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patients and to prevent their relapse to ethanol use. Although the most severe consequences of withdrawal appear
during the initial week of sobriety, protracted components
of withdrawal persist for many months (8). Protracted withdrawal symptoms include insomnia, anergia, and depressed
mood. The effort to rid oneself of withdrawal symptoms
may be an important motivator for relapse to ethanol use.
As will be reviewed later, this phase of recovery is also associated with gains in cognitive function, cortical activity, and
brain structure.
Nutritional deficits complicate the natural history of alcoholism (9). If thiamine-deficient individuals ingest glucose before thiamine repletion, the resulting demand on
thiamine pyrophosphate-dependent metabolic processes
compromises neuronal metabolic functions and may produce cell death associated with the Wernicke-Korsakoff syndrome (10). This eponym refers to a constellation of learning and memory impairment, psychosis, and motor
findings.
This chapter provides a brief and selective overview of
the basic and clinical neuroscience of alcoholism. Ethanol
is now known to have multiple specific actions in the brain
that contrast with the historical focus on its nonspecific
perturbation of neuronal membrane bulk lipids (11,12).
This chapter discusses the acute and chronic effects of
ethanol at its protein targets in the brain, and the neural
circuitry of human alcoholism that has become the focus
of structural and functional neuroimaging studies.
MOLECULAR TARGETS OF THE ACTION OF
ETHANOL: RELEVANCE TO INTOXICATION
AND DEPENDENCE
Amino Acid Neurotransmission
Glutamate
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FIGURE 100.1. The relative potency of ethanol for its protein targets in the brain. Shown is
the relationship between amounts of alcohol consumed and neurotransmission, neuroexcitatory
components, and behavioral actions.
ionotropic and metabotropic receptors to transduce its signal. The ionotropic receptors, receptor-gated ion channels,
include the N-methyl-D-aspartate (NMDA) -amino-3-hydroxy-5-methyl-4-isoxazoleproprionate (AMPA), and kainate receptors (13). NMDA receptors are gated by membrane potential and the simultaneous binding of both
glycine and glutamate (14). Ethanol at concentrations as
low as 5 mM (20 mg%) inhibits ion flux through the
NMDA receptor-gated ion channels, making NMDA receptors one of the highest affinity ethanol targets in the
brain (Fig. 100.1) (see ref. 15 for review). It shows lower
affinity for AMPA and kainate glutamate receptors (15).
Ethanol effects on the NMDA receptor function are dependent on the concentration of glycine and the phosphorylation status of the receptor. In cultured cerebellar granule
cells, ethanol lowered the NMDA receptor affinity for glycine, and ethanol effects were partially reversed by raising
glycine levels (16). A protein kinase C (PKC)-mediated
phosphorylation event may gate the effects of ethanol on
glycine affinity at the NMDA receptor (16). Other protein
kinases (e.g., tyrosine kinases such as Fyn and Src) may also
play a role in ethanols actions on the NMDA receptor (17).
Regional variations in NMDA receptor subunit composition contribute to distinctions in ethanol effects on
NMDA receptor function across brain regions (see ref. 14
for review). Functional NMDA receptors are composed of
an NR1 subunit, with at least eight splice variants, and one
NR2 subunit from among the four known subtypes (NR2
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FIGURE 100.2. Similarity of the effects of placebo (open circles), ketamine 0.1 mg/kg (solid circles), and ketamine 0.5 mg/kg (solid squares) to ethanol (left), marijuana (middle), and cocaine
(right) in alcoholic patients (n 20). Values are expressed as mean standard error of the
mean (SEM). Ketamine effects were significantly more similar to ethanol than both marijuana
and cocaine by post-hoc contrast (F1 6.7, p .02). (Data are from ref. 70.)
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GABA
Acamprosate: A Putative Glutamatergic Pharmacotherapy for Alcoholism. Acamprosate is a homotaurine derivative without ethanol-like behavioral effects that reduces alcohol consumption in animals (53). This drug is a
promising agent for treating alcoholism (54,55). It reduces
NMDA receptor function, contributing to its capacity to
suppress ethanol withdrawal (56). However, it also has promotes some NMDA receptor-mediated effects (57). The site
of action of acamprosate is not known and the mechanisms
related to its efficacy are not fully understood.
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symptoms. These changes may in part reflect ethanol dependence and withdrawal-related effects on the levels or function of enzymes regulating GABA synthesis and degradation
(80).
Reductions in GABAA receptor binding in postmortem
and antemortem neuroimaging studies may reflect the combined effects of vulnerability, ethanol dependence, and alcoholism-related neurotoxicity. Some postmortem studies
found reductions in GABAA/benzodiazepine (BZ) binding,
but other studies had conflicting results (8183). Variability
between studies may reflect a compensatory up-regulation
in BZ/GABAA binding that follows alcoholism-related neurotoxicity (84) or the failure to employ ligands that differentiate between subtypes of GABAA receptors. In vivo, positron emission tomography (PET) and single photon
emission computed tomography (SPECT) neuroreceptor
imaging has provided evidence of reductions in BZ binding
(Fig. 100.3) (85,86). Neurotoxicity contributed to, but did
not account for, reductions in BZ receptor binding in patients (87). Reductions in BZ binding may be consistent
with evidence of reduced regional brain metabolic sensitivity
to lorazepam in ethanol-dependent individuals (88). However, metabolic blunting did not rapidly recover with sobriety (89), raising the possibility that this deficit reflected
genetic vulnerability or irreversible toxicity.
Psychopharmacologic studies also implicate GABA systems in withdrawal and relapse. Clearly, drugs facilitating
GABAA receptor function including BZs, barbiturates, and
anticonvulsants suppress acute ethanol withdrawal (90).
FIGURE 100.3. Transaxial slice of regions where benzodiazepine receptor distribution volume
in alcoholic patients was significantly lower than in comparison subjects based on a statistical
parametric mapping analysis (yellow). Single photon emission computed tomography (SPECT)
data were superimposed on an MRI template. (From Abi-Dargham A, Krystal JH, Anjivel S, et al.
Alterations of benzodiazepine receptors in type II alcoholics measured with SPECT and [123I]iomazenil. Am J Psychiatry 1998;155:15501555, with permission.) See color version of figure.
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The BZ antagonist flumazenil may reduce ethanol intoxication in humans at doses greater than required to antagonize
BZ effects (91). However, this drug does not produce
ethanol withdrawal symptoms in ethanol-dependent individuals (92). It is not yet clear whether flumazenil exposure
during ethanol withdrawal alters the course of recovery from
ethanol dependence.
Neurosteroids
There is growing interest in the role of neuroactive intermediates in sex steroid synthesis and metabolism in alcoholism
(93). Allopregnanolone, a coagonist of the steroid anesthetic
site of the GABAA receptor, shares discriminative stimulus
properties with ethanol and suppresses the ethanol abstinence syndrome in animals (94,95). Allopregnanolone also
may potentiate the effects of ethanol (96). Allopregnanolone
levels, like those of its precursor progesterone, vary markedly
during the menstrual cycle. In the late luteal phase, drops
in allopregnanolone levels may contribute to premenstrual
mood disturbances (97) and increase the intensity of the
discriminative stimulus properties of ethanol (98). These
factors may increase ethanol consumption during this phase
of the menstrual cycle (99). Supporting this view, higher
allopregnanolone levels in the late luteal phase are associated
with reduced triazolam self-administration in women (100).
Thus, cyclical variation in neurosteroid levels may be a focus
for future pharmacotherapies for female alcoholics.
Preclinical Studies
Serotonin (5-HT)
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(208). Neuronal loss appears to be primarily loss of pyramidal neurons, with relative sparing of interneurons (208).
Another study was unable to replicate neuronal loss using
uniform sampling and unbiased neuron counting methods
(209). However, even when neurons are extant, they may
exhibit structural deficits consistent with neurotoxicity
(210). Generally, cortical and limbic brain shrinkage and
neuronal loss may be more prominent in individuals whose
alcohol dependence is complicated by Wernickes encephalopathy and Korsakoffs psychosis (211). The WernickeKorsakoff syndrome has been associated with abnormalities
in frontal cortex, as well as in several subcortical structures
including the thalamus, hippocampus, mamillary bodies,
and amygdala (10).
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FIGURE 100.4. The top two panels illustrate the relationship between drinking severity and
duration with gray and white matter volume loss in ethanol-dependent patients. The bottom
two panels illustrate the interaction between alcoholism and volume loss with age. Top figures:
The relationship between cortical gray matter rate of change and the amount of alcohol consumed
during the follow-up period (left) (Spearman rho 0.52, p .04) and between the cortical
gray matter rate of change and the estimated amount of time during past 5 years that alcoholic
patients (group 1) met Diagnostic and Statistical Manual of Mental Disorders, third edition revised
(DSM-III-R) criteria for alcohol dependence during the follow-up period (right) (Spearman rho
0.53, p .04). One alcoholic patient who reported 950 kg of alcohol consumption is omitted
from the left panel so as not to distort scaling. The darker circle represents two patients with
overlapping values. (From Pfefferbaum A, Sullivan EV, Rosenbloom MJ, et al. A controlled study
of cortical gray matter and ventricular changes in alcoholic men over a 5-year interval. Arch Gen
Psychiatry 1998;55:905912.) Bottom figures: Cortical gray (left) and white matter (right) volume
changes with age in ethanol-dependent patients. Data from individual ethanol-dependent patients are expressed as age-corrected Z-scores plotted as a function of age. (From Pfefferbaum
A, Lim KO, Zipursky RB, et al. Brain gray and white matter volume loss accelerates with aging
in chronic alcoholics: a quantitative MRI study. Alcohol Clin Exp Res 1992;16:10781089, with
permission.)
1434
a characteristic of antisocial alcoholism (252). Familial history of alcoholism appears to compound the negative consequences of social drinking on cognitive function (253).
However, children of alcoholics exhibit attenuated impairment in attention and memory relative to individuals with
a familial alcoholism history (254). Thus it is possible that
cognitive responses to ethanol may also contribute to the
risk for making the transition from social drinking to alcoholism.
Although traits associated with the vulnerability to alcoholism contribute to cognitive deficits seen in ethanoldependent patients, they do not account for the deficits
in patients (255). Ethanol-dependent patients show many
impairments in cognitive function. Deficits in the level of
performance and efficiency of verbal skills, learning and
memory, problem-solving and abstracting, and perceptualmotor skills have been described (256). Cognitive deficits
may reflect in part the degree of neurotoxicity related to
alcoholism. For example, young ethanol-dependent patients
may show normal brain volumes on MRI and normal cognitive function (257,258). With repeated episodes of ethanol
withdrawal and advancing age, cognitive deficits become
more pronounced (259).
Cognitive function improves over the initial year of sobriety; however, the domains of cognitive function do not
recover at the same rate and recovery may be partial (260,
261). Poor cognitive function at the time that treatment is
initiated appears to predict improved alcohol-related treatment outcomes (262). However, progress in treatment may
be reflected in improved cognitive function (263). Consistent with the view that treatment may modulate cognitive
recovery, some cognitive deficits in recovering patients appear to respond to cognitive rehabilitation (264).
In summary, the behavioral studies describe the display
of deficits in cognitive functions that may have implications
for circuitry dysfunction in alcoholism: executive function
deficits associated with the prefrontal cortex, visual-spatial
deficits associated with the parietal cortex, and learning/
memory deficits that may involve the hippocampus and
related temporal cortical structures. Overall, these studies
are consistent with the findings related to reduced tissue
volume on MRI, reductions in cortical metabolism with
fluorodeoxyglucose (FDG)-PET (242), and information
processing deficits in ERP studies (265). This overlap implies a connection between alterations in brain structure,
function, and behavior related to alcoholism.
THE INTERPLAY OF THE NEURAL
CIRCUITRY AND NEUROCHEMISTRY OF
ALCOHOLISM: IMPLICATIONS FOR
TREATMENT
Ethanol has multiple specific effects on amino acid, monoamine, and neuropeptide neurotransmitter systems, and
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ACKNOWLEDGMENTS
This work was supported by the National Institute on Alcohol Abuse and Alcoholism (NIAAA) (grants KO2 AA
00261-01 and RO1 AA11321-01A1) and the Department
of Veterans Affairs (Alcohol Research Center, Clinical Neurosciences Division, National Center for Posttraumatic
Stress Disorder). The authors thanks Ms. Shawndra Poharski for her assistance in preparing this manuscript.
19.
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