Printer Friendly

Translational studies of alcoholism: bridging the gap.

What currently is known about alcohol's effects on the brain has benefited from translational research-the parallel study of humans with alcohol dependence and of animal models that mimic targeted aspects of this complex disease. Human studies provide a full depiction of the consequences of chronic alcohol exposure, but they are limited by ethical considerations for experimentation of rigorous controls of relevant variables. Animal models, on the other hand, can distinguish components of the addiction processes but cannot fully represent the human condition.

In humans, 40 to 60 percent of the risk for alcoholism can be attributed to genetic factors. These genetic factors interact with environmental factors (e.g., early-life stress, family structure, peer pressure, or the social environment; McKenzie et al. 2005) to influence an individual's vulnerability to alcohol problems (Prescott and Kendler 1999). The genetic component has been modeled by breeding animal strains (predominantly rats and mice) with a high preference for alcohol (e.g., the alcohol preferring [P] and nonpreferring [NP] rats, high-alcohol-drinking [HAD] and low-alcohol-drinking [LAD] rats, the high-alcohol-preferring [HAP] mouse, and C57 black mice). The environment also has been modeled, for example, by separating young monkeys from their mothers, which reproduces early-life stress (Barr et al. 2004).

The last quarter century has seen a plethora of technologies capable of exploring the human animal in vivo, and many have been applied to alcohol-related research. Currently available noninvasive human technologies (reviewed elsewhere in this two-part series) include electroencephalogram (EEG) (Rangaswamy and Porjesz, pp. 238-242), functional magnetic resonance imaging (WRI) (Nagel and Kroenke, pp. 243-246; Rosenbloom and Pfefferbaum, Part 2), magnetic resonance spectroscopy (MR spectroscopy) (Nagel and Kroenke, pp. 243-246), single- photon emission computed tomography (SPECT) (e.g., Abi-Dargham et al. 1998), and positron emission tomography (PET) (Thanos et al., pp. 233-237). Further investigation of alcohol's effects at the cellular (e.g., He and Crews 2008; Tupala and Tiihonen 2004), molecular (e.g., Alexander-Kaufinan et al. 2007), and genetic (e.g., Dodd et al. 2006; Saba et al., pp. 272-274) levels is made possible by carefully screened human postmortem brain tissue (Harper et al. 2003x).

Even with these new technologies, animal models continue to have a vital role, enabling researchers to better interpret the implications of new findings. Moreover, the wide variation (or heterogeneity) of alcoholic populations examined with respect to genetic predisposition, age of onset, pattern of drinking, frequency of withdrawals, length of sobriety, nutritional, and hepatic status has hampered researchers' attempts to isolate only those specific brain regions affected by alcohol per se. This heterogeneity, and the complexity that it introduces, makes it difficult to thoroughly characterize the disorder (see Oscar-Berman 2000). Animal models, in contrast to the indefinite natural course of alcohol use in humans, allow researchers to determine alcohol toxicity in a way that allows them to control for multiple genetic, environmental, and alcohol consumption factors.

Alcohol dependence is defined in the Diagnostic and Statistical Manual, Fourth Edition (DSM-IV) as the pres ence of three of a total of seven possible criteria within a 12-month period (figure IA; American Psychiatric Association 1994). The diagnosis of alcohol abuse with DSM-IV criteria has helped standardize the classification of alcoholics, both across national and international research facilities and time (Harper et al. 2003b).

In modeling alcoholism, a series of conditions that attempt to parallel DSM-IV criteria have been estab lished (figure 113; Cicero et al. 1971). Of the currently available animal models, the monkey (e.g., Macaca fascicularis) and the P rat best fulfill these criteria. The nonhuman primate is particularly suitable, as it has genetic, neuroanatomical, behavioral, and social similarities with humans (Premack 2007). Furthermore, in contrast to other species (notably the wild-type rat), monkeys will self-administer alcohol (Grant et al. 2008). The P rat was developed from a Wistar foundational stock in Indiana and is in its 65th generation for selection of alcohol preference. The P rat is well-characterized behaviorally and neurobio logically (Li et al. 1993; McBride and Li 1998) and satisfies the criteria proposed as essential for an animal model of alcoholism (Cicero et al. 1971).

The goal of this review is to identify key findings in humans, highlighting current theories regarding the brain systems involved in alcoholism, and to examine the currently available animal models of alcoholism within the context of those theories. What should emerge is that (1) human studies are necessary to identify and classify the brain systems predisposing individuals to develop alcohol use disorders and those modified by alcohol; (2) animal models of alcoholism are essential for a mechanistic understanding of how chronic voluntary alcohol consumption becomes compulsive, how brain systems become damaged, and how damage resolves; and (3) human studies then must create methods for testing target mechanisms of alcohol dependency identified in rigorous animal studies.


Neurobiological theories of alcoholism offer a framework from which to develop, design, and test hypothesis-driven experiments in human alcoholics and animal models of alcoholism. Here, we present exemplary theories derived from these studies. These theories involve mechanisms of disinhibition, reward, habit formation, stress, and inflammation and have implications for recovery. Findings from animal models that have either helped in the development or aided in the support of these theories as they inform our understanding of the mechanisms of human alcoholism are highlighted (see chapter 9; Koob and Le Moal 2006).


About one-half to two-thirds of alcohol-dependent individuals develop mild-to-moderate deficits in complex cognitive and motor processes. The skills typically affected are related to executive func tioning, a multicomponent, higher-order cognitive construct involved in the self-regulation of goal-directed behavior. Deficits in executive functioning are associated with tasks related to working memory, problem solving, temporal ordering, and response inhibition (see Fein et al. 1990; Oscar-Berman and Marinkovic 2007 for reviews of behaviors modified by alcoholism; Sullivan et al. 2000b).


The class of behaviors associated with executive dysfunction has a common psychological mechanism disinhibition, which describes the behavior of individuals who exhibit a limited capacity to edit or manage their immediate impulsive response to a situation or are poorly motivated to do so (e.g., DSM-IV criteria 3, inability to control alcohol use, Fein et al. 1990; Finn et al. 1992; Oscar-Berman and Hunter 1993; Parsons 1993; Sinha et al. 1989; Sullivan et al. 2003). Alcoholics lacking impulse control also tend to exhibit novelty-seeking, aggressive, and antisocial behaviors and are sometimes referred to as type II alcoholics (Cloninger et al. 1985). When monkeys are separated from their mothers at birth for 6 months, they demonstrate behaviors such as infrequent social interactions, less competent social behaviors, and higher alcohol consumption rates compared with their mother-reared peers (Higley et al. 1996). These behaviors generally are consistent with the type II alcoholic personality. In rodents, disinhibition has been quantified using the plus-maze test, which draws on the animals' aversion to open areas and their desire to explore novel environments. Mice administered alcohol spend more time in open areas than mice not exposed (Durcan and Lister 1988). Heightened exploration of novel environments is evidence of disinhibition.

Executive dysfunction is associated with damage to the dorsolateral prefrontal cortex and its subcortical connections, whereas disinhibited behavior is linked to the orbitofrontal cortex and its circuitry (Cummings 1995) (figure 2).

Postmortem examination of brain tissue of human alcoholics without co-occurring complications that could alter results demonstrates a decreased number of neurons in the superior frontal cortex compared with control subjects (Kril et al. 1997). Furthermore, deficits in regional tissue volume, especially prevalent in the prefrontal cortex of similar alcoholics (Pfefferbaum et al. 1992), have been quantified using various anatomical MRI methods (reviewed by Adalsteinsson et al. 2002; Sullivan and Pfefferbaum 2008). However, little evidence exists that shows frontal tissue damage in animal models of alcoholism. For example, postmortem evaluation of the canine brain after 1 year of alcohol exposure did not reveal statistically significant differences in frontal cortical thickness or neuron population compared with unexposed animals (Hansen et al. 1991). In the rat, neuronal damage has been observed in several cortical regions (e.g., entorhinal, insular, piriform, and perirhinal cortices) after administration of alcohol in a pattern reflective of binge drinking (i.e., delivery of alcohol three times daily for 4 days; Collins et al. 1996), but neuronal loss in the frontal association cortex has been reported only when the alcohol exposure protocol included bouts of thiamine deficiency (Kril and Homewood 1993).

In summary, alcoholics appear to have either innate or acquired behaviors characterized psychologically as disinhibition, and this characteristic is shared by monkeys and rodents exposed to alcohol. However, only humans show evidence of tissue shrinkage as well as atrophy in prefrontal cortical regions as a consequence of chronic alcohol exposure. Despite the absence of evidence for prefrontal damage in animal models of alcoholism, they have been indispensable in helping to distinguish the mechanisms underlying alcohol's effects on these prefrontal regions.

The prefrontal cortex is fundamentally composed of functional modules of excitatory pyramidal projection neurons and inhibitory ([gamma]-aminobutyric acid [DABA]) interneurons. The processing of information within these local circuits is critically dependent on GABA acting on GAB[A.sub.A] receptors (Krimer and Goldman-Rakic 2001; Ticku and Mehta 1990); (figure 3). A feline model was the first to provide evidence that alcohol modifies GAB[A.sub.A] receptor function. Using extracellular single-unit recordings in the precruciate cortex of anesthetized cats, it was found that alcohol (given at doses associated with human intoxication) rapidly and reversibly enhanced GAB[A.sub.A] and its receptor activity, thus creating an overall inhibitory effect. This enhancement was specific to GABA, as the effect was not observed with glycine, dopamine, or serotonin (Nestoros 1980).

Human electrophysiology research also contributed to discerning the role GABA plays in response to alcohol exposure. The [beta] wave, typically observed in normal waking consciousness, describes brain activity greater than 12 Hz that arises from frontal brain regions and is generated by inhibitory interneurons (Whittington et al. 2000). The [beta] wave is accentuated and rhythmic in the resting EEG of alcoholics and children of alcoholics (Porjesz and Rangaswamy 2007). Collaborative Studies on the Genetics of Alcoholism (COGA) researchers recently identified a significant linkage between the [beta] wave and a GAB[A.sub.A] receptor gene in alcoholic individuals (Porjesz et al. 2002). Taken together, these findings have led to the hypothesis that subtle alterations in the structure or function of GAB[A.sub.A] receptors may disrupt local cortical processing and information the cortex relays to other brain regions, thereby contributing to the deficits in executive function seen in alcoholism (Agrawal et al. 2006). More research is needed to determine whether altered GAB[A.sub.A] receptors in the prefrontal cortex underlie the deficits in executive control of behavior observed in alcoholics. Nevertheless, the associations between a GAB[A.sub.A] receptor variant, the [beta] wave, and disinhibited behavior in alcoholics clearly demonstrates the unique relationship between the brain's structure and function, and animal models have been vital in helping to better understand this relationship.

Limitations of Animal Models of Disinhibition. The nonhuman primate is an especially appropriate model for studying disinhibition at the behavioral and frontal brain level because the size of the monkey's cerebral cortex is similar to that seen in humans (Grant and Bennett 2003). Other animal models, however, do not correspond as well.

For example, postmortem studies in rats suggest that the distributions of GAB[A.sub.A] receptors differs from that of humans (Richards et al. 1987). This could have significant implications. A distinct distribution of receptors or differing subunit expression across species could lead to variations in the brain's function at the molecular, cellular, and electrophysiological levels. For example, the P300, the most robust feature of event-related potentials (i.e., electrophysiological responses to stimuli with characteristic waveforms) (see Rangaswamy and Porjesz, pp. 238-242), manifested in response to unpredictable stimuli (Kaufmann et al. 1982) and emanating partially from the frontal cortex, is reduced in alcoholics (Begleiter et al. 1984; Johnson et al. 1984; Polich et al. 1994). Yet, in a recently developed mouse model of high alcohol consumption, the high-alcohol-preferring animals had an increased P3 latency when compared with the low-alcohol-preferring mice (Slawecki et al. 2003).


Frontocerebellar Circuitry

Despite evidence for compromised executive function and volume deficits in the frontal lobes of alcoholics, few instances have shown that frontal abnormalities predict impaired executive function (Adams et al. 1995; Cardenas et al. 2007; Dao-Castellana et al. 1998; Rosse et al. 1997). This has spawned theories that there must be alternative or additional areas of brain disruption associated with alcoholism.

In one study, dogs that were given alcohol at levels which mimicked intoxication in humans (i.e., the dogs achieved a blood alcohol level [BAL] of 231 [+ or -] 18 mg/dl) showed a general decline in brain blood flow measured with tracer microspheres. The decline was most marked and persistent in the cerebellum (Friedman et al. 1984), an area of the brain that is particularly vulnerable to damage from excessive alcohol exposure. Indeed, postmortem studies support this finding, showing neuronal loss (Baker et al. 1999; Harper 1998; Phillips et al. 1987; Torvik and Torp 1986) and cellular dysmorphology (Andersen 2004; Victor et al. 1959) in the cerebellum of alcoholics. MRI also reveals significant volume deficits of the cerebellum of alcoholics that are especially profound in the anterior superior vermis (Andersen 2004; Sullivan et al. 2000x). These findings also are evident in animal models. Lower neuronal counts (Tavares and Paula-Barbosa 1982) and cellular dysmorphology (Dlugos and Pentney 1997; Pentney et al. 1989) have been observed in the cerebellum of the rat brain chronically exposed to alcohol. MRI of the P rat with moderate BALs of 125 mg/dl also demonstrated modifications in the cerebellum (Pfefferbaum et al. 2006x).

The importance of these findings is far-reaching. The cerebellum now is recognized to contribute significantly to functions classically associated with the frontal lobes, including verbal associative learning, word production, problem solving, cognitive planning, attentional set shifting, and working memory (Courchesne et al. 1994; Schmahmann 2000). Our updated understanding of cerebellar function has been supported by anatomical evidence in the monkey (Cebos apella) that cerebellar projections extend as far as area 46 (roughly corresponding with the dorsolateral prefrontal cortex, Kelly and Strick 2003; figure 4), suggesting the presence of a pathway whereby the cerebellum may access executive functions.


In alcoholics, certain regions of cerebellar volume shrinkage are better predictors of executive impairment than frontal lobe volumes (Sullivan et al. 2003). Still, the relationship between the degree of cerebellar damage and cognitive functioning in alcoholics has not been unequivocally established (Davila et al. 1994; Johnson-Greene et al. 1997), and the theory that frontocerebellar degradation contributes to the cognitive sequelae of alcoholism warrants further investigation (Fitzpatrick et al. 2008).

Limitations of Animal Models of Frontocerebellar Circuitry. As with other brain structures, the cerebellum as a whole is disproportionately enlarged in humans and nonhuman primates compared with lower species (Semendeferi and Damasio 2000; Sultan and Braitenberg 1993), and its volume of white matter is exponentially greater in more (phylogenetically) recent species (Bush and Allman 2003). The organization of cerebellar inputs from the cortex via the pons (i.e., mossy fibers) is significantly different in humans than in rats (Paula-Barbosa and Sobrinho-Simoes 1976). Cerebellar activation of cortical regions also has been shown to differ among the rat, cat, and monkey (Tolbert et al. 1978; Yamamoto et al. 2004). In addition, the GAB[A.sub.A] receptor distribution in the cerebellum has been found to be different between humans and rats (Kume and Albin 1994). The distribution of dopamine receptors in the cerebellum also differs between the mouse, rat, guinea pig, cat, and monkey (Camps et al. 1990). Finally, the pattern of cerebellar pathology in response to alcohol in rodents is markedly different from that observed in humans (Tavares et al. 1987). Such ubiquitous evidence for structural differences in the cerebellum among various species has implications for function and suggests that the study of frontocerebellar circuitry disruption in alcoholism may be difficult in animal models.


One of the original theories of alcohol abuse was that alcohol is consumed for its rewarding (e.g., antianxiety) properties. A reward reinforces behavior; positive reinforcement describes a situation in which a rewarding stimulus (i.e., alcohol) increases the probability of (and motivation for) an appetitive instrumental response (i.e., alcohol seeking; discussed in this issue and in Part 2).

A large body of research on alcohol addiction has focused on the mesolimbic dopaminergic system (e.g., Brodie et al. 1990), with dopamine neurons in the ventral tegmental area (VTA) and their targets in the ventral striatum (i.e., nucleus accumbens) playing a key role in this circuitry inextricably linked to the concept of reward (figure 5, left panel).

An increase in dopamine release in the nucleus accumbens is associated with the presence of a rewarding stimulus such as food (Blum et al. 2000), but release may be three- to fivefold higher in response to alcohol, at least in acute stages (Di Chiara and Imperato 1988; Wise 2002). In humans, various methods have confirmed that key elements of the reward circuit are activated during initial alcohol use and the early binge/ intoxication stage. Long-term alcohol exposure reduces the volume of key basal ganglia structures, including the dorsolateral prefrontal cortex, insula, nucleus accumbens, and amygdala (Makris et al. 2008) (figure 5, right panel). In the P rat, 8 weeks of exposure to free-choice alcohol resulted in changes in basal ganglia structures (i.e., caudate, putamen, nucleus accumbens, globus pallidus, substantia nigra, and ventral tegmental area) (Sable et al. 2005).


Classically, a major impediment to the reward theory of alcoholism has been that unlike cocaine or amphetamine, agents that act directly on the dopamine transporter to increase dopamine release, no direct effect of alcohol on dopamine neurons could be demonstrated. Now, various results from animal studies have converged to provide a potential mechanism for alcohol-induced dopamine release. When R-opioid receptors in the VTA of wild-type Sprague-Dawley rats are activated, there is an increase in dopamine release (measured with in vivo microdialysis) in the nucleus accumbens (Spanagel et al. 1992). Indeed, V-opioid receptor activation hyperpolarizes (i.e., suppresses or inactivates) GABAergic interneurons in the VTA, thereby releasing dopaminergic neurons from spontaneous inhibition (Johnson and North 1992) and facilitating dopamine release (Di Chiara and North 1992; Margolis et al. 2003).

Increased dopamine release also has been measured using an electrophysiological technique known as patch-clamp recording. Studies using midbrain slices from the rat showed that alcohol, by activating V-opioid receptors localized on GABAergic interneurons of the VTA, inhibits GABAergic transmission, thereby facilitating dopamine cell firing and enhancing dopamine release in the nucleus accumbens (Xiao et al. 2007). This mechanism of action was further substantiated by evidence that alcohol- stimulated dopamine release is decreased in mice in which the [mu]-opioid receptor is genetically altered (or knocked out) (Job et al. 2007). This is particularly relevant to the human condition because researchers speculate that innate differences in dopamine neurotransmission may predispose individuals to excessive alcohol consumption (see Cowen and Lawrence 1999).

Limitations of Animal Models of Reward. Humans and rodents react differently to pharmacological agents that target dopamine receptors located both locally in the VTA and distally in the striatum and prefrontal cortex (Wood et al. 2006). Even within a species, strains may have different dopamine receptor binding properties and distributions (Yaroslavsky et al. 2006; Zamudio et al. 2005); more "effective" receptors may be associated with innate deficits in dopamine levels. The subregional topography of the dopamine transporter, responsible for dopamine uptake after its release, also has been shown to be inconsistent across species (e.g., rodent, monkey, and human) (Smith and Porrino 2008), a finding that also may have a significant impact on extracellular dopamine levels and innate responses to rewarding stimuli.

Habit Formation

At some point between initial exposure and dependence, the consumption of alcohol seems to proceed automatically, as a habitual response to antecedent stimuli. This transition may be the result of a complex interchange between executive and habit systems (Relish et al. 2008). Habitual drinking behavior becomes difficult to break using cognitive mechanisms because of an underperformance of executive systems (Jentsch and Taylor 1999), an overperformance of habit systems (Robbins and Everitt 1999), or because of an imbalance between the two systems (Bechara 2005).

Although not explored comprehensively, brain systems potentially contributing to habit formation include the striatum, cerebellum, amygdala, and, in limited conditions (e.g., trace conditioning; see below for more information), the hippocampus. Indeed, any system involved in "automatic" or implicit learning (i.e., learning without awareness) is fundamental for the establishment of habits (for reviews, Eichenbaum and Cohen 2001). Recent work in rodents has focused on the contribution of the corticostriatal network to habit formation. This work suggests that a switch occurs in the control of instrumental behavior so that the associative or medial striatum, important in the early, goal-directed stage of action, is overridden by the sensonmotor or lateral striatum at the later, more habitual stage (reviewed by Yin, Part 2). Furthermore, several types of classical conditioning/implicit learning paradigms, including eye-blink conditioning (McGlinchy-Berroth et al. 1994), visual discrimination learning (Rogers et al. 2000), and contextual cue discrimination learning (Greene et al. 2007), have been shown in both animal and human studies to be critically dependent on selective cerebellar sites.

The amygdala is another brain structure implicated in habit formation. It plays a role in emotional regulation and behavioral control (for review, see McBride 2002). It has been connected to a specific type of conditioned learning-Pavlovian fear conditioning (Volkow et al. 2002)in which a neutral conditioned stimulus is paired with a fear-inducing unconditioned stimulus, so that animals come to exhibit a conditioned fear response to the conditioned stimulus. Extensive evidence indicates that the basolateral amgydala is critical for experimental extinction of this acquired fear (Akirav and Maroun 2007).

Although there is support for (Alvarez et al. 1989) and against (Kril et al. 1997) neuronal loss in the amg dala of chronic alcoholics, several in vivo MRI studies provide evidence for volume deficits in the amygdala of abstinent, long-term chronic alcoholics (Fein et al. 2006; Makris et al. 2008). Furthermore, modifications of the GAB[A.sub.A] receptor in the basolateral amygdala have been reported in Cynomolgus macaques exposed to alcohol for 18 months (Anderson et al. 2007). How altered GABA receptor function, loss of neurons, or volume reductions in the amygdala contribute to the formation of an alcohol habit remains to be seen.

In another specific form of classical conditioning-termed trace conditioning-a silent period elapses between the occurrence of the conditioned stimulus and the delivery of the unconditioned stimulus (i.e., the conditioned stimulus and unconditioned stimulus are not paired at precisely the same moment, but rather, there is a silent period between the presentation of the conditioned stimulus and unconditioned stimulus).

Evidence from animal (Weible et al. 2006) and human (Cheng et al. 2008) research suggests that the hip pocampus plays a critical role during trace eye-blink conditioning. MRI provides in vivo evidence for volume deficits in the anterior hippocampus of chronic alcoholic individuals (Agartz et al. 1999; Sullivan et al. 1995). However, other than its effect on volume shrinkage, alcohol does not appear to have an effect on the number of hippocampal neurons, per se, as shown in studies using postmortem human hippocampal tissue (Harding et al. 1997; Kril et al. 1997). In contrast to the human condition, chronic exposure to alcohol in rodents induces a decrease in neuronal counts in CAI to CA4 regions of the hippocampus in female Sprague-Dawley (Bengoechea and Gonzalo 1991) and male Long-Evans (Walker et al. 1980) rats and a decrease in the number of pyramidal neurons in CAI and CA2 regions of the hippocampus of mice (Pawlak et al. 2002). Compared with humans, rodents have a disproportionately larger hippocampal volume, which may account for the notable differences in neuronal loss observed between humans and rodents. Nonetheless, modified hippocampal anatomy may contribute to impaired trace eye-blink conditioning in rats exposed to a binge-like patterns of alcohol in the early postnatal period (Tran et al. 2007) and in nonamnesic alcoholic individuals (McGlinchey et al. 2005).

In humans, both the striatum and the cerebellum have been shown to participate in the automatization process during the late learning stage of a repeated visuomotor sequence (Doyon et al. 1997) and of a sequence of finger movements (Doyon et al. 1998). Yet the collaborative contributions of the striatum, cerebellum, amygdala, and hippocampus to the formation of an alcohol consumption habit have yet to be demonstrated.


The hypothalamus, which controls consummatory behavior and basic drives related to food, water, sex, and temperature (Miller 1958), is a complex brain region with reciprocal connections to numerous structures, including the cortex, striatum, hippocampus, amygdala, cerebellum, and thalamus (Afifi and Bergman 1998). The paraventricular nucleus is located in the anterior division of the hypothalamus and includes magnocellular and parvocellular cells. Parvocellular cells are responsible for the release of the stress-associated hormone, corticoptropin-releasing factor (CRF), which regulates the secretion of the pituitary hormone, adrenocorticotropin. Adrenocorticotropin (also known as ACTH or corticoptropin), in turn, stimulates the adrenal gland to boost the synthesis of corticosteroid hormones (e.g., glucocorticoids such as cortisol and mineralocorticoids such as aldosterone) (Heimer 1995) (figure 6A).

Both acute and chronic alcohol consumption activate the hypothalamicpituitary-adrenal (HPA) axis, and chronic alcoholism is associated with low basal cortisol and blunted ACTH and cortisol responses to CRF (Adinoff et al. 1990). Disruption of the HPA axis following exposure to alcohol has been demonstrated in rodents (Rasmussen et al. 2000). In the Rhesus Macaque, a single-nucleotide polymorphism in the CRF gene (-2232 C>G) conferred a decreased sensitivity of the CRF promoter to corticosteroid regulation in vitro and was associated with lower levels of CRF in cerebrospinal fluid. Monkeys with this polymorphism tended to be more exploratory and exhibited increased alcohol consumption compared with the monkeys in which this single nucleotide was unmodified (Barr et al. 2008).

The link between the body's response to stress and alcohol is complex. One theory-the negative rein forcement theory-states that people continue to self-administer alcohol even after the rewarding effects of alcohol are blunted and when alcohol use causes adverse effects on lifestyle (DSM-IV criteria 6) or exacerbates psychological and physiological problems (DSM-IV criteria 7) in order to avoid the negative emotional states (e.g., stress) associated with withdrawal (see the article by Gilpin and Koob, pp. 185-195). The mechanisms behind this negative reinforcement are believed to involve an extensive extrahypothalamic CRF system centered on the extended amygdala (figure 6B).

Evidence for increased CRF activity in the extended amygdala, which may contribute to excessive alcohol consumption, has come from alcohol-dependent rats (i.e., rats exposed to alcohol vapor for 4 weeks, during which BALs reached -200 mg/dl). Dependent animals display a significant increase in self-administration of alcohol compared with baseline self-administration (Valdez et al. 2002). Injections of the CRF antagonist Dphe-CR[F.sub.12-41] into the central nucleus of the amygdala, but not the lateral bed nucleus of the stria terminalis or nucleus accumbens shell (figure 60 in alcohol-dependent animals, reduced alcohol self-administration (Funk et al. 2006). Because blocking CRF receptors reduced alcohol consumption, these results support the view that CRF in the central nucleus of the amygdala plays a role in mediating excessive alcohol consumption in dependent animals.

Although no studies to date have used dogs to explore the stress theory of alcohol abuse, the nervous pointer dog is a candidate for future research. Not all pointer dogs are nervous, but in those animals in which anxious behavior is noted, catecholamine alterations occur (Gurguis et al. 1990). Recent evidence has found that brainstem catecholamines, some of which are activated by stressors, may mediate HPA axis hyperactivity in alcoholism (Choi et al. 2008).

Limitations of Animal Models of Stress. CRF initializes the synthesis of corticosteroid hormones, which, in turn, act on glucocorticoid receptors in the brain. Glucocorticoid receptors act as nuclear transcription factors and contribute to the regulation of brain cell properties by modifying the transcription of responsive genes, and therefore, protein synthesis (de Kloet et al. 2005).

In adulthood there is high consistency across animal species in terms of the brain regions that express glu cocorticoid receptors, although the levels of expression can differ (e.g., rodents exhibit relatively high glucocorticoid receptor expression in the CAI-2 subfields of the hippocampus and primates exhibit relatively high glucocorticoid receptor expression in the neocortex) (Pryce 2008). Significantly, the relative densities of these receptors differ considerably during postnatal development, creating species-specific periods of critical vulnerability. For example, early life stress in a species that exhibits low glucocorticoid receptor expression in infancy could be less harmful than early life stress in a species that exhibits high glucocorticoid receptor expression, because there are fewer receptors to mediate the effects of elevated cortisol (Fuchs and Flugge 2002). These findings are relevant when modeling alcoholism in animals, especially in light of evidence that the onset of stress-related disorders is age dependent.


Inflammatory responses to alcohol may contribute to alcohol-related brain damage. Systemic cytokines (i.e., signalling proteins used extensively in cellular communication), particularly tumor necrosis factor-[alpha] (TNF[alpha]), may enter the brain to initiate inflammatory

processes (Qin et al. 2007). The brain's immune defense cells (i.e., microglia) respond by activating central proinflammatory cytokines (e.g., interleukin 1[beta] [ILI R] and TNF(x), which, in turn, can stimulate microglia to produce monocyte chemoattractant protein 1 (MCP-1, Qin et al. 2007). MCP-1 directly induces programmed cell death (i.e., neuronal apoptosis) (Kalehua et al. 2004). Thus, increased MCP-1 observed in brain tissue (VTA, substantia nigra, hippocampus, and amygdala) from alcoholics relative to control subjects (He and Crews 2008) could directly cause neuronal damage and thus could be one of the mechanisms contributing to alcohol-related neuronal loss and brain atrophy.


Various lines of evidence now support the contention that white matter in the brain is particularly sensitive to the damaging effects of alcohol. MR diffusion tensor imaging (DTI) in humans reveals abnormalities in the white matter subadjacent to frontal cortical regions (i.e., centrum semiovale) and the corpus callosum (Nagel and Kroenke, pp. 242-246; see also the article by Rosenbloom and Pfefferbaum, Part 2) and implicates deficits in both myelination and axonal integrity (Pfefferbaum et al. 2000, 2006b,c, Pfefferbaum and Sullivan 2002, 2005). Postmortem studies of brains of human alcoholics support the finding that white matter is especially affected (Badsberg-tensen and Pakkenberg 1993; De la Monte 1988; Harper and Kril 1991, 1994), and volume reductions, demyelination, loss of myelinated fibers, and axonal deletions also have been observed (Alling and Bostrom 1980; Harper et al. 1988; Harper and Kril 1989; Kril et al. 1997).

Consistent with these results are molecular studies of human brains which show that the expression of genes encoding myelin proteins (Lewohl et al. 2000; Mayfield et al. 2002) and the actual levels of myelin-associated proteins are decreased in people with alcoholic relatives compared with control cases without a family history of alcoholism (Hasin et al. 2006; Lewohl et al. 2005).

In dogs exposed to alcohol for 1 year, fewer glial cells were found in the temporal and frontal cortices compared with control animals (Hansen et al. 1991), suggesting a reduced capacity for myelin generation. In rats longitudinally exposed to alcohol, in vivo MRI revealed that alcohol significantly slowed corpus callosum growth compared with control animals (Pfefferbaum et al. 2006x), and postmortem analysis suggests that the corpus callosum is significantly thinner in the alcohol-exposed group compared with the control group (He et al. 2007).

In light of the evidence indicating that brain white matter is especially vulnerable to the damaging effects of alcohol, neuroinflammation appears to be a likely mechanism of harm to this constituent of the brain. MCP-1 is associated with demyelination in a variety of experimental animal models (Kim and Perlman 2005), and microglia can cause white matter damage via excitotoxicity (i.e., they can impair glutamate uptake by reducing the expression of glutamate transporters) (Mature et al. 2006, 2007).

Inflammation in the adult hippocampus may interfere with memory by inhibiting neurogenesis (Das and Basu 2008). In rats, binge-like exposure to alcohol is marked by local neuroinflammation, which inhibits hippocampal neurogenesis (Nixon and Crews 2002). Increases in TNFoc and MCP1 mRNA levels were observed in male C57BL/6J mice given alcohol intragastrically for 1 day. Ten daily doses of alcohol significantly elevated both mRNA and protein levels of TNFoc and MCP-1; however, neither a single dose nor 10 daily doses of alcohol inhibited neurogenesis in the hippocampus of these mice (Qin et al. 2008). Thus, a causal relationship between alcohol-induced neuroinflammation and alcohol-induced suppression of neurogenesis has yet to be established, and further work is required to demonstrate how prolonged elevations in brain cytokines may contribute to neuropathology.

Limitations of Animal Models of Inflammation. The neuroinflammation theory of alcohol-related neuronal loss and brain atrophy is relatively new. As a result, there have been few studies designed to specifically test the hypothesis. With respect to the effects of neuroinflammation on neurogenesis, major differences exist between the rat and mouse stem/ progenitor cells that are involved in neurogenesis (Ray and Gage 2006), which warrants caution when drawing inferences from one species to another.

Evidence for Recovery with Abstinence

From the earliest computed tomography (CT) studies to current MRI studies aimed at tracking evidence for brain structural recovery, there has been positive support for at least partial reversal of brain tissue shrinkage with abstinence from alcohol (CT studies: Cala et al. 1983; Carlen et al. 1984, 1986) (MRI studies: Cardenas et al. 2007; Pfefferbaum et al. 1995, 1998).

Indeed, alcoholic brain pathology can be subsumed under Carlen's two-component hypothesis (Carlen et al. 1984), one reflecting permanent change (i.e., irreversible neuronal cell death), notably in the superior frontal association cortex, and one reflecting a transient change, such as shrinkage without cell death, thereby permitting volume to change (up or down) without long-term damage. Indeed, the majority of shrinkage with drinking does not necessarily reflect "neuronal loss." Rather, the controlled longitudinal imaging studies demonstrating volume reductions likely reflect nonneuronal loss and neuronal cell body and process shrinkage. That brain volume can increase and that this increase predicts improvement in neuropsychological test performance (Cardenas et al. 2007; Rosenbloom et al. 2007; Sullivan et al. 2000b) supports the contention that little neuronal death occurs with alcoholism.

Animal Models of Recovery

In aged Fisher 344 rats, recovery after long-term treatment with alcohol was associated with a restoration of the total number of synapses on Purkinje neurons of the cerebellum lost during exposure (Dlugos and Pentney 1997). Furthermore, abstinence for 5 weeks indicated a twofold increase in new neurons formed in neurogenetic zones of abstinent animals compared with alcohol-naive animals (Nixon and Crews 2004). This increase in neurogenesis during abstinence from chronic alcohol exposure may be related to the recovery of brain volume deficits (Pfefferbaum et al. 1995) and cognitive deficits in abstinent alcoholics (Sullivan et al. 2000c).


Together, studies in humans and animal models provide support for the involvement of specific brain structures over the course of alcohol addiction. Researchers have identified genetic variants of key inhibitory receptors in the prefrontal cortex that may produce a heritable vulnerability to alcohol, perhaps accounting for the disinhibited personality type observed in certain alcoholics and which leads to a predisposition to develop alcoholism.


The prefrontal cortex and its complex circuitry with the basal ganglia also is likely involved in the acute reinforcing (or rewarding) effects of alcohol. Furthermore, modified prefrontal inhibitory receptors may contribute to dysregulation in other brain regions targeted by the prefrontal cortex, such as the cerebellum. The basal ganglia, cerebellum, amygdala, and hippocampus may collectively contribute to the formation of an alcohol habit. The HPA axis additionally has a role in the development of dependence, as well as the vulnerability to stress-induced relapse. Inflammatory cascades initiated by chronic alcohol consumption are a factor that may contribute to alcohol-induced neuropathology.

Each theory, linked to specific brain structures, has helped to describe the mechanisms associated with the transition from controlled drinking to compulsive consumption or dependence. The development of each theory depended critically on information acquired from animal models, whether they met all the criteria necessary for an animal model of alcoholism or not. Figure 7 is a simplified schematic of the brain structures modified by alcohol and illustrates reciprocal connections between basal ganglia, limbic structures (i.e., hippocampus and amygdala), and cerebellum, each driven by inputs from the cortex, with reciprocal connections to the cortex via the thalamus. Also illustrated are the reciprocal connections between basal ganglia, limbic structures, and cerebellum with the hypothalamus. Not illustrated but germane to the course of alcohol addiction are modifying aminergic (dopamine and norepinephrine), cholinergic, serotonergic, peptidergic, and hormonal influences on the various structures.

In moving forward, a challenge will be to develop a theory that accounts for the brain structures uniquely targeted by alcohol. Perhaps different neural circuits are important at different stages across the time course from first drink to dependence. Alternatively, differential involvement of these circuits across alcoholics could contribute to heterogeneity in brain regions affected. A theory that unifies the brain circuitries modified by alcohol may very well have a major impact on our understanding of brain function in general.


This work was supported by NIAAA grants AA010723 and AA017168.


The authors declare that they have no competing financial interests.


ABI-DARGHAM, A.; KRYSTAL, J.H.; ANILVEL, S.; ET AL. Alterations of benzodiazepine receptors in type II alcoholic subjects measured with SPECT and [1231]iomazenil. American Journal of Psychiatry 155:1550-1555, 1998. PMID: 9812116

ADALSTEINSSON, E.; SULUVAN, E.V.; AND PEEEEERBAUM, A. Biochemical, functional and microstructural magnetic resonance imaging (MRI). In Liu, Y., and Lovinger, D.M., Eds. Methods in Alcohol-Related Neuroscience Research. Boca Raton, FL: CRC Press, 2002, pp. 345-372.

ADAMS, K.M.; GILMAN, S.; KOEPPE, R.; ET AL. Correlation of neuropsychological function with cerebral metabolic rate in subdivisions of the frontal lobes of older alcoholic patients measured with [1sFlfluorodeoxyglucose and positron emission tomography. Neuropsychology 9:275-280, 1995.

ADINOFF, B.; MARTIN, P.R.; BONE, G.H.; ET AL. Hypothalamic-pituitary-adrenal axis functioning and cerebrospinal fluid corticotropin releasing hormone and corticotropin levels in alcoholics after recent and long-term abstinence. Archives of General Psychiatry 47:325-330, 1990. PMID: 2157379

AFIFI, AX, AND BERGMAN, R.A. Functional Neuroanatomy Text andAtlas. New York: McGraw-HILL, 1998.

AGARTZ, L; MOMENAN, R.; RAWLINGS, R.R.; ET AL. Hippocampal volume in patients with alcohol dependence. Archives of General Psychiatry 56:356-363, 1999. PMID: 10197833

AGRAWAL, A.; EDENBERG, H.J.; FOROUD, T.; ET AL. Association of GABRA2 with drug dependence in the collaborative study of the genetics of alcoholism sample. Behavior Genetics 36:640-650, 2006. PMID: 16622805

AKIRAV, L, AND MAROUN, M. The role of the medial prefrontal cortex-amygdala circuit in stress effects on the extinction of fear. Neural Plasticity 2007:30873, 2007. PMID: 17502909

ALEXANDER-KAUFMAN, K.; HARPER, C.; WILCE, P.; AND MATSUMOTO, I. Cerebellar vermis proteome of chronic alcoholic individuals. Alcoholism: Clinical and Experimental Research 31:1286-1296, 2007. PMID: 17561921

ALLING, C., AND BOSTROM, K. Demyelination of the mamillary bodies in alcoholism: A combined morphological and biochemical study. Acta Neuropathologica (Berl) 50:77-80, 1980. PMID: 6769291

ALVAREZ, L; GONZALO, L.M.; AND LLOR, J. Effects of chronic alcoholism on the amygdaloid complex: A study in human and rats. Histology and Histopathology 4:183-192, 1989. PMID: 2520455 American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorder 4th Edition (DSM--IV). Washington, DC: 228: American Psychiatric Association, 1994.

ANDERSEN, B.B. Reduction of Purkinje cell volume in cerebellum of alcoholics. Brain Research 1007:10-18, 2004. PMID: 15064131

ANDERSON, N.J.; DAUNAIS, J.B.; FRIEDMAN, D.P.; ET AL. Long-term ethanol self-administration by the nonhuman primate, Macaca fascicularis, decreases the benzodiazepine sensitivity of amygdala GABA(A) receptors. Alcoholism: Clinical and Experimental Research 31:1061-1070, 2007. PMID: 17428292

BADSBERG-JENSEN, G., AND PAKKENBERG, B. Do alcoholics drink their neurons away? Lancet 342:1201-1204,1993. PMID: 7901529

BAKER, K.G.; HARDING, A.J.; HALLIDAY, G.M.; ET AL. Neuronal loss in functional zones of the cerebellum of chronic alcoholics with and without Wernicke's encephalopathy. Neuroscience 91:429-438, 1999. PMID: 10366000

BARR, C.S.; DVOSKIN, R.L.; YUAN, Q.; ET AL. CRH haplotype as a factor influencing cerebrospinal fluid levels of corticotropin-releasing hormone, hypothalamic-pituitary-adrenal axis activity, temperament, and alcohol consumption in rhesus macaques. Archives of General Psychiatry 65:934-944, 2008. PMID: 18678798

BARR, C.S.; SCHWANDT, M.L.; NEWMAN, T.K.; AND HIGLEY, J.D. The use of adolescent nonhuman primates to model human alcohol intake: Neurobiological, genetic, and psychological variables. Annals of the New York Academy of Sciences 1021:221-233, 2004. PMID: 15251892

BECHARA, A. Decision making, impulse control and loss of willpower to resist drugs: A neurocognitive perspective. Nature Neuroscience 8:1458-1463, 2005. PMID: 16251988

BEGLEITER, H.; PORJESZ, B.; BIHARI, B.; AND KISSIN, B. Event-related brain potentials in boys at risk for alcoholism. Science 225:1493-1496, 1984. PMID: 6474187

BENGOECHEA, O., AND GONZALO, L.M. Effects of alcoholization on the rat hippocampus. Neuroscience Letters 123:112-114, 1991. PMID: 2062446

BLUM, K.; BRAVERMAN, E.R.; HOLDER, J.M.; ET AL. Reward deficiency syndrome: A biogenetic model for the diagnosis and treatment of impulsive, addictive, and compulsive behaviors. Journal of Psychoactive Drugs 32 (Suppl.):i-iv, 1-112, 2000. PMID: 11280926

BRODIE, M.S.; SHEFNER, S.A.; AND DUNWIDDIE, T.V. Ethanol increases the firing rate of dopamine neurons of the rat ventral tegmental area in vitro. Brain Research 508:65-69, 1990. PMID: 2337793 BUSH, E.C., AND ALLMAN, J.M. The scaling of white matter to gray matter in cerebellum and neocortex. Brain, Behavior and Evolution 61:1-5, 2003. PMID: 12626858

CALA, L.A.; JONES, B.; BURNS, P.; ET AL. Results of computerized tomography, psychometric testing and dietary studies in social drinkers, with emphasis on reversibility after abstinence. Medical journal of Australia 2:264-269, 1983. PMID: 6646037

CAMPS, M.; KELLY, P.H.; AND PALACIOS, J.M. Autoradiographic localization of dopamine D 1 and D 2 receptors in the brain of several mammalian species. Journal of Neural Transmission. General Section 80:105-127, 1990. PMID: 2138461

CARDENAS, V.A.; STUDHOLME, C.; GAZDZINSKI, S.; ET AL. Deformation-based morphometry of brain changes in alcohol dependence and abstinence. Neuroimage 34:879-887, 2007. PMID: 17127079

CARLEN, P.L.; WILKINSON, D.A.; WORTZMAN, G.; AND HOLGATE, R. Partially reversible cerebral atrophy and functional improvement in recently abstinent alcoholics. Canadian journal of Neurological Sciences 11:441-446, 1984. PMID: 6518426

CARLEN, P.L.; PENN, R.D.; FORNAZZARI, L.; ET AL. Computerized tomographic scan assessment of alcoholic brain damage and its potential reversibility. Alcoholism: Clinical and Experimental Research 10:226-232, 1986. PMID: 3526941

CHENG, D.T.; DISTERHOFT, J.F.; POWER, J.M.; ET AL. Neural substrates underlying human delay and trace eyeblink conditioning. Proceedings of the National Academy of Sciences of the United States of America 105:8108-8113, 2008. PMID: 18523017

CHOI, LY.; LEE, S.; AND RIVIER, C. Novel role of adrenergic neurons in the brain stem in mediating the hypothalamic-pituitary axis hyperactivity caused by prenatal alcohol exposure. Neuroscience 155: 888-901, 2008. PMID: 18588946

CICERO, T.J.; SNIDER, S.R.; PEREZ, V.J.; AND SWANSON, L.W. Physical dependence on and tolerance to alcohol in the rat. Physiology &Behavior 6:191-198,1971. PMID: 5166470

CLONINGER, C.R.; BOHMAN, M.; SIGVARDSSON, S.; AND VON KNORRING, A.L. Psychopathology in adopted-out children of alcoholics: The Stockholm Adoption Study. Recent Developments in Alcoholism 3:37-51, 1985. PMID: 3975456

COLLINS, M.A.; CORSO, T.D.; AND NEAFSEY, E.J. Neuronal degeneration in rat cerebrocortical and olfactory regions during subchronic "binge" intoxication with ethanol: Possible explanation for olfactory deficits in alcoholics. Alcoholism: Clinical and Experimental Research 20:284-292, 1996. PMID: 8730219

COURCHESNE, E.; TOWNSEND, J.; AKSHOOMOFF, N.A.; ET AL. Impairment in shifting attention in autistic and cerebellar patients. Behavioral Neuroscience 108:848-865, 1994. PMID: 7826509

COWEN, M.S., AND LAWRENCE, A.J. The role of opioid-dopamine interactions in the induction and maintenance of ethanol consumption. Progress in Neuro-Psychopharmacology &Biological Psychiatry 23:1171-1212,1999. PMID: 10581642

CUMMINGS, J.L. Anatomic and behavioral aspects of frontal-subcortical circuits. Annals of the New York Academy of Sciences 769:1-13, 1995. PMID: 8595019

DAO-CASTELLANA, M.H.; SAMSON, Y.; LEGAULT, F.; ET AL. Frontal dysfunction in neurologically normal chronic alcoholic subjects: Metabolic and neuropsychological findings. Psychological Medicine 28:1039-1048, 1998. PMID: 9794011

DAS, S., AND BASU, A. Inflammation: A new candidate in modulating adult neurogenesis. Journal of Neuroscience Research 86:1199-1208, 2008. PMID: 18058947

DAVILA, M.D.; SHEAR, P.K.; LANE, B.; ET AL. Mammillary body and cerebellar shrinkage in chronic alcoholics: An MRI and neuropsychological study. Neuropsychology 8:433-444, 1994.

DE KLOET, E.R.; JOELS, M.; AND HOLSBOER, F. Stress and the brain: From adaptation to disease. Nature Reviews. Neuroscience 6:463-4475, 2005. PMID: 15891777

DE LA MONTE, S.M. Disproportionate atrophy of cerebral white matter in chronic alcoholics. Archives ofNeurology 45:990-992, 1988. PMID: 3415529

DI CHIARA, G., AND IMPERATO, A. Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats. Proceedings of the National Academy of Sciences of the United States of America 85:5274-5278,1988. PMID: 2899326

DI CHIARA, G., AND NORTH, R.A. Neurobiology of opiate abuse. Trends in Pharmacological Sciences 13:185-193,1992. PMID: 1604711

DLUGOS, C.A., AND PENTNEY, R.J. Morphometric evidence that the total number of synapses on Purkinje neurons of old F344 rats is reduced after long-term ethanol treatment and restored to control levels after recovery. Alcohol &Alcoholism 32:161-172,1997. PMID: 9105510

DODD, P.R.; BUCKLEY, S.T.; ECKERT, AL.; ET AL. Genes and gene expression in the brains of human alcoholics. Annals of the New York Academy of Sciences 1074:104-115, 2006. PMID: 17105908

DOYON, J.; GAUDREAU, D.; LAFORCE, R., JR.; ET AL. Role of the striatum, cerebellum, and frontal lobes in the learning of a visuomotor sequence. Brain and Cognition 34:218-245, 1997. PMID: 9220087

DOYON, J.; LAFORCE, R., JR.; BOUCHARD, G.; ET AL. Role of the striatum, cerebellum and frontal lobes in the automatization of a repeated visuomotor sequence of movements. Neuropsychologia 36:625-641, 1998. PMID: 9723934

DURCAN, M.J., AND LISTER, R.G. Time course of ethanol's effects on locomotor activity, exploration and anxiety in mice. Psychopharmacology (Berl) 96:67-72,1988. PMID: 2906444

EICHENBAUM, H., AND COHEN, N.J. From Conditioning to Conscious Recollection. Oxford: Oxford University Press, 2001.

FEIN, G.; BACHMAN, L.; FISHER, S.; AND DAVENPORT, L. Cognitive impairments in abstinent alcoholics. Western Journal ofMedicine 152:531-537,1990. PMID: 2190421

FEIN, G.; LANDMAN, B.; FRAN, H.; ET AL. Brain atrophy in long-term abstinent alcoholics who demonstrate impairment on a simulated gambling task. Neuroimage 32:1465-1471, 2006. PMID: 16872844

FINN, P.R.; EARLEYWINE, M.; AND PIHL, R.O. Sensation seeking, stress reactivity, and alcohol dampening discriminate the density of a family history of alcoholism. Alcoholism: Clinical and Experimental Research 16:585-590, 1992. PMID: 1626660

FITZPATRICK, L.E.; JACKSON, M.; AND CROWE, S.F. The relationship between alcoholic cerebellar degeneration and cognitive and emotional functioning. Neuroscience and Biobehavioral Reviews 32:466-485, 2008. PMID: 17919727

FRIEDMAN, H.S.; LOwERY, R.; ARCHER, M.; ET AL. The effects of ethanol on brain blood flow in awake dogs. Journal of Cardiovascular Pharmacology 6:344-348, 1984. PMID: 6200726

FUCHS, E., AND FLUGGE, G. Social stress in tree shrews: Effects on physiology, brain function, and behavior of subordinate individuals. Pharmacology, Biochemistry, andBehavior 73:247-258, 2002. PMID: 12076743

FUNK, C.K.; O'DELL, L.E.; CRAWFORD, E.F.; AND KoOB, G.F. Corticotropin-releasing factor within the central nucleus of the amygdala mediates enhanced ethanol self-administration in withdrawn, ethanol-dependent rats. Journal of Neuroscience 26:11324-11332, 2006. PMID: 17079660

GRANT, K.A., AND BENNETT, A.J. Advances in nonhuman primate alcohol abuse and alcoholism research. Pharmacology & Therapeutics 100:235-255, 2003. PMID: 14652112

GRANT, K.A.; HELMS, C.M.; ROGERS, L.S.; AND PURDY, R.H. Neuroactive steroid stereo-specificity of ethanol-like discriminative stimulus effects in monkeys. Journal of Pharmacology and Experimental Therapeutics 326:354-361, 2008. PMID: 18436788

GREENE, A.J.; GROSS, W.L.; ELSINGER, C.L.; AND RAO, S.M. Hippocampal differentiation without recognition: An fMRI analysis of the contextual cueing task. Learning &Memory 14:548-553, 2007. PMID: 17690338

GURGUIS, G.N.; KLEIN, E.; MEFFORD, I.N.; AND UHDE, T.W. Biogenic amines distribution in the brain of nervous and normal pointer dogs: A genetic animal model of anxiety. Neuropsychopharmacology 3:297-303, 1990. PMID: 1698064

HANSEN, LA.; NATELSON, B.H.; LEMERE, C.; ET AL. Alcohol-induced brain changes in dogs. Archives of Neurolou 48:939-942, 1991. PMID: 1953418

HARDING, A.J.; WONG, A.; SVOBODA, M.; ET AL. Chronic alcohol consumption does not cause hippocampal neuron loss in humans. Hippocampus 7:78-87,1997. PMID: 9138671

HARDER, C. The neuropathology of alcohol-specific brain damage, or does alcohol damage the brain? Journal of Neuropathology and Experimental Neurology 57:101-110,1998. PMID: 9600202

HARDER, C., AND KRIL, J. Patterns of neuronal loss in the cerebral cortex in chronic alcoholic patients. Journal of the Neurological Sciences 92:81-89, 1989. PMID: 2769304

HARDER, C., AND KRIL, J. An introduction to alcohol-induced brain damage and its causes. Alcohol andAlcoholism (Suppl. 2):237-243,1994. PMID: 8974342

HARDER, C.; KRIL, J.; AND DALY, J. Does a "moderate" alcohol intake damage the brain? journal of Neurology, Neurosurgery, and Psychiatry 51:909913,1988. PMID: 3204399

HARDER, C., AND KRIL, J. If you drink your brain will shrink: Neuropathological considerations. Alcohol and Alcoholism (Suppl. 1):375-380, 1991. PMID: 1845566

HARDER, C.; DIXON, G.; SHEEDY, D.; AND GARRICK, T. Neuropathological alterations in alcoholic brains: Studies arising from the New South Wales Tissue Resource Centre. Progress in Neuro-Psychopharmacology and Biological Psychiatry 27:951-961, 2003a. PMID: 14499312

HARDER, C.; GARRICK, T.; MATSUMOTO, L; ET AL. How important are brain banks for alcohol research? Alcoholism: Clinical and Experimental Research 27:310-323, 2003b. PMID: 12605081

HASIN, D.S.; LIU, X.; ALDERSON, D.; AND GRANT, B.F. DSM-IV alcohol dependence: A categorical or dimensional phenotype? Psychological Medicine 36:1695-1705, 2006. PMID: 17038207

HE, J., AND CREWS, F.T. Increased MCP-1 and microglia in various regions of the human alcoholic brain. Experimental Neurology 210:349-358, 2008. PMID: 18190912

HE, X.; SULLIVAN, E.V.; STANKOVIC, R.K.; ET AL. Interaction of thiamine deficiency and voluntary alcohol consumption disrupts rat corpus callosum ultrastructure. Neuropsychopharmacology 32:2207-2216, 2007. PMID: 17299515

HEIMER, L. The Human Brain and Spinal Cord: Functional Neuroanatomy and Dissection Guide. New York: Springer-Verlag, 1995.

HIGLEY, J.D.; SUOMI, S.J.; AND LINNOILA, M. A nonhuman primate model of type II excessive alcohol consumption? Part 1. Low cerebrospinal fluid 5-hydroxyindoleacetic acid concentrations and diminished social competence correlate with excessive alcohol consumption. Alcoholism: Clinical and Experimental Research 20:629-642, 1996. PMID: 8800378

JENTSCH, J.D., AND TAYLOR, J.R. Impulsivity resulting from frontostriatal dysfunction in drug abuse: Implications for the control of behavior by reward-related stimuli. Psychopharmacology 146:373-390,1999. PMID: 10550488

JOB, M.O.; TANG, A.; HALL, F.S.; ET AL. Mu (tt) opicid receptor regulation of ethanol-induced dopamine response in the ventral striatum: Evidence of genotype specific sexual dimorphic epistasis. Biological Psychiatry 62:627-634, 2007. PMID: 17336938

JOHNSON, R.; PFEFFERBAUM, A.; HART, T.; AND KOPELL, B.S. P300 latency in chronic alcoholics and depressed patients: A preliminary report. In Karrer, R.; Cohen, J.; Tueting, P. Eds. Brain and Information: Event Related Potentials. New York: New York Academy of Science, 1984, pp. 585-591.

JOHNSON, S.W., AND NORTH, R.A. Opicids excite dopamine neurons by hyperpolarization of local interneurons. Journal of Neuroscience 12:483-4488, 1992. PMID: 1346804

JOHNSON-GREENE, D.; ADAMS, K.M.; GILMAN, S., ET AL. Impaired upper limb coordination in alcoholic cerebellar degeneration. Archives ofNeurology 54:436-439,1997. PMID: 9109745

KALEHUA, A.N.; NAGEL, J.E.; WHELCHEL, L.M.; ET AL. Monocyte chemoattractant protein-1 and macrophage inflammatory protein-2 are involved in both excitotoxin-induced neurodegeneration and regeneration. Experimental Cell Research 297:197-211, 2004. PMID: 15194436

KAUFMANN, F.; KAUFMANN, R.; AND SALAPATEK, P. The effect of change in a stimulus sequence on P300. Neuropsychologia 20:4391145, 1982. PMID: 7133381

KELLY, R.M., AND STRICK, P.L. Cerebellar loops with motor cortex and prefrontal cortex of a nonhuman primate. Journal of Neuroscience 23:8432-8444, 2003. PMID: 12968006

KIM, T.S., AND PERLMAN, S. Viral expression of CCL2 is sufficient to induce demyelination in RAG 1-/- mice infected with a neurotropic coronavirus. Journal of Virology 79:7113-7120, 2005. PMID: 15890951

KOOB, G.F., AND LE MOAL, M. Neurobiological theories of addiction. In: Neurobiology of Addiction. Oxford: Elsevier, 2006.

KRIL, J.J., AND HOMEWOOD, J. Neuronal changes in the cerebral cortex of the rat following alcohol treatment and thiamin, deficiency. Journal of Neuropathology and Experimental Neurology 52:586-593,1993. PMID: 8229077

KRIL, J.J.; HALLIDAY, G.M.; SVOBODA, M.D.; AND CARTWRIGHT, H. The cerebral cortex is damaged in chronic alcoholics. Neuroscience 79:983-998, 1997. PMID: 9219961

KRIMER, L.S., AND GOLDMAN-RAKIC, P.S. Prefrontal microcircuits: Membrane properties and excitatory input of local, medium, and wide arbor interneurons. Journal of Neuroscience 21:3788-3796, 2001. PMID: 11356867

KUME, A., AND ALBIN, R.L. Quantitative autoradiography of 4'-ethynyl-4-n-[2,3-3H2]propylbicycloorthobenzoate binding to the GABAA receptor complex. European Journal of Pharmacology 263:163-173, 1994. PMID: 7821348

LEWOHL, J.M.; WANG, L.; MILES, M.F.; ET AL. Gene expression in human alcoholism: Microarray analysis of frontal cortex. Alcoholism: Clinical and Experimental Research 24:1873-1882, 2000. PMID: 11141048

LEWOHL, J.M.; WIxEY, J.; HARPER, C.G.; AND DODD, P.R. Expression of MBP, PLP, MAG, CNP, and GFAP in the human alcoholic brain. Alcoholism: Clinical and Experimental Research 29:1698-1705, 2005. PMID: 16205370

LI, T.K.; LUMENG, L.; AND DOOLITTLE, D.P. Selective breeding for alcohol preference and associated responses. Behavior Genetics 23:163-170, 1993. PMID: 8099788

MAKRIS, N.; OSCAR-BERMAN, M.; JAFFIN, S.K.; ET AL. Decreased volume of the brain reward system in alcoholism. Biological Psychiatry 64:192-202, 2008. PMID: 18374900

MARGOLIS, E.B.; HIELMSTAD, G.O.; BoNCI, A.; AND FIELDS, H.L. Kappa-opioid agonists directly inhibit rnidbrain dopaminergic neurons. Journal of Neuroscience 23:9981-9986, 2003. PMID: 14602811

MATUTE, C.; ALBERDI, E.; DOMERCQ, M.; ET AL. Excitotoxic damage to white matter. Journal of Anatomy 210:693-702, 2007. PMID: 17504270

MATUTE, C.; DOMERCQ, M.; AND SANCHEZ-GOMEZ, M.V. Glutamate-mediated glial injury: Mechanisms and clinical importance. Glia 53:212-224, 2006. PMID: 16206168

MAYFIELD, R.D.; LEWOHL, J.M.; DODD, P.R.; ET AL. Patterns of gene expression are altered in the frontal and motor cortices of human alcoholics. Journal of Neurochemistry 81:802-813, 2002. PMID: 12065639

MCBRIDE, W.J. Central nucleus of the amygdala and the effects of alcohol and alcohol-drinking behavior in rodents. Pharmacology, Biochemistry, andBehavior 71:509-515, 2002. PMID: 11830185

MCBRIDE, W.J., AND LI, T.K. Animal models of alcoholism: Neurobiology of high alcohol-drinking behavior in rodents. Critical Reviews in Neurobiology 12.339-369, 1998. PMID: 10348615

MCGLINCHEY, R.E.; FORTIER, C.B.; CAPOZZI, S.M.; AND DISTERHOFT, J.F. Trace eyeblink conditioning in abstinent alcoholic individuals: Effects of complex task demands and prior conditioning. Neuropsychology 19:159-170, 2005. PMID: 15769200

MCGLINCHEY-BERROTH, R.; CARRILO, M.C.; ARMFIELD, S.; ET AL. Intact delay eyebfink conditioning in medial temporal amnesia but not in alcoholic Korsakoff amnesia (abs). Society for Neuroscience, Abstracts 20:430, 1994.

MCKENZIE, J.F.; PINGER, R.R.; AND KOTECKI, J.E. An Introduction to Community Health. Boston: Jones & Bartlett Publishers, 2005.

MILLER, R.A. Hypophyseal and extrahypophyseal factors affecting glomerular nucleolar and nuclear hypertrophy, following enucleation of the adrenal in the rat. American Journal of Anatomy 103:187-199,1958. PMID: 13636988

NESTOROS, J.N. Ethanol specifically potentiates GABA-mediated neurotransmission in feline cerebral cortex. Science 209:708-710, 1980. PMID: 7394531

NIxoN, K., AND CREWS, F.T. Binge ethanol exposure decreases neurogenesis in adult rat hippocampus. Journal of Neurochenristry 83:1087-1093, 2002. PMID: 12437579

NIXON, K., AND CREWS, F.T. Temporally specific burst in cell proliferation increases hippocampal neurogenesis in protracted abstinence from alcohol. Journal ofNeuroscience 24:9714-9722, 2004. PMID: 15509760

OSCAR-BERMAN, M. Neuropsychological vulnerabilities in chronic alcoholism. In Noronha, A.; Eckardt, M.; and Warren, K., Eds. Review of NIAAAs Neuroscience and Behavioral Research Portfolio, NIAAA Research Monograph No. 34. Bethesda, MD: National Institutes of Health, 2000, pp. 437 472.

OSCAR-BERMAN, M., AND HUNTER, N. Frontal lobe changes after chronic alcohol ingestion. In: Hunt, WA, and Nixon, S.J., Eds. Alcohol-Induced Brain Damage, NMAA Research Monographs No. 22. Rockville, MD: National Institutes of Health, 1993, pp. 121-156.

OSCAR-BERMAN, M., AND MARINKOVIC, K. Alcohol: Effects on neurobehavioral functions and the brain. Neuropsychology Review 17:239-257, 2007. PMID: 17874302

PARSONS, O. Impaired neuropsychological cognitive functioning in sober alcoholics. In: Hunt WA, and Nixon, S.J., Eds. Alcohol Induced Brain Damage. NMAA Research Monograph No. 22. Rockville, MD: National Institutes of Health, 1993, pp. 173-194.

PAULA-BARBOSA, M.M., AND SOBRINHO-SIMOES, M.A. An ultrastructural morphometric study of mossy fiber endings in pigeon, rat and man. Journal of Comparative Neurology 170:365-379, 1976. PMID: 993373

PAWLAK, R.; SKRZYPIE, A.; SULKOWSKI, S.; AND BUCZKO, W. Ethanol-induced neurotoxicity is counterbalanced by increased cell proliferation in mouse dentate gyrus. Neuroscience Letters 327:83-86, 2002. PMID: 12098641

PENTNEY, R.; QUACKENBUSH, L.J.; AND O'NEILL, M. Length changes in dendritic networks of cerebellar Purkinje cells of old rats after chronic ethanol treatment. Alcoholism: Clinical and Experimental Research 13:4131119, 1989. PMID: 2665558

PFEFFERBAUM, A., AND SULLIVAN, E.V. Microstructural but not microstructural disruption of white matter in women with chronic alcoholism. NeuroImage 15:708-718, 2002. PMID: 11848714

PFEFFERBAUM, A., AND SULLIVAN, E.V. Disruption of brain white matter microstructure by excessive intracellular and extracellular fluid in alcoholism: Evidence from diffusion tensor imaging. Neuropsychopharmacology 30:423-432, 2005. PMID: 15562292

PFEFFERBAUM, A.; ADALSTEINSSON, E.; SOOD, R.; ET AL. Longitudinal brain magnetic resonance imaging study of the alcohol-preferring rat. Part II: Effects of voluntary chronic alcohol consumption. Alcoholism: Clinical and Experimental Research 30:1248-1261, 2006a. PMID: 16792573

PFEFFERBAUM, A.; ADALSTEINSSON, E.; AND SULLIVAN, E.V. Supratentorial profile of white matter microstructural integrity in recovering alcoholic men and women. Biological Psychiatry 59:364-372, 2006c. PMID: 16125148

PFEFFERBAUM, A.; SULLIVAN, E.V.; HEDEHUS, M.; ET AL. In vivo detection and functional correlates of white matter microstructural disruption in chronic alcoholism. Alcoholism: Clinical and Experimental Research 24:1214-1221, 2000. PMID: 10968660

PFEFFERBAUM, A.; ADALSTEINSSON, E.; AND SULLIVAN, E.V. Dysmorphology and microstructural degradation of the corpus callosum: Interaction of age and alcoholism. Neurobiology of Aging 27:994-1009, 2006b. PMID: 15964101

PFEFFERBAUM, A.; LIM, K.O.; ZIPURSKY, R.B.; ET AL. Brain gray and white matter volume loss accelerates with aging in chronic alcoholics: A quantitative MRI study. Alcoholism: Clinical and Experimental Research 16:1078-1089, 1992. PMID: 1471762

PFEFFERBAUM, A.; SULLIVAN, E.V.; MATHALON, D.H.; ET AL. Longitudinal changes in magnetic resonance imaging brain volumes in abstinent and relapsed alcoholics. Alcoholism: Clinical and Experimental Research 19:1177-1191, 1995. PMID: 8561288

PFEFFERBAUM, A.; SULLIVAN, E.V.; ROSENBLOOM, M.J.; ET AL. A controlled study of cortical gray matter and ventricular changes in alcoholic men over a five-year interval. Archives of General Psychiatry 55:905-912,1998. PMID: 9783561

PHILLIPS, S.C.; HARPER, C.G.; AND KRIL, J. A quantitative histological study of the cerebellar vermis in alcoholic patients. Brain 110:301-314, 1987. PMID: 3567526

POUCH, J.; POLLOCK, V.E.; AND BLOOM, F.E. Meta-analysis of P300 amplitude from males at risk for alcoholism. Psychological Bulletin 115:55-73, 1994. PMID: 8310100

PORJESZ, B.; ALMASY, L.; EDENBERG, H.J.; ET AL. Linkage disequilibrium between the beta frequency of the human EEG and a GABAA receptor gene locus. Proceedings of the National Academy of Sciences of the United States ofAmerica 99:3729-3733, 2002. PMID: 11891318

PORJESZ, B., AND RANGASWAMY, M. Neurophysiological endophenotypes, CNS disinhibition, and risk for alcohol dependence and related disorders. Scientific World journal7:131-141, 2007. PMID: 17982586

PREMACK, D. Human and animal cognition: Continuity and discontinuity. Proceedings of the National Academy of Sciences of the United States of America 104:13861-13867,2007. PMID: 17717081

PRESCOTT, C.A., AND KENDLER, K.S. Age at first drink and risk for alcoholism: A noncausal association. Alcoholism: Clinical and Fxperimental Research 23:101-107,1999. PMID: 10029209

PRYCE, C.R. Postnatal ontogeny of expression of the corticosteroid receptor genes in mammalian brains: Inter-species and infra-species differences. Brain Research Reviews 57:596-605, 2008. PMID: 17916381

QN, L.; Wu, X.; BLOCK, M.L.; ET AL. Systemic LPS causes chronic neuroinflammation and progressive neurodegeneration. Glia 55:453-462, 2007. PMID: 17203472

QN, L.; HE, J.; HANES, R.N.; ET AL. Increased systemic and brain cytokine production and neuroinflammation by endotoxin following ethanol treatment. Journal of Neuroinflammation 5:10, 2008. PMID: 18348728

RASMUSSEN, D.D.; BOLDT, B.M.; BRYANT, C.A.; ET AL. Chronic daily ethanol and withdrawal: 1. Long-term changes in the hypothalamo-pituitaryadrenal axis. Alcoholism: Clinical and Fxperimenual Research 24:1836-1849, 2000. PMID: 11141043

RAY, J., AND GAGE, F.H. Differential properties of adult rat and mouse brain-derived neural stem/progenitor cells. Molecular and Cellular Neurosciences 31:560-573, 2006. PMID: 16426857

REDISH, AD.; JENSEN, S.; AND JOHNSON, A. A unified framework for addiction: Vulnerabilities in the decision process. Behavioral and Brain Sciences 31:415-437; discussion 437-487, 2008. PMID: 18662461

RICHARDS, J.G.; SCHOCH, P.; HARING, P.; ET AL. Resolving GAB[A.sub.A]/benzodiazepine receptors: Cellular and subcellular localization in the CNS with monoclonal antibodies. Journal of Neuroscience 7:1866-1886, 1987. PMID: 3037041

ROBBINS, T.W., AND EVERITT, B.J. Drug addiction: Bad habits add up. Nature 398:567-570, 1999. PMID: 10217139

ROGERS, R.D.; ANDREWS, T.C.; GRASBY, P.M.; ET AL. Contrasting cortical and subcortical activations produced by attentional-set shifting and reversal learning in humans. Journal of Cognitive Neuroscience 12:142-162, 2000. PMID: 10769312

ROSENBLOOM, M.J.; ROHLFING, T.; O'REILLY, A.W.; ET AL. Improvement in memory and static balance with abstinence in alcoholic men and women: Selective relations with change in brain structure. Psychiatry Research 155:91-102, 2007. PMID: 17407808

ROSSE, R.B.; RIGGS, R.L.; DIETRICH, A.M.; ET AL. Frontal cortical atrophy and negative symptoms in patients with chronic alcohol dependence. Journal of Neuropsychiatry and Clinical Neurosciences 9:280-282, 1997. PMID: 9144110

SABLE, H.J.; RODD, Z.A.; BELL, R.L.; ET AL. Effects of ethanol drinking on central nervous system functional activity of alcohol-preferring rats. Alcohol 35:129-135, 2005. PMID: 15963426

SCHMAHMANN, J. The role of the cerebellum in affect and psychosis. Journal of Neurohnguistics 13:189-214, 2000.

SEMENDEFERI, K., AND DAMASIO, H. The brain and its main anatomical subdivisions in living hominoids using magnetic resonance imaging. Journal of Human Evolution 38:317-332, 2000. PMID: 10656781

SINHA, R.; PARSONS, O.A.; AND GLENN, S.W. Drinking variables, affective measures and neuropsychological performance: Familial alcoholism and gender correlates. Akohol6:77-85, 1989. PMID: 2719819

SLAWECKI, C.J.; GRAHAMS, N.J.; ROTH, J.; ET AL. EEG and ERP profiles in the high alcohol preferring (HAP) and low alcohol preferring (LAP) mice: Relationship to ethanol preference. Brain Research 961:243-254, 2003. PMID: 12531491

SMITH, H.R., AND PORRINO, L.J. The comparative distributions of the monoamine transporters in the rodent, monkey, and human amygdala. Brain Structure &Function 213:73-91, 2008. PMID: 18283492

SPANAGEL, R.; HERZ, A.; AND SHIPPENBERG, T.S. Opposing tonically active endogenous opioid systems modulate the mesolimbic dopaminergic pathway. Proceedings of the National Academy of Sciences of the United States of America 89:2046-2050, 1992. PMID: 1347943

SULLIVAN, EN., AND PFEFFERBAUM, A. Neuroimaging of the Wernicke Korsakoff Syndrome. Alcohol andAlcoholism, 2008. In press.

SULLIVAN, E.V.; DESHMUKH, A.; DESMOND, J.E.; ET AL. Cerebellar volume decline in normal aging, alcoholism, and Korsakoffs syndrome: Relation to ataxia. Neuropsychology 14:341-352, 2000a. PMID: 10928737

SULLIVAN, E.V.; MARSH, L.; MATHALON, D.H.; ET AL. Anterior hippocampal volume deficits in nonamnesic, aging chronic alcoholics. Alcoholism: Clinical and Experimental Research 19:110-122, 1995. PMID: 7771636

SULLIVAN, E.V.; ROSENBLOOM, M.J.; AND PFEFFERBAUM, A. Pattern of motor and cognitive deficits in detoxified alcoholic men. Alcoholism: Clinical and Experimental Research 24:611-621, 2000c. PMID: 10832902

SULLIVAN, E.V.; ROSENBLOOM, M.J.; LIM, K.O.; AND PFEFFERBAUM, A. Longitudinal changes in cognition, gait, and balance in abstinent and relapsed alcoholic men: Relationships to changes in brain structure. Neuropsychology 14:178-188, 2000b. PMID: 10791858

SULLIVAN, E.V.; HARDING, A.J.; PENTNEY, R.; ET AL. Disruption of frontocerebellar circuitry and function in alcoholism. Alcoholism: Clinical and Experimental Research 27:301-309, 2003. PMID: 12605080

SULTAN, F., AND BRAITENBERG, V. Shapes and sizes of different mammalian cerebella. A study in quantitative comparative neuroanatomy. Journal fur Hirnforschung 34:79-92, 1993. PMID: 8376757

TAVARES, MA, AND PAULA-BARBOSA, M.M. Alcohol-induced granule cell loss in the cerebellar cortex of the adult rat. Experimental Neurology 78:574-582, 1982. PMID: 6890906

TAVARES, M.A.; PAULA-BARBOSA, M.M.; AND CADETS-LEITE, A. Chronic alcohol consumption reduces the cortical layer volumes and the number of neurons of the rat cerebellar cortex. Alcoholism: Clinical and Experimental Research 11:315-319, 1987. PMID: 3307500

TICKU, M.K., AND MEHTA, A.K. Gammaaminobutyric acid: A receptor desensitization in mice spinal cord cultured neurons: Lack of involvement of protein kinases A and C. Molecular Pharmacology 38:719-724, 1990. PMID: 2172778

TOLBERT, D.L.; BANTLI, H.; AND BLOEDEL, J.R. Organizational features of the cat and monkey cerebellar nucleocortical projection. Journal of Comparative Neurology 182:39-56,1978. PMID: 100532

TORVIK, A., AND TORP, S. The prevalence of alcoholic cerebellar atrophy: A morphometric and histological study of an autopsy material. Journal of Neurological Science 75:43-51, 1986. PMID: 3746340

TRAN, T.D.; STANTON, M.E.; AND GOODLETT, C.R. Binge-like ethanol exposure during the early postnatal period impairs eyeblink conditioning at short and long CS-US intervals in rats. Developmental Psychobiology 49:589-605, 2007. PMID: 17680607

TUPALA, E., AND TIIHONEN, J. Dopamine and alcoholism: Neurobiological basis of ethanol abuse. Progress in Neuro-Psychopharmacology &Biological Psychiatry 28:1221-1247, 2004. PMID: 15588749

VALDEZ, G.R.; ROBERTS, A.J.; CHAN, K.; ET AL. Increased ethanol self-administration and anxiety like behavior during acute ethanol withdrawal and protracted abstinence: Regulation by corticotrophin-releasing factor. Alcoholism: Clinical and Experimental Research 26:1494-1501, 2002. PMID: 12394282

VICTOR, M.; ADAM, R.D.; AND MANCALL, E.L. A restricted form of cerebellar degeneration occurring in alcoholic patients. Archives of Neurology 1:577-688,1959.

VOLKOW, N.D.; FOWLER, J.S.; WANG, G.J.; AND GOLDSTEIN, R.Z. Role of dopamine, the frontal cortex and memory circuits in drug addiction: Insight from imaging studies. Neurobiology of Learning andMemory78:610-624, 2002. PMID: 12559839

WALKER, D.W.; BARNES, D.E.; ZORNETZER, S.F.; ET AL. Neuronal loss in hippocampus induced by prolonged ethanol consumption in rats. Science 209:711-713,1980. PMID: 7394532

WEIBLE, A.P.; O'REILLY, J.A.; WEISS, C.; AND DISTERHOFT, J.F. Comparisons of dorsal and ventral hippocampus corms ammonis region 1 pyramidal neuron activity during trace eye-blink conditioning in the rabbit. Neuroscience 141:1123-1137, 2006. PMID: 16753261

WHITTINGTON, M.A.; TRAUB, R.D.; KOPELL, N.; ET AL. Inhibition-based rhythms: Experimental and mathematical observations on network dynamics. International journal of Psychophysiology 38:315-336, 2000. PMID: 11102670

WISE, R.A. Brain reward circuitry: Insights from unsensed incentives. Neuron 36:229-240, 2002. PMID: 12383779

WOOD, M.D.; SCOTT, C.; CLARKE, K.; ET AL. Aripiprazole and its human metabolite are partial agonists at the human dopamine D2 receptor, but the rodent metabolite displays antagonist properties. European Journal of Pharmacology 546:88-94, 2006. PMID: 16925992

XIAO, C.; ZHANG, J.; KRNJEVIC, K.; AND YE, J.H. Effects of ethanol on midbrain neurons: Role of opioid receptors. Alcoholism: Clinical and Exjperinzental Research 31:1106-1113, 2007. PMID: 17577392

YAMAMOTO, T.; NISHIMURA, Y.; MATSUURA, T.; ET AL. Cerebellar activation of cortical motor regions: Comparisons across mammals. Progress in Brain Research 143:309-317, 2004. PMID: 14653175

YAROSLAVSKY, I.; COLLETTI, M.; JIAO, X.; AND TEJANI-BUTT, S. Strain differences in the distribution of dopamine (DA-2 and DA-3) receptor sites in rat brain. Life Sciences 79:772-776, 2006. PMID: 16574158

ZAMUDIO, S.; FREGOSO, T.; MIRANDA, A.; ET AL. Strain differences of dopamine receptor levels and dopamine related behaviors in rats. Brain Research Bulletin 65:339-347, 2005. PMID: 15811600

NATALIE M. ZAHR, PH.D., is a postdoctoral fellow at SRI International Menlo Park, California, and a research scientist with professor EDITH V. SULLIVAN, PH.D., who is a professor in the Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, California.
Figure 1 A) DSM-IV criteria for alcohol dependence.
B) Criteria for an animal model of alcoholism.

A DSM-IV Criteria for Alcohol Dependence

1) Tolerance, as defined by either of the following:
a) need for markedly increased amounts of alcohol to
achieve intoxication or desired effect

b) markedly diminished effect with continued use of the
same amount of alcohol

2) Withdrawal, as manifested by either of the following:

a) characteristic withdrawal (e.g., insomnia, psychomotor
agitations, anxiety, nausea, or vomiting)

b) alcohol is taken to relieve or avoid withdrawal symptoms

3) Alcohol often is taken in larger amounts or over a
longer period than was intended

4) There is a persistent desire or unsuccessful effort to
cut down or control alcohol use/reduce use (i.e., inability
to control use)

5) A great deal of time is spent in activities necessary to
obtain alcohol, use alcohol, or recover from its effects

6) Important social, occupational, or recreational activities
are given up or reduced because of alcohol use

7) Alcohol use is continued despite knowledge of having
a persistent or recurrent physical or psychological
problem that is likely to have been caused or exacerbated
by alcohol (e.g., continued drinking despite
recognition that an ulcer was made worse by alcohol

B Criteria for an Animal Model of Alcoholism

1) The animal should orally self-administer alcohol

2) The amount of alcohol consumed should result in
pharmacologically relevant blood alcohol levels

3) Alcohol should be consumed for its post-ingestive
pharmacological effects and not strictly for its caloric
value or taste

4) Alcohol should be positively reinforcing, or in other
words, the animals must be willing to work for alcohol

5) Chronic alcohol consumption should lead to the
expression of metabolic and functional tolerance

6) Chronic consumption of alcohol should lead to dependence,
as indicated by withdrawal symptoms after
access to alcohol is terminated

7) The animal should display characteristics associated
with relapse
COPYRIGHT 2008 U.S. Government Printing Office
No portion of this article can be reproduced without the express written permission from the copyright holder.
Copyright 2008 Gale, Cengage Learning. All rights reserved.

Article Details
Printer friendly Cite/link Email Feedback
Author:Zahr, Natalie M.; Sullivan, Edith V.
Publication:Alcohol Research & Health
Geographic Code:1U9CA
Date:Sep 22, 2008
Previous Article:Communication networks in the brain: neurons, receptors, neurotransmitters, and alcohol.
Next Article:Strategies to study the neuroscience of alcoholism: introduction.

Related Articles
Alcoholism's elusive genes: it runs in families and ruins lives, but is alcoholism inherited?
New discovery links alcoholism and genetics.
Proposed alcoholism gene fails again.
Gene in the bottle: a controversial alcoholism gene gets a new twist.
Alcoholism: nurture may often outdo nature.
Low response to alcohol may boost risk of alcoholism.
Brain data fuel alcoholism gene clash.
Variations in alcohol-metabolizing enzymes in people of East Indian and African descent from Trinidad and Tobago.
Systems genetics of alcoholism.

Terms of use | Privacy policy | Copyright © 2020 Farlex, Inc. | Feedback | For webmasters