits. A recent functional connectivity analysis demonstrates reductions in global network efficiency. Despite this progress much remains unknown about the impact of prenatal alcohol exposure on the brain, and continued research efforts are essential.

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Fetal Alcohol Spectrum Disorders: Recent Neuroimaging Findings.

The GABAB agonist baclofen has been shown to alter ethanol intake in human and animal studies (E. M. Moore et al., 2007). GABA-subB receptors are located within the ventral tegmental area (VTA; A. Imperato & G. DiChiara, 1986) and therefore may be involved in modulating voluntary ethanol intake. The present study assessed the effects of baclofen in a variation on a new mouse model of binge-like ethanol intake that takes advantage of the nocturnal nature of this species (J. S. Rhodes, K. Best, J. K. Belknap, D. A. Finn, & J. C. Crabbe, 2005; J. S. Rhodes et al., 2007). Baclofen or saline was microinjected into the anterior or posterior VTA of male C57BL/6J mice. Immediately afterward, mice were presented with ethanol, water, or sugar water using the Drinking in the Dark model, a procedure of fluid administration for 2 hr, 3 hr into the dark cycle). Fluid intake was recorded at 30, 60, 90, and 120 min; retro-orbital sinus bloods were sampled upon termination of the 120-min ethanol access period. Baclofen reduced binge-like ethanol intake when microinjected into the anterior VTA, whereas posterior VTA microinjections did not alter ethanol intake. Baclofen had no effect on water or sugar water intake when administered to anterior or posterior VTA. These results add to the growing literature suggesting that GABA-subB receptor systems are important in the modulation of binge-like ethanol intake and suggest that the GABA-subB receptor system may have different roles in anterior versus posterior VTA.

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Site-specific microinjection of baclofen into the anterior ventral tegmental area reduces binge-like ethanol intake in male C57BL/6J mice.

Prenatal alcohol exposure can cause a number of physical, behavioral, cognitive, and neural impairments, collectively known as fetal alcohol spectrum disorders (FASD). This article examines basic research that has been or could be translated into practical applications for the diagnosis or treatment of FASD. Diagnosing FASD continues to be a challenge, but advances are being made at both basic science and clinical levels. These include identification of biomarkers, recognition of subtle facial characteristics of exposure, and examination of the relation between face, brain, and behavior. Basic research also is pointing toward potential new interventions for FASD involving pharmacotherapies, nutritional therapies, and exercise interventions. Although researchers have assessed the majority of these treatments in animal models of FASD, a limited number of recent clinical studies exist. An assessment of this literature suggests that targeted interventions can improve some impairments resulting from developmental alcohol exposure. However, combining interventions may prove more efficacious. Ultimately, advances in basic and clinical sciences may translate to clinical care, improving both diagnosis and treatment.

Advances in Diagnosis and Treatment of Fetal Alcohol Spectrum Disorders: From Animal Models to Human Studies

GABA receptor systems have long been implicated in alcoholism, and GABAergic drugs have demonstrated efficacy in altering alcohol intake in some rodent models. The present study was designed to assess the effects of baclofen, muscimol, and gaboxadol (THIP) in a variation on a new mouse model of binge-like ethanol intake. Three hours into their dark cycle, male and female C57BL/6J mice were given access to a 20% unsweetened ethanol solution for 2 h each day, for four days. On day five, mice received varying doses of baclofen, muscimol or THIP and were allowed access to 20% ethanol for 60 min. Baclofen dose-dependently increased binge-like ethanol intake, while both muscimol and THIP reduced ethanol intake. Subsequent studies testing the effect of baclofen, muscimol and THIP on water intake using the same procedure revealed that whereas baclofen had no significant effect, muscimol and THIP both reduced the measure. These results add to the growing literature suggesting a role for GABA receptor systems in the modulation of ethanol intake. However, whereas the role of GABAB receptor systems seems selective in the modulation of binge-like ethanol intake, the role for GABAA receptor systems appears to also extend to general fluid intake.

GABAergic modulation of binge-like ethanol intake in C57BL/6J mice

Alcohol (ethanol) use often begins during the teenage years, a sensitive period during which a number of neurobiological, hormonal, and behavioral changes occur. A recent survey suggests that approximately 26% of high school seniors have had 5 or more drinks in a row (i.e., have engaged in binge drinking) during the previous 2 weeks (Johnston et al., 2008). Moreover, clinical reports indicate that adolescents frequently exhibit the symptoms of alcohol dependence. For example, some adolescents have difficulty controlling their alcohol intake and display signs of tolerance (Hawkins et al., 1997; Spear, 2000; Stewart and Brown, 1995). Such alcohol use during adolescence may have profound effects on brain development maturation, and may even influence the propensity to use the drug in later life.

The development of useful animal models is crucial if we are to understand the complex interaction between alcohol sensitivity and the neurobiological changes that occur during the period of adolescence. Although human adolescents undergo developmental changes unparalleled in lower organisms, other mammalian species (including rodents) also experience a developmental period similar to adolescence (Spear, 2000). In rats and mice, the term “adolescence” is used to describe animals aged from weaning (P21) to adulthood (P60); animals that are no longer infants, but that are not yet adults (Laviola et al., 2003). The period of adolescence has also been subdivided into more discrete intervals described as early (P21–34), middle (P34–46), and late (P46–59) adolescence (Spear, 2000). Adolescent rodents model many of the behaviors believed to be hallmarks of human adolescence, including elevated levels of social play and affiliative behaviors (Meaney and Stewart, 1981; Panksepp, 1981). These behaviors peak at P32 and display an ontogenetic shift toward more aggressive and competitive behaviors, including the establishment of dominant and subordinate relationships (Terranova et al., 1993, 1998).

A number of studies have demonstrated that adolescent rats also exhibit altered behavioral sensitivity to ethanol. Adolescent rats have been documented to display reduced sensitivity to the sedative/hypnotic (Little et al., 1996; Silveri and Spear, 1998; Silveri and Spear, 1999), motor impairing (White et al., 2002), hypothermic (Silveri and Spear, 2000), and anxiolytic (Varlinskaya and Spear, 2002) effects of ethanol. Adolescent rats have demonstrated increased sensitivity to still other ethanol-related behavioral traits. Adolescent rats are more sensitive to the amnestic (Markwiese et al., 1998) and social faciliatory (Varlinskaya and Spear, 2002) actions of ethanol. Moreover, recent evidence suggests that adolescent rats may develop greater acute (within session) ethanol tolerance (Silveri and Spear, 1998; Varlinskaya and Spear, 2006), and consume greater amounts of ethanol (Doremus et al., 2005; Maldonado et al., 2008; Vetter et al., 2007), compared to their adult counterparts. Taken together, the above evidence indicates that rodents might provide a powerful model system for investigating the neurobiological underpinnings of ethanol’s actions during the critical developmental period of adolescence.

Although much is known about the behavioral actions of ethanol in adolescent rats, little work has been done in adolescent mice despite the fact that mice have been one of the most widely used animal models in ethanol research for decades. For example, the adult members of the C57BL/6J (B6) and DBA/2J (D2) inbred mouse strains have been shown to differ widely in ethanol behavioral sensitivity; B6 animals readily consume more ethanol using 2-bottle choice procedures (McClearn and Rodgers, 1959) and are less sensitive to ethanol’s locomotor stimulant (Phillips et al., 1994), hangover (Metten and Crabbe, 1994), and reinforcing actions (Cunningham et al., 1992). Because the ethanol behavioral sensitivities of adult B6 and D2 mice are so extensively characterized, examination of adolescent sensitivity in these strains may provide a useful picture of how ethanol behavioral sensitivity during adolescence relates to that of adulthood.

Several recent studies reported that B6 mice will drink significant amounts of a 20% ethanol solution if it is presented from 2 to 4 hours, 3 hours into the dark cycle (Moore et al., 2007; Rhodes et al., 2005, 2006). Called Drinking in the Dark (DID), B6 mice consume large amounts of ethanol (4 to 8 g ethanol kg body weight), often reaching blood ethanol concentrations of 100 mg ethanol/dl plasma, or greater. Blood ethanol concentrations are physiologically relevant, producing significant motor incoordination on the rotarod (Rhodes et al., 2006) and balance beam motor tasks (Moore et al., 2007; Rhodes et al., 2006). However, the mice are not water deprived at any time except during the ethanol access period and are therefore not “artificially” motivated to drink the ethanol solution, and lengthy periods of sucrose-fading or ethanol concentration ramping are not required. This gives the model an advantage over classical 2-bottle choice tests when attempting to assess ethanol intake during the relatively short period of adolescence in mice.

Interestingly, DID appears to mimic the kind of binge-type ethanol intake that is characteristic of ethanol intake in human adolescents. Indeed, binge drinking, consumption of ≥5 drinks during a single occasion with blood ethanol concentrations reaching 80 mg/dl (NIAAA National Advisory Council, 2004) accounted for an estimated 56% of drinking among youth aged 12 to 17 years old in 2003, and this estimate increased to 69% in adolescents aged 18 years old and older (Miller et al., 2008). Thus, use of DID to investigate ethanol intake among adolescent mice may provide a more valid approach to investigating whether adolescents do indeed consume more ethanol than their adult counterparts. In the current study, we assess ethanol intake in adolescent and adult B6 and D2 mice using DID procedures. We show that consistent with the literature, B6 adults exhibit greater ethanol intake compared to D2 adults. We also show that although adolescent mice consume more ethanol than their adult counterparts, and that such adolescent ethanol exposure increases ethanol intake in adulthood, both effects depend on genotype.

Adolescent C57BL/6J (but not DBA/2J) Mice Consume Greater Amounts of Limited-Access Ethanol Compared to Adults and Display Continued Elevated Ethanol Intake into Adulthood

Eileen M. Moore

Papers

Fetal Alcohol Spectrum Disorders: Recent Neuroimaging Findings.

Site-specific microinjection of baclofen into the anterior ventral tegmental area reduces binge-like ethanol intake in male C57BL/6J mice.

Advances in Diagnosis and Treatment of Fetal Alcohol Spectrum Disorders: From Animal Models to Human Studies

GABAergic modulation of binge-like ethanol intake in C57BL/6J mice

Adolescent C57BL/6J (but not DBA/2J) Mice Consume Greater Amounts of Limited-Access Ethanol Compared to Adults and Display Continued Elevated Ethanol Intake into Adulthood