0
We're unable to sign you in at this time. Please try again in a few minutes.
Retry
We were able to sign you in, but your subscription(s) could not be found. Please try again in a few minutes.
Retry
There may be a problem with your account. Please contact the AMA Service Center to resolve this issue.
Contact the AMA Service Center:
Telephone: 1 (800) 262-2350 or 1 (312) 670-7827  *   Email: subscriptions@jamanetwork.com
Error Message ......
Original Article |

Cortical γ-Aminobutyric Acid Type A–Benzodiazepine Receptors in Recovery From Alcohol Dependence:  Relationship to Features of Alcohol Dependence and Cigarette Smoking FREE

Julie K. Staley, PhD; Christopher Gottschalk, MD; Ismene L. Petrakis, MD; Ralitza Gueorguieva, PhD; Stephanie O’Malley, PhD; Ronald Baldwin, PhD; Peter Jatlow, PhD; Nicolaas Paul L. G. Verhoeff, MD, PhD; Edward Perry, MD; David Weinzimmer, BA; Erin Frohlich, BA; Elizabeth Ruff, BA; Christopher H. van Dyck, MD; John P. Seibyl, MD; Robert B. Innis, MD, PhD; John H. Krystal, MD
[+] Author Affiliations

Author Affiliations: Yale University School of Medicine, New Haven, Conn (Drs Staley, Gottschalk, Petrakis, Gueorguieva, O’Malley, Baldwin, Jatlow, Verhoeff, Perry, van Dyck, Seibyl, Innis, and Krystal, Mr Weinzimmer, and Mss Frohlich and Ruff); Veterans Affairs Connecticut Healthcare System, West Haven, Conn (Drs Staley, Petrakis, Baldwin, Verhoeff, Perry, Innis, and Krystal, Mr Weinzimmer, and Mss Frohlich and Ruff); and Institute for Neurodegenerative Disorders, New Haven (Dr Seibyl). Dr Baldwin is now with the Department of Radiology, Vanderbilt University, Nashville, Tenn, Dr Verhoeff is with the University of Toronto, Toronto, Ontario, and Dr Innis is with the Molecular Imaging Branch, National Institute of Mental Health, Bethesda, Md.


Arch Gen Psychiatry. 2005;62(8):877-888. doi:10.1001/archpsyc.62.8.877.
Text Size: A A A
Published online

Context  Adaptations in γ-aminobutyric acid type A (GABAA)–benzodiazepine receptors contribute to the neurobiology of human alcohol dependence and withdrawal.

Objective  To study GABAA-benzodiazepine receptor adaptations in subjects with alcohol dependence over the first month of sobriety.

Design  Inpatients who were not receiving medication, were either smokers or nonsmokers, and had alcohol dependence completed 2 iodine I 123–labeled iomazenil single-photon emission computed tomographic scans: 1 scan at a mean ± SD of 4.9 ± 2.5 days of sobriety (n = 23) and 1 scan at a mean ± SD of 29.8 ± 7.6 days of sobriety (n = 20). Participants in a matched group of healthy subjects (n = 15) completed 1 single-photon emission computed tomographic scan.

Participants  Men with alcohol dependence (n = 27) and a matched healthy comparison group (n = 15).

Main Outcome Measures  123I-iomazenil single-photon emission computed tomographic images were converted to units of distribution volume (regional activity/free 123I-iomazenil) and were analyzed using voxel-based statistical parametric mapping and regions of interest analyses. The relationships between 123I-iomazenil distribution volume, clinical features of alcohol dependence, and smoking status were evaluated.

Results  123I-iomazenil uptake was elevated in several cortical regions, with a more prominent increase in nonsmokers with alcohol dependence as compared with smokers with alcohol dependence at 1 week of abstinence from alcohol. No significant differences were observed at 4 weeks of abstinence. At 1 week of abstinence, frontal 123I-iomazenil uptake correlated with the severity of alcohol withdrawal and the number of days since the last alcoholic drink was consumed. No significant associations were observed for smokers with alcohol dependence.

Conclusions  These data demonstrate time-dependent regulation of cortical GABAA-benzodiazepine receptors associated with the recovery from alcohol dependence. Higher GABAA-benzodiazepine receptor levels during acute withdrawal may reflect a compensation for reduced receptor function, which is thought to contribute to alcohol tolerance and withdrawal. The subsequent decline may reflect “normalization” of GABAA receptor function with sobriety. Smoking may attenuate GABAA receptor adaptations associated with alcohol dependence and may contribute to the comorbidity between alcoholism and smoking.

Figures in this Article

Several lines of evidence implicate γ-aminobutyric acid type A (GABAA) receptors in the neurobiology of alcohol tolerance and dependence, including (1) facilitatory effects of ethanol on γ2L-containing GABAA receptors,1 (2) generalization between the discriminative stimulus effects of ethanol and GABAA receptor agonists, (3) cross-tolerance between ethanol and benzodiazepines (BZs), and (4) the ability of BZs and other GABAA receptor agonists to suppress alcohol withdrawal.2,3 In fact, BZs are the principal pharmacotherapy for alcohol withdrawal symptoms.46 While there is controversy regarding whether ethanol has primarily direct or indirect facilitatory effects on GABAA receptors,2,7,8 recent evidence of potent direct ethanol effects on GABAA receptor subgroups and the mapping of molecular domains of GABAA receptors through which ethanol acts9 highlight the importance of GABAA receptors for ethanol action. Ethanol and BZ enhance GABAergic function through distinct interactions with the GABAA receptor complex.10

Neuroimaging studies of patients with alcohol dependence who have been sober for at least 1 month generally suggest that GABAA receptors are decreased. All1114 but one15 of these studies demonstrated decreased binding of the BZ antagonists carbon 11–labeled flumazenil and iodine I 123–labeled iomazenil in frontal, parietal, and temporal cortices. These studies may be consistent with cerebral metabolic data suggesting that the response to lorazepam is decreased in patients who have been sober for 6 to 32 days16 and continues to decrease over 2 months of abstinence.17 However, it is possible that both the receptor-based and metabolic neuroimaging findings could reflect neurotoxic consequences of alcoholism or GABA-related disturbances that preceded the onset of alcohol dependence. Human postmortem studies report unchanged,18,19 increased,20 and decreased21,22 binding of BZ agonists in the frontal cortex, hippocampus, and cerebellum. In a small study of recently detoxified patients with alcohol dependence, 2 subjects demonstrated increased GABAA-BZ receptor availability whereas the other 3 subjects exhibited unchanged or slightly decreased GABAA-BZ receptor availability.23 When reviewed collectively with the earlier in vivo studies in subjects with alcoholism who have been abstinent for greater than 1 month, these studies suggest that levels of GABAA-BZ receptors are elevated or similar to control levels during acute abstinence and decreased with prolonged abstinence, and they also suggest that factors other than the length of abstinence may alter the levels of GABAA-BZ receptors during alcohol withdrawal.

We hypothesized that some of the conflicts in the existing literature might reflect the confounding effects of time-dependent changes in GABAA-receptor populations during recovery (return to baseline) from alcohol dependence as well as other clinical features, including severity of alcohol dependence and withdrawal, subtype of alcoholism (reflected in age at onset), and the frequent comorbidity of alcohol dependence and tobacco smoking. The objectives of the current study were to directly evaluate whether GABAA-BZ–receptor levels change over time during recovery from alcohol dependence, to explore the relationships to clinical correlates of alcohol dependence, and to determine if tobacco smoking modifies GABAA-BZ receptors during early sobriety.

SUBJECTS

Thirty-six men with alcohol dependence and 15 age-matched healthy men provided written informed consent for participation in this study. The study was approved by the Department of Psychiatry Research Committee, Human Investigation Committee, and Radiation Safety Committee, Yale University School of Medicine (New Haven, Conn), and the Human Subjects Subcommittee of the West Haven Veterans Affairs Connecticut Healthcare System (West Haven, Conn). Eligibility was evaluated with a structured interview, physical examination, laboratory blood tests, urine drug screen, and an electrocardiogram. Control subjects had no history or evidence of a serious medical or neurological illness, did not meet criteria for any psychiatric or substance abuse diagnosis as determined by the Structured Clinical Interview for DSM-IV nonpatient version, had no history of a DSM-IV Axis I psychiatric disorder in a first-degree relative, and had not used psychotropic substances other than alcohol, nicotine, or tobacco for at least 1 year preceding the study. Control subjects drank less than 8 alcoholic drinks per week as defined by the timeline follow-back (ie, 1 drink = 12 oz of beer, 5 oz of wine [10% alcohol], 1.5 oz of hard liquor, etc)24 and were asked to refrain from alcoholic and caffeine-containing drinks for 2 weeks preceding the single-photon emission computed tomographic (SPECT) scan.

Participants in the alcohol-dependent group met DSM-IV criteria for alcohol dependence and currently had no other Axis I disorder other than nicotine dependence, as determined by the Structured Clinical Interview for DSM-IV.25 They had no medical or neurological disorders that might compromise the interpretation of the SPECT data, had not taken any psychotropic medications in the last month, and demonstrated alcohol withdrawal symptoms of a Clinical Institute Withdrawal Assessment4 score of less than 10 at the initial assessment. Subjects with alcohol dependence were accepted with abnormal liver function test values for γ-glutamyltransferase, serum glutamic oxaloacetic transaminase, and serum glutamate pyruvate transaminase of up to 3 times the upper normal limit in recognition of the effect of recent drinking on liver function.

Subjects with alcohol dependence were admitted into the Connecticut Mental Health Center Clinical Neuroscience Research Unit (New Haven) for 1 month. They were monitored for alcohol withdrawal symptoms using the Clinical Institute Withdrawal Assessment every 6 hours after admission until scores were consistently 0. Patients with Clinical Institute Withdrawal Assessment ratings of 10 or higher were evaluated to determine if immediate BZ administration was necessary. The BZs were automatically given if the Clinical Institute Withdrawal Assessment score exceeded 12. Once BZs were administered, no subsequent tests were performed for at least 1 month; ie, the first imaging session was cancelled and, since long-term BZ administration does not alter GABAA-BZ receptor levels,26 subjects were encouraged to participate in the second scan. Of the 36 patients who signed consent forms, 10 subjects were excluded for the following reasons: (1) withdrew consent and terminated participation before completing an imaging session; (2) did not have a magnetic resonance image taken; (3) had abnormal magnetic resonance image results; (4) had first-degree family history of depression; (5) had cocaine use discovered after the study; or (6) there was difficulty in placing the intravenous needle and/or collecting blood samples during the SPECT scan. Three subjects with alcohol dependence participated in the second scan but did not participate in the first scan because they received BZ to treat withdrawal symptoms, the camera was not available (because of a change in location), and entrance into the study was after the first week of abstinence. Six subjects with alcohol dependence dropped out after the first scan and did not participate in the second scan. Alcohol consumption in the month preceding the SPECT scan was determined using the timeline follow-back.24 Age at onset of alcohol dependence was obtained from the Structured Clinical Interview for DSM-IV. Antisocial personality disorder was determined using the Structured Clinical Interview for DSM-IV Axis II. Severity of alcohol dependence was assessed using the Alcohol Dependence Scale,27 and alcohol craving was assessed on the day of the SPECT scan using the Tiffany Scale.28 Subjects with alcohol dependence had SPECT images taken within 10 days and/or at 4 weeks after their last alcoholic drink.

Smokers in the control group and the alcohol-dependent group were instructed to maintain their normal smoking patterns. Inpatient smokers with alcohol dependence were limited to smoking 4 times per day. Smoking characteristics, including the ages at which the subjects began smoking, the total number of years they smoked, the number of cigarettes smoked per day, and the number of attempts to quit smoking, were documented. Nicotine dependence was evaluated using the Fagerstrom Test for Nicotine Dependence.29,30 Plasma cotinine (the principal metabolite of nicotine) was measured on the day of the SPECT scan. All nonsmokers with alcohol dependence and 8 of the 10 control nonsmokers were “never smokers” as defined by a lifetime history of smoking less than 40 cigarettes or nicotine-related products.

PLASMA COTININE ASSAY

Cotinine concentrations in serum were assayed using reverse-phase high-performance liquid chromatography. The procedure31 was modified by substitution of an aqueous microvolume back-extraction clean-up step in place of solvent evaporation. Following the addition of an internal standard (2-phenylimidazole), cotinine was extracted from alkalinized serum with a 40:60 mixture of dichloromethane and hexane. Following a microvolume back-extraction into 0.1M phosphoric acid, the aqueous phase was analyzed by reverse-phase chromatography on a C6 reverse-phase column using a mobile phase of 10% acetonitrile buffered to pH 4.8 and containing 20 mL of triethylamine and 0.6 g/L of octane-sulfonic acid. Between-day coefficients of variation, in routine use at concentrations of 20 μg/L and 200 μg/L, were 11.6% and 6.6%, respectively.

123I-IOMAZENIL SPECT IMAGING AND MAGNETIC RESONANCE IMAGING

123I-iomazenil was prepared as described previously.32 The average yield was a mean ± SD of 63.0% ± 11.7% (n = 57 preparations) and its radiochemical purity was a mean ± SD of 97.8% ± 1.8%. All participants were pretreated with saturated potassium iodide to reduce thyroid uptake of 123I. 123I-iomazenil was administered by intravenous injection (71.3 ± 2.1 MBq, 72.6 ± 1.9 MBq, and 72.5 ± 1.5 MBq for subjects with alcohol dependence at 1 week of abstinence, subjects with alcohol dependence at 4 weeks of abstinence, and control subjects, respectively) plus constant infusion (275.9 ± 7.3 MBq/h, 280.1 ± 7.7 MBq/h, and 278.2 ± 5.1 MBq/h, respectively). The duration of infusion was 6.5 hours with a mean ± SD total injected dose of 221.2 ± 3.1 MBq for subjects with alcohol dependence and 223.2 ± 1.8 MBq for control subjects. Prior to imaging, 5 external fiducial markers containing 0.037 MBq of 123I were placed on the scalp to provide a common reference for coregistration with emission images. Simultaneous transmission and emission scans were acquired with a line source containing 740 MBq of cobalt 57 on a PRISM 3000XP 3-headed camera (Picker International, Cleveland, Ohio). Three consecutive 12-minute emission scans were acquired in continuous mode between 330 and 370 minutes of 123I-iomazenil infusion. Three venous blood samples were collected at the midpoint of the SPECT scan (at 350 minutes) for measurement of free 123I-iomazenil.32123I-iomazenil SPECT has 83% to 90% reproducibility.33

Magnetic resonance imaging was performed on a Signa 1.5T system (General Electric Co, Milwaukee, Wis). Axial images were acquired parallel to the anteroposterior commissural line with an echo time of 5 milliseconds; repetition time of 24 milliseconds; matrix 256 × 192; number of excitations of 1; field of view of 24 cm; and 124 contiguous slices with a thickness of 1.2 mm.

IMAGE ANALYSIS

Emission data from SPECT scans were reconstructed from counts acquired in the 123I photopeak (159 keV) with a 20% symmetric window using a Butterworth filter (power factor = 10, cutoff = 0.24 cm). An attenuation map was reconstructed from the transmission and flood data and was used for nonuniform attenuation correction.34 The magnetic resonance image was coregistered to the emission image and reoriented to the intercommissural plane. Standardized 2-dimensional region of interest templates were placed on the medial frontal cortex (12.3 cm2), anterior cingulate (3.1 cm2), hippocampal-amygdala area (5.4 cm2), and cerebellum (25 cm2). Three-dimensional volumes of interest were transferred to coregistered SPECT images. Regional activities from right and left hemispheres were averaged, decay corrected, and expressed as kilobecquerels per cubic centimeter using a calibration factor of 337.44 Bq/cpm derived from a 123I-distributed source phantom. Regional activities (kilobecquerels per cubic centimeter) were normalized to free 123I-iomazenil (kilobecquerels per milliliter) plasma levels.35

STATISTICAL ANALYSES

A voxel-based analysis was conducted using statistical parametric mapping (SPM99; FIL, Wellcome Department of Imaging Neuroscience, University College of London, London, England). For each subject, a mean image was made from the 3 123I-iomazenil emission scans scaled to the total volume of distribution (VT; milliliters per cubic centimeter). A mean iomazenil VT template was made from all study subjects and was spatially normalized to the SPECT blood flow template in SPM99 using a mask to occlude uncommon brain areas. Thereafter, each mean VT map from each subject was spatially normalized to the mean iomazenil SPECT VT template and smoothed using a gaussian kernel of 12 mm × 12 mm × 12 mm. Statistical analyses between comparison groups were conducted without global normalization. Overall effects were determined using an F threshold of 300 between 5 groups, including controls, smokers with alcohol dependence who were abstinent from alcohol for less than 1 week, nonsmokers with alcohol dependence who were abstinent from alcohol for less than 1 week, smokers with alcohol dependence who were abstinent from alcohol for less than 4 weeks, and nonsmokers with alcohol dependence who were abstinent from alcohol for less than 4 weeks. The t statistic images were thresholded to a minimum cluster size of 42 voxels, calculated based on the nominal resolution, ie, the full width at half maximum of a point source in water in the Picker Prism 3000XP SPECT camera. Between-group analyses were conducted comparing subjects in the control and alcohol-dependent groups. In the alcohol-dependent groups, the relationship between 123I-iomazenil VT and various clinical measures of alcohol dependence were explored. The anatomic location of the most significant voxel in clusters demonstrating statistical significance after corrections for multiple comparisons was determined after conversion of Montreal Neurological Institute stereotaxic coordinates to Talairach coordinates and submission of the results to Talairach Daemon.36,37

Region of interest data were analyzed using SAS version 8.2 (SAS Institute Inc, Cary, NC). Data were examined for normality using normal probability plots and Kolmogorov-Smirnov test statistics. Differences in VT between subjects in the control and alcohol-dependent groups and between smokers and nonsmokers were assessed using a mixed-effects regression model with 123I-iomazenil VT as the dependent variable and with group (subjects with alcohol dependence or control subjects), smoking status (yes or no), region of interest, and interactions as fixed factors and unstructured variance-covariance matrix across regions. Nonsignificant interactions were dropped from the model for parsimony. Age was considered as a covariate but was not significant and was dropped from the model. Correlations with clinical variables for the patients were also assessed using mixed models with 123I-iomazenil VT as the dependent variable and smoking, region of interest, 1 clinical variable at a time, and all possible interactions as independent variables. Different slopes for smokers and nonsmokers were estimated to illustrate the relationship between significant clinical variables and the dependent variable. Statistical significance was considered at P = .05. Bonferroni correction was used to correct for multiple comparisons for post hoc region of interest analyses.

CLINICAL POPULATION

Twenty-three men with alcohol dependence, including 15 smokers and 8 nonsmokers, and 15 control men, including 5 smokers and 10 nonsmokers, were included in the clinical population (Table 1). Smokers in the alcohol-dependent and control groups demonstrated similar Fagerstrom Test for Nicotine Dependence scores. Smokers with alcohol dependence tended to have lower plasma cotinine levels compared with control smokers (t17 = 2, P = .06). Subjects with alcohol dependence reported smoking, on average, 1 pack of cigarettes per day, which was similar to control smokers; however, once they became inpatients where they had up to 4 escorted “smoking breaks” each day, they were not able to match their outpatient smoking frequency, as demonstrated by differences in plasma cotinine levels and the severity of nicotine withdrawal (Table 1). More than half of the men with alcohol dependence exhibited a paternal history of alcohol dependence, with a higher proportion of this family history in nonsmokers as compared with smokers. The average age at onset, the severity of alcohol dependence, and alcohol craving were similar between smokers and nonsmokers. An insignificant trend toward greater severity of alcohol withdrawal symptoms was noted in the nonsmokers as compared with smokers (Table 2). Smokers with alcohol dependence drank more alcohol than nonsmokers with alcohol dependence in the past month.

Table Graphic Jump LocationTable 1. Demographics and Smoking Characteristics of Healthy Nonsmokers, Healthy Smokers, Nonsmokers With Alcohol Dependence, and Smokers With Alcohol Dependence*
Table Graphic Jump LocationTable 2. Characteristics of Nonsmokers With Alcohol Dependence and Smokers With Alcohol Dependence*
123I-IOMAZENIL UPTAKE AT 1 AND 4 WEEKS OF SOBRIETY

There were no between-group differences in the injected dose, bolus-infusion ratio, and time of scan (data not shown). There was a trend difference in mean ± SD levels of total 123I-iomazenil: control nonsmokers, 0.18 ± 0.04 kBq/mL; control smokers, 0.16 ± 0.03 kBq/mL; nonsmokers with alcohol dependence who were abstinent from alcohol for less than 1 week, 0.15 ± 0.03 kBq/mL; smokers with alcohol dependence who were abstinent from alcohol for less than 1 week, 0.14 ± 0.03 kBq/mL; nonsmokers with alcohol dependence who were abstinent from alcohol for less than 4 weeks, 0.16 ± 0.05 kBq/mL; and smokers with alcohol dependence who were abstinent from alcohol for less than 4 weeks, 0.14 ± 0.04 kBq/mL; where F2,31 = 3.06 and P = .06. There was also a trend difference in mean ± SD levels of free 123I-iomazenil: control nonsmokers, 0.07 ± 0.02 kBq/mL; control smokers, 0.05 ± 0.01 kBq/mL; nonsmokers with alcohol dependence who were abstinent from alcohol for less than 1 week, 0.05 ± 0.01 kBq/mL; smokers with alcohol dependence who were abstinent from alcohol for less than 1 week, 0.05 ± 0.01 kBq/mL; nonsmokers with alcohol dependence who were abstinent from alcohol for less than 4 weeks, 0.05 ± 0.01 kBq/mL; and smokers with alcohol dependence who were abstinent from alcohol for less than 4 weeks, 0.05 ± 0.01 kBq/mL; where F2,31 = 5.30 and P = .01, with lower levels in subjects with alcohol dependence compared with levels in control subjects. The difference in 123I-iomazenil clearance is corrected for in the outcome measure, VT, which is equal to the total regional activity divided by the free 123I-iomazenil in blood. Plasma 123I-iomazenil levels were similar between smokers and nonsmokers.

123I-iomazenil uptake was higher throughout the brain for subjects with alcohol dependence, but the degree of difference and significance varied in a region-dependent manner. A voxel-based analysis designed to determine if there was any group × time interaction in a 1-way analysis of variance of alterations in 123I-iomazenil uptake between (1) control nonsmokers, n = 10, plus control smokers, n = 5 (123I-iomazenil VT uptake did not differ between control smokers and nonsmokers, and n = 5 is too small for voxel-based analyses; therefore, control smokers and nonsmokers were pooled); (2) smokers with alcohol dependence who were abstinent from alcohol for less than 1 week (n = 15); (3) nonsmokers with alcohol dependence who were abstinent from alcohol for less than 1 week (n = 8); (4) smokers with alcohol dependence who were abstinent from alcohol for less than 4 weeks; and (5) nonsmokers with alcohol dependence who were abstinent from alcohol for less than 4 weeks. This analysis demonstrated significant differences in left frontal inferior and middle gyrus, Brodmann areas (BAs) 11 and 47; right occipital lobe, BA 19; left and right temporal lobe, BA 21; and the cingulate gyrus, BA 31. The most significant cluster (with the highest F value) was noted in the frontal cortex. A plot of this cluster demonstrated higher 123I-iomazenil uptake in nonsmokers with alcohol dependence who were abstinent from alcohol for less than 1 week compared with smokers with alcohol dependence who were abstinent from alcohol for 1 week and control subjects. This effect appeared to normalize by 4 weeks of abstinence (Figure 1).

Place holder to copy figure label and caption
Figure 1.

Voxel-based analysis using statistical parametric mapping (SPM99; FIL, Wellcome Department of Imaging Neuroscience, University College of London, London, England) of F test of all effects for iodine I 123–labeled iomazenil regional distribution volume (VT; all F5,53>300). A, The projection views illustrate the regions where 123I-iomazenil regional distribution volume is altered (set-level P value = 0 for all clusters; height threshold F = 300.00; extent threshold k = 0 voxels) for the comparison illustrated in the design matrix, including group 1, all control subjects (10 nonsmokers and 5 smokers; scan numbers 1-15); group 2, smokers with alcohol dependence (AS) who were abstinent from alcohol for less than 1 week (n = 15; scan numbers 16-31); group 3, nonsmokers with alcohol dependence (ANS) who were abstinent from alcohol for less than 1 week (n = 8; scan numbers 32-38); group 4, AS who were abstinent from alcohol for less than 4 weeks (n = 14; scan numbers 39-52); and group 5, ANS who were abstinent from alcohol for less than 4 weeks (n = 6; scan numbers 53-58). B, Plot of the activity (fitted and adjusted responses for all effects) at the voxel with the highest F value, suggesting that the ANS who have been abstinent from alcohol for less than 1 week have higher uptake compared with all other groups. C, The region localization of significant clusters on mean 123I-iomazenil regional distribution volume maps of all study participants. D, Representative magnetic resonance image from a single subject.

Graphic Jump Location

Analysis of the t statistic maps comparing nonsmokers with alcohol dependence who were abstinent from alcohol for less than 1 week vs control subjects (n = 15) indicated significantly higher 123I-iomazenil uptake in the frontal (BA 47), insular (BA 13), occipital (BAs 17 and 19), temporal (BA 21), and parietal (BA 40) cortices as an overall group (P = 0; set-level) and as 6 individual clusters after corrections for multiple comparisons, with a P value range of .002 to .05 (Figure 2). The effects of smoking were also examined using a mixed-model analysis for 4 brain areas, including medial frontal cortex, anterior cingulate cortex, hippocampal-amygdala area, and cerebellum. There was significant group by smoking interaction (F1,34 = 5.54; P = .02) with significant differences between control subjects and nonsmokers with alcohol dependence who were abstinent from alcohol for 1 week (28.4%, 29.5%, 31.6%, and 13.7% for medial frontal cortex, anterior cingulate cortex, hippocampal-amygdala area, and cerebellum, respectively; F1,34 = 6.24; P = .02), but not between control subjects and smokers with alcohol dependence who were abstinent for 1 week (14%, 14%, 6.2%, and 5.2% for medial frontal cortex, anterior cingulate cortex, hippocampal-amygdala area, and cerebellum, respectively; F1,34 = 0.81; P = .37) (Figure 3, Table 3). There were no significant differences between smokers in the control and alcohol-dependent groups and nonsmokers in these groups who were abstinent from alcohol for 4 weeks. There was a significant positive association between the number of days of abstinence from alcohol for nonsmokers with alcohol dependence (t19 = 2.35, P = .03) but not for smokers with alcohol dependence (t19 = −0.34, P = .70) (Table 4). Pearson product correlations demonstrated statistically significant correlation coefficients between days of abstinence from alcohol and 123I-iomazenil uptake in medial frontal cortex and cerebellum (Figure 4), suggesting that GABAA-BZ receptors increased over the first week of abstinence in nonsmokers with alcohol dependence but not in smokers with alcohol dependence.

Place holder to copy figure label and caption
Figure 2.

Voxel-based analysis (t test) demonstrating higher iodine I 123–labeled iomazenil uptake in nonsmokers with alcohol dependence who were abstinent from alcohol for less than 1 week compared with control subjects. A, The t statistic map (t53; height threshold t = 3.25; extent threshold k = 42 voxels) illustrates brain regions with higher 123I-iomazenil regional distribution volume in nonsmokers with alcohol dependence who were abstinent from alcohol for less than 1 week (n = 8) compared with control subjects (n = 15), as illustrated in the design matrix (group 3>group 1). (For explanation of groups and scan numbers, see Figure 1A legend.) B, Scatter plot illustrates the regional distribution volume (VT) centered around the mean at the voxel with the highest F value for controls (1 on the x-axis) and nonsmokers with alcohol dependence (3 on the x-axis). C, The region localization of significant clusters on mean 123I-iomazenil regional distribution volume maps of all study participants. D, Representative magnetic resonance image from a single subject.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 3.

Scatterplots illustrating individual iodine I 123–labeled iomazenil regional distribution volume (VT) values for region of interest analyses. Regional distribution volume (regional activity/free plasma parent) determined from the region of interest analyses for each individual subject is illustrated for the medial frontal cortex (A), anterior cingulate cortex (B), hippocampal-amygdala area (C), and cerebellum (D) for the healthy nonsmokers (HNS), healthy smokers (HS), nonsmokers with alcohol dependence (ANS) who were abstinent from alcohol for less than 1 week, smokers with alcohol dependence (AS) who were abstinent from alcohol for less than 1 week, ANS who were abstinent from alcohol for less than 4 weeks, and AS who were abstinent from alcohol for less than 4 weeks. The mixed-regression analysis suggested that when analyzed as a group, the ANS who were abstinent from alcohol for less than 1 week were greater in the total volume of distribution than HNS and HS, and when analyzed individually, this comparison was significant only in the hippocampal-amygdala area.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 4.

Graph illustrating the correlation between iodine I 123–labeled iomazenil uptake and the number of days since the last alcoholic drink was consumed. The correlation between the number of days since consuming the last alcoholic drink and individual 123I-iomazenil regional distribution volume (VT) values were plotted for the medial frontal cortex (mFC) and cerebellum (CB) for nonsmokers with alcohol dependence who were abstinent from alcohol for less than 1 week of abstinence (A) and smokers with alcohol dependence with less than 1 week of abstinence from alcohol (B). Note the significant correlation between 123I-iomazenil VT and the number of days since consuming the last alcoholic drink in the nonsmoker group and the lack of correlation in the smoker group.

Graphic Jump Location
Table Graphic Jump LocationTable 3. Benzodiazepine-Receptor Distribution Volume in Different Brain Regions of Subjects in Control and Alcohol-Dependent Groups*
Table Graphic Jump LocationTable 4. Correlation of Iodine I 123–Labeled Iomazenil Uptake in Subjects With Alcohol Dependence Who Were Abstinent From Alcohol for Less Than 1 Week

Voxel-based comparisons of 123I-iomazenil uptake between subjects with alcohol dependence who were abstinent from alcohol for less than 1 week and for less than 4 weeks did not yield significant differences in gray matter brain areas (data not shown). Likewise, in the mixed-model analysis, 123I-iomazenil VT was not significantly different between smokers and nonsmokers with alcohol dependence between 1 and 4 weeks of abstinence from alcohol. These findings are not consistent with the early findings in the F test analysis, most likely because of the small number of subjects in the alcohol-dependent nonsmoker groups.

RELATIONSHIP BETWEEN 123I-IOMAZENIL UPTAKE AND CLINICAL FEATURES

The relationship between regional 123I-iomazenil uptake and various clinical characteristics of the subjects with alcohol dependence were assessed (Figure 4 and Figure 5; Table 2 and Table 4). A significant positive correlation with 123I-iomazenil uptake in medial frontal cortex and cerebellum and the days since the last alcoholic drink was consumed was noted at 1 week of abstinence in nonsmokers with alcohol dependence but not in smokers with alcohol dependence. Voxel-based comparisons in subjects with alcohol dependence who were abstinent from alcohol for less than 1 week demonstrated significant positive correlation with the severity of alcohol withdrawal in the occipital lobe (BAs 17, 18, and 19) and the cerebellum, which was also demonstrated in the cerebellum region of interest analysis. There were no significant correlations with the other clinical variables.

Place holder to copy figure label and caption
Figure 5.

Voxel-based analysis demonstrating the correlation between iodine I 123–labeled iomazenil regional distribution volume (VT) and the severity of alcohol withdrawal. Voxel-based correlation between the severity of alcohol withdrawal was determined using the Clinical Institute Withdrawal Assessment (CIWA) and 123I-iomazenil VT values for all subjects with alcohol dependence (n = 23) with less than 1 week of abstinence from alcohol. A, The t statistic map (t16; height threshold t = 3.69; extent threshold k = 42 voxels). Design matrix shows relationship between 7 clinical variables, where group 4 is the peak CIWA score; the scan numbers refer to the 23 smokers and nonsmokers with alcohol dependence who were abstinent from alcohol for less than 1 week. B, Plot of the activity (fitted and adjusted responses) at less than 1 week of abstinence from alcohol; distribution volumes (VT) are centered around the mean at the highest t statistic value. C, The region localization of significant clusters on mean 123I-iomazenil VT maps of all study participants. D, Representative magnetic resonance image from a single subject.

Graphic Jump Location

The present study evaluated adaptive changes in GABAA-BZ–receptor availability in subjects with alcohol dependence over the first month of sobriety using SPECT and 123I-iomazenil. 123I-iomazenil is a potent competitive BZ antagonist with weak inverse agonist properties38,39 that has pharmacological specificity similar to flumazenil, a well-known, structurally related BZ antagonist,3943 and Ro4513, a partial inverse agonist. 123I-iomazenil binds to all α1 through α6 subtypes and thus is a measure of all GABAA receptors in the brain. The present findings demonstrate higher 123I-iomazenil binding to GABAA-BZ receptors in the parietal, frontal, cingulate, temporal, insular, and occipital cortices of nonsmokers with alcohol dependence at 1 week of abstinence from alcohol but not of smokers with alcohol dependence at 1 week of abstinence from alcohol, as compared with the control group. The GABAA-BZ–receptor availability correlated with the severity of alcohol withdrawal in all of the subjects with alcohol dependence and correlated positively with the number of days since the last alcoholic drink was consumed by the nonsmokers with alcohol dependence but not the smokers with alcohol dependence. The time-dependent changes in GABAA-BZ–receptor availability are supported by an earlier study17 that demonstrated a time-dependent change in response to BZ challenge in orbitofrontal and cingulate cortices in subjects with alcoholism who were abstinent from alcohol for 2 to 3 weeks and for 6 to 8 weeks. Collectively, these findings suggest that both time since consuming the last alcoholic drink and smoking status are critical variables that need to be taken into account when studying the adaptations in GABAA-BZ–receptor expression throughout recovery from alcohol dependence.

Increased GABAA-BZ–receptor expression, as well as augmented GABA-mediated enhancement of BZ binding, has been observed in the superior frontal cortex of postmortem human brain from subjects with alcohol dependence who were without complications.18,19,44 Since BZ binding is differentially sensitive to α subunits,45 the increase may be a consequence of subunit changes that occur in response to abrupt withdrawal after chronic alcohol consumption.46 In postmortem frontal cortex from humans with alcoholism, α1 and β3 messenger RNA (mRNA) is enhanced whereas α2, α3, and α4 mRNA is not significantly altered.47,48 In rats chronically treated with ethanol, levels of cortical α1, α2, and α5 mRNA and α1, α2, and α3 polypeptides are decreased whereas α4 mRNA levels are increased.4953 During withdrawal, α1 and α4 levels rapidly normalize.54,55 The decrease in α1 subunit levels appears to be owing to ethanol-induced internalization of cortical α1-GABAA receptors56 that results in decreased cell surface and increased intracellular GABAA-BZ receptors. It is not clear whether iomazenil labels cell surface or intracellular receptors or binds to both receptor populations. If iomazenil labels both populations, then the observed increase reflects increased internalized or intracellular receptors in addition to decreased cell surface receptors, which would have an overall net effect of decreased GABAA-BZ–receptor function during early sobriety.

EFFECTS OF SMOKING AND RELEVANCE TO GABAA-BZ RECEPTORS

The up-regulation in 123I-iomazenil uptake and the correlation with days since consuming the last alcoholic drink observed in nonsmokers with alcohol dependence were attenuated in smokers, suggesting that smoking suppressed the increase in levels of GABAA-BZ receptors during early sobriety. This finding is of great importance given the high prevalence (up to 90%) of smoking among subjects with alcohol dependence. While smokers tend to suffer from more severe alcohol dependence,5759 they also report feeling less intoxicated on alcohol challenge.60 In the present study, there was a trend for smokers with alcohol dependence to report fewer alcohol withdrawal symptoms, suggesting that smoking may reduce the severity of withdrawal. In support of this, mice treated long-term with ethanol develop a greater and long-lasting response to inverse agonists, suggesting that BZ inverse agonists may antagonize ethanol intoxication.61,62 These findings, combined with the observation for a tendency for 123I-iomazenil to correlate with the reported severity of withdrawal in the nonsmokers with alcohol dependence but not in smokers with alcohol dependence, suggest that the greater the adaptive increase in GABAA-BZ–receptor expression is, the more severe the withdrawal symptoms are. Thus, it would appear that smoking might prevent GABAA- receptor adaptations associated with alcohol dependence and withdrawal. Furthermore, these findings predict that smokers with alcohol dependence should have greater success with abstaining from alcohol should they continue to smoke during acute withdrawal. Moderate smokers tend to increase the intensity of smoking during ethanol detoxification to suppress ethanol withdrawal symptoms.63

Several constituents of tobacco smoke may play a role in the impact of smoking. Nicotine directly stimulates GABA neuronal activity and may, therefore, suppress alcohol withdrawal symptoms.64 Cigarette smoke also contains β-carbolines that have been measured in the plasma from smokers in the control and alcohol-dependent groups.65 The β-carbolines are well known as monoamine oxidase inhibitors but have also been suggested to be GABAA-BZ– receptor inverse agonists and to antagonize some of the effects of ethanol. There has been some debate about whether the β-carbolines reach sufficient levels in the brain to have pharmacological effects.66,67 They do achieve sufficient levels to inhibit monoamine oxidase enzymes,6871 but they have a 2- to 10-fold lower affinity for binding to GABAA-BZ receptors as compared with monoamine oxidase.66,67,7274 Definitive conclusions about the role of the β-carbolines on GABAA-BZ–receptor availability in the present study without plasma measures are speculative, and this should be addressed in future studies. Additionally, other compounds in tobacco smoke or other receptor mechanisms may be responsible for the opposing effects of tobacco smoke on alcohol withdrawal symptoms.

RELATIONSHIP OF SMOKING TO CHANGES IN CORTICAL GABA DURING EARLY RECOVERY

Interpretation of the current study in light of concurrent cortical GABA level measurements made in the same subjects may shed light on the functional implications of the time-dependent changes in 123I-iomazenil observed in subjects in this study.75 The GABA levels are modulated by GABAA-BZ receptors to maintain GABAergic neurotransmission. For example, clonazepam produces a substantial decrease in cortical GABA levels measured using 1H-magnetic resonance spectroscopy in healthy human subjects.76 Thus, it is possible that a shift from α4 or α6 BZ-insensitive, inverse agonist–sensitive GABAA receptors to α1 BZ-sensitive GABAA receptors during the recovery from alcohol dependence would be marked by a decline in cortical GABA levels. In fact, nonsmokers with alcohol dependence in this study exhibited normal cortical GABA levels in the first week of abstinence from alcohol that declined over the first month of sobriety75 and remained low over the next 5 months whereas smokers with alcohol dependence demonstrated low cortical GABA levels that did not vary between 1 and 4 weeks of abstinence.75,77 In nondrinkers, cortical GABA levels do not vary between men who do and who do not smoke.78 The effects of smoking on GABAA-BZ–receptor availability have yet to be evaluated. The relationship of the subunit substitutions during alcohol dependence and withdrawal to GABAA-receptor function is not clear. However, there is a wealth of data demonstrating decreased GABAA- receptor function in response to chronic ethanol use that may occur owing to increased inverse agonist–sensitive α4 subunits that increase the sensitivity to inverse agonists that would reduce GABAA-receptor function. With sobriety, the restoration of BZ-sensitive, inverse agonist–insensitive GABAA receptors may alleviate a GABAA-BZ–receptor functional deficit and may contribute to the decline in cortical GABAA binding and GABA levels associated with recovery. It is not yet clear whether the reductions in GABA levels, 123I-iomazenil uptake, and lorazepam response that may persist with extended sobriety reflect a persisting consequence of alcohol dependence, alcohol dependence–related neurotoxicity, or a preexisting trait.79

IMPLICATIONS FOR TREATMENT OF ALCOHOL WITHDRAWAL

The current data suggest that GABAA-receptor adaptations may contribute to acute ethanol withdrawal and to the recovery from alcohol dependence. While BZ treatments are the predominant detoxification strategy, a growing number of alternative approaches are being explored, including anticonvulsant medications and N-methyl-D-aspartate glutamate receptor antagonists.80,81 The current data raise the possibility that treatments that accelerate the normalization of GABAA-receptor populations may increase the rate of recovery whereas treatments that have ethanol-like effects on GABAA-receptor populations may delay recovery. The effects of these detoxification strategies on alcohol-related adaptations in human GABAA-receptor populations are currently unknown. However, there is growing interest in the possibility that these treatments might avoid the negative effects of BZ-assisted detoxification on the initiation of abstinence in patients who have completed acute detoxification.80 In this regard, it is possible that substances in tobacco smoke, such as BZ inverse agonist β-carbolines1 or nicotine, may provide clues to novel pharmacotherapeutic approaches to alcohol dependence that might prevent or treat acute withdrawal symptoms and promote the initiation and maintenance of sobriety.

Correspondence: Julie K. Staley, PhD, Department of Psychiatry, Yale University School of Medicine & VACHS 116A2, 950 Campbell Ave, West Haven, CT 06516 (julie.staley@yale.edu).

Submitted for Publication: July 30, 2004; final revision received January 10, 2005; accepted January 13, 2005.

Funding/Support: This work was supported by the Dana Foundation, New York, NY, the Veterans Affairs Mental Illness Research, Education, and Clinical Center for Dual Diagnosis, and the Veterans Affairs Alcohol Research Center, West Haven, Conn, and grants K01AA00288, K05 AA014715-01, RO1 AA1132, and P50 DA13334 from the National Institutes of Health, Bethesda, Md.

Previous Presentation: These findings have been presented in part at the Ninth Annual Meeting of the Society on Research on Nicotine and Tobacco; February 19-22, 2003; New Orleans, La; the Annual Meeting of the Society for Neuroscience; November 2002; Orlando, Fla; the Congreso Internacional las Neurosciencias y las Adicciones: Nuevos Desarrollos, Nuevas Esperanzas; June 2002; Mexico City, Mexico; the 25th Annual Meeting of the Research Society on Alcoholism; June 2002; San Francisco, Calif; the 26th Annual Meeting of the Research Society on Alcoholism; June 2003; Miami, Fla; and the 42nd Annual Meeting of the American College for Neuropsychopharmacology; December 2003; San Juan, Puerto Rico.

Acknowledgment: We thank Louis Amici and Nina Sheung for their expert technical assistance in the synthesis and metabolite analyses of 123I-iomazenil.

Davies  M The role of GABAA receptors in mediating the effects of alcohol in the central nervous system. J Psychiatry Neurosci 2003;28263- 274
PubMed
Grobin  AMatthews  DDevaud  LMorrow  A The role of GABA(A) receptors in the acute and chronic effects of ethanol. Psychopharmacology (Berl) 1998;1392- 19
PubMed Link to Article
Krystal  JTabakoff  B Ethanol abuse, dependence, and withdrawal: neurobiology and clinical implications. Davis  KCharney  DCoyle  JNemeroff  Ceds.Psychopharmacology A Fifth Generation of Progress. Philadelphia, Pa Lippincott Williams & Wilkins2002;1425- 1443
Sullivan  JSykora  KSchneiderman  JNaranjo  CSellers  E Assessment of alcohol withdrawal: the revised clinical institute withdrawal assessment for alcohol scale (CIWA-Ar). Br J Addict 1989;841353- 1357
PubMed Link to Article
Sullivan  JSwift  RLewis  D Benzodiazepine requirements during alcohol withdrawal syndrome: clinical implications of using a standardized withdrawal scale. J Clin Psychopharmacol 1991;11291- 295
PubMed Link to Article
Littleton  JLittle  H Current concepts of ethanol dependence. Addiction 1994;891397- 1412
PubMed Link to Article
Grobin  APapadeas  SMorrow  A Regional variations in the effects of chronic ethanol administration on GABA(A) receptors expression: potential mechanisms. Neurochem Int 2000;37453- 461
PubMed Link to Article
Morrow  AVanDoren  MPenland  SMatthews  D The role of GABAergic neuroactive steroids in ethanol action, tolerance and dependence. Brain Res Brain Res Rev 2001;3798- 109
PubMed Link to Article
Mihic  SYe  QWick  MKoltchine  VVKrasowski  MDFinn  SEMascia  MPValenzuela  CFHanson  KKGreenblatt  EPHarris  RAHarrison  NL Sites of alcohol and volatile anesthetic action on GABAA and glycine receptors. Nature 1997;389385- 389
PubMed Link to Article
Olsen  R Drug interactions at the GABA receptor-ionophore complex. Annu Rev Pharmacol Toxicol 1982;22245- 277
PubMed Link to Article
Gilman  SKoeppe  RAdams  KJohnson-Greene  DJunck  LKluin  KJBrunberg  JMartorello  SLohman  M Positron emission tomographic studies of cerebral benzodiazepine-receptor binding in chronic alcoholics. Ann Neurol 1996;40163- 171
PubMed Link to Article
Abi-Dargham  AKrystal  JAnjivel  SScanley  BEZoghbi  SBaldwin  RMRajeevan  NEllis  SPetrakis  ILSeibyl  JPCharney  DSLaruelle  MInnis  RB Alterations of benzodiazepine receptors in type II alcoholics measured with SPECT and [123I]iomazenil. Am J Psychiatry 1998;1551550- 1555
PubMed
Lingford-Hughes  AActon  PGacinovic  SSuckling  JBusatto  GFBoddington  SJBullmore  EWoodruff  PWCosta  DCPilowsky  LSEll  PJMarshall  EJKerwin  RW Reduced levels of GABA-benzodiazepine receptor in alcohol dependency in the absence of grey matter atrophy. Br J Psychiatry 1998;173116- 122
PubMed Link to Article
Lingford-Hughes  AActon  PGacinovic  SBoddington  SJCosta  DCPilowsky  LSEll  PJMarshall  EJKerwin  RW Levels of gamma-aminobutyric acid-benzodiazepine receptors in abstinent, alcohol-dependent women: preliminary findings from an 123I-iomazenil single photon emission tomography study. Alcohol Clin Exp Res 2000;241449- 1455
PubMed
Jalan  RTurjanski  NTaylor-Robinson  SKoepp  MJRichardson  MPWilson  JABell  JDBrooks  DJ Increased availability of central benzodiazepine receptors in patients with chronic hepatic encephalopathy and alcohol related cirrhosis. Gut 2000;46546- 552
PubMed Link to Article
Volkow  NWang  GHitzemann  RFowler  JSWolf  APPappas  NBiegon  ADewey  SL Decreased cerebral response to inhibitory neurotransmission in alcoholics. Am J Psychiatry 1993;150417- 422
PubMed
Volkow  NWang  G-JOverall  JHitzemann  RFowler  JSPappas  NFrecska  EPiscani  K Regional brain metabolic response to lorazepam in alcoholics during early and late alcohol detoxification. Alcohol Clin Exp Res 1997;211278- 1284
PubMed Link to Article
Tran  VSynder  SMajor  LHawley  R GABA receptors are increased in the brains of alcoholics. Ann Neurol 1981;9289- 292
PubMed Link to Article
Dodd  PThomas  GHarper  CKril  J Amino acid neurotransmitter receptor changes in cerebral cortex in alcoholism: effect of cirrhosis of the liver. J Neurochem 1992;591506- 1515
PubMed Link to Article
Kril  JDodd  PGundlach  ADavies  NWatson  WEJohnston  GAHarper  CG Necropsy study of GABA/benzodiazepine receptor binding sites in brain tissue from chronic alcoholic patients. Clin Exp Neurol 1988;25135- 141
PubMed
Freund  GBallinger  W Decrease of benzodiazepine receptors in frontal cortex of alcoholics. Alcohol 1988;5275- 282
PubMed Link to Article
Freund  GBallinger  W Loss of muscarinic and benzodiazepine neuroreceptors from hippocampus of alcohol abusers. Alcohol 1989;623- 31
PubMed Link to Article
Litton  JNeiman  JPauli  SFarde  LHindmarsh  THalldin  CSedvall  G PET analysis of [11C]flumazenil binding to benzodiazepine receptors in chronic alcohol dependent men and healthy controls. Psychiatry Res 1993;501- 13
PubMed Link to Article
Sobell  LCSobell  MB Timeline follow-back: a technique for assessing self-reported alcohol consumption. Litten  RZAllen  JPeds.Measuring Alcohol Consumption Psychosocial and Biochemical Methods Totowa, NJ Humana Press1992;41- 72
American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders; Fourth Edition.  Washington, DC American Psychiatric Association1994;
Fujita  MWoods  SVerhoeff  NAbi-Dargham  ABaldwin  RMZoghbi  SSSoares  JCJatlow  PAKrystal  JHRajeevan  NCharney  DSSeibyl  JPInnis  RB Changes of benzodiazepine receptors during chronic benzodiazepine administration in humans. Eur J Pharmacol 1999;368161- 172
PubMed Link to Article
Skinner  HAHorn  JL Alcohol Dependence Scale (ADS) User's Guide.  Toronto, Ontario Addiction Research Foundation of Ontario1984;
Tiffany  SSingleton  EHaertzen  CAHenningfield  JE The development of a cocaine craving questionnaire. Drug Alcohol Depend 1993;3419- 28
PubMed Link to Article
Heatherton  TKozlowski  LFrecker  RFagerstrom  K The Fagerstrom Test for Nicotine Dependence: a revision of the Fagerstrom Tolerance Questionnaire. Br J Addict 1991;861119- 1127
PubMed Link to Article
Pomerleau  CCarton  SLutzke  MFlessland  KPomerleau  O Reliability of the Fagerstrom Tolerance Questionnaire and the Fagerstrom Test for Nicotine Dependence. Addict Behav 1994;1933- 39
PubMed Link to Article
Hariharan  MVanNoord  TGreden  JF A high performance liquid chromatographic method for routine simultaneous determination of nicotine and cotinine in plasma. Clin Chem 1988;34724- 729
PubMed
Zoghbi  SBaldwin  RSeibyl  Jal-Tikriti  MSZea-Ponce  YLaruelle  MSybirska  EHWoods  SWGoddard  AWMalison  RTZimmerman  RCharney  DSSmith  EOHoffer  PBInnis  RB Pharmacokinetics of the SPECT benzodiazepine receptor radioligand [123I]iomazenil in human and nonhuman primates. Int J Rad Appl Instrum B 1992;19881- 888
PubMed Link to Article
Abi-Dargham  AGandelman  MZoghbi  SLaruelle  MBaldwin  RMRandall  PZea-Ponce  YCharney  DSHoffer  PBInnis  RB Reproducibility of SPECT measurement of benzodiazepine receptors in human brain with iodine-123-iomazenil. J Nucl Med 1995;36167- 175
PubMed
Rajeevan  NZubal  IRambsy  SZoghbi  SSeibyl  JInnis  R Significance of nonuniform attenuation correction in quantitative brain SPECT imaging. J Nucl Med 1998;391719- 1726
PubMed
Abi-Dargham  ALaruelle  MSeibyl  JRattner  ZBaldwin  RMZoghbi  SSZea-Ponce  YBremner  JDHyde  TMCharney  DSHoffer  PBInnis  RB SPECT measurement of benzodiazepine receptors in human brain with [123I]iomazenil: kinetic and equilibrium paradigms. J Nucl Med 1994;35228- 238
PubMed
Lancaster  JSummerlin  JRainey  LFreitas  CFox  P The Talairach Daemon: a database server for Talairach atlas labels. Neuroimage 1997;5S633
Lancaster  JWoldorff  MParsons  LLiotti  MFreitas  CSRainey  LKochunov  PVNickerson  DMikiten  SAFox  PT Automated Talairach atlas for functional brain mapping. Hum Brain Mapp 2000;10120- 131
PubMed Link to Article
Beer  HBlauenstein  PHasler  PDelaloye  BRiccabona  GBangerl  IHunkeler  WBonetti  EPPieri  LRichards  JG In vitro and in vivo evaluation of iodine-123-Ro16-0154: a new imaging agent for SPECT investigations of benzodiazepine receptors. J Nucl Med 1990;311007- 1014
PubMed
Johnson  EWoods  SMcBride  BBaldwin  RInnis  R Receptor binding characterization of 125I-Ro16-0154: potential probe for SPECT brain imaging. Life Sci 1990;471535- 1546
PubMed Link to Article
Innis  RAl-Tikriti  MZoghbi  SBaldwin  RMSybirska  EHLaruelle  MAMalison  RTSeibyl  JPZimmermann  RCJohnson  EW SPECT imaging of the benzodiazepine receptor: feasibility of in vivo potency measurements from stepwise displacement curves. J Nucl Med 1991;321754- 1761
PubMed
Innis  RZoghbi  SJohnson  EWoods  Sal-Tikriti  MBaldwin  RSeibyl  JMalison  RZubal  GCharney  DHeninger  GHoffer  P SPECT imaging of the benzodiazepine receptor in non-human primate brain with [123I]Ro 16-0154. Eur J Pharmacol 1991;193249- 252
PubMed Link to Article
Sybirska  EAl-Tikriti  MZoghbi  SBaldwin  RJohnson  EInnis  R SPECT imaging of the benzodiazepine receptor: autoradiographic comparison of receptor density and radioligand distribution. Synapse 1992;12119- 128
PubMed Link to Article
Odano  INakajima  TMiyashita  KTakahashi  NFujita  MNaritomi  HFurusawa  THayashi  SSakai  K In vivo autoradiographic benzodiazepine binding with 125I-iomazenil. Kaku Igaku 1993;30761- 767
PubMed
Dodd  PKril  JThomas  GWatson  WJohnston  GHarper  C Receptor binding sites and uptake activities mediating GABA neurotransmission in chronic alcoholics with Wernicke encephalopathy. Brain Res 1996;710215- 228
PubMed Link to Article
Pritchett  DLuddens  HSeeberg  P Type I and type II GABAA-benzodiazepine receptors produced in transfected cells. Science 1989;2451389- 1391
PubMed Link to Article
Lewohl  JHuygens  FCrane  DDodd  P GABAA receptor alpha-subunit proteins in human chronic alcoholics. J Neurochem 2001;78424- 434
PubMed Link to Article
Lewohl  JCrane  DDodd  P Expression of the alpha1, alpha2, and alpha3 isoforms of the GABAA receptor in human alcoholic brain. Brain Res 1997;751102- 112
PubMed Link to Article
Mitsuyama  HLittle  KSieghart  WDevaud  LMorrow  A GABAA receptor alpha1, alpha4, and alpha3 subunit mRNA and protein expression in the frontal cortex of human alcoholics. Alcohol Clin Exp Res 1998;22815- 822
PubMed
Montpied  PMorrow  AKaranian  JGinns  EMartin  BPaul  S Prolonged ethanol inhalation decreases gamma-aminobutyric acidA receptor alpha subunit mRNAs in the rat cerebral cortex. Mol Pharmacol 1991;39157- 163
PubMed
Mhatre  MTicku  M Chronic ethanol administration alters gamma-aminobutyric acid A receptor gene expression. Mol Pharmacol 1992;42415- 422
PubMed
Morrow  AHerbert  JMontpied  P Differential effects of chronic ethanol administration on GABA-A receptor alpha1 and alpha6 subunit mRNA levels in rat cerebellum. Mol Cell Neurosci 1992;3251- 258
Link to Article
Mhatre  MPena  GSieghart  WTicku  M Antibodies specific for GABAA receptor alpha subunits reveal that chronic alcohol treatment down-regulates alpha subunit expression in rat brain regions. J Neurochem 1993;611620- 1625
PubMed Link to Article
Devaud  LSmith  FGrayson  DMorrow  A Chronic ethanol consumption differentially alters the expression of gamma-aminobutyric acidA receptor subunit mRNAs in rat cerebral cortex: competitive, quantitative reverse transcriptase-polymerase chain reaction analysis. Mol Pharmacol 1995;48861- 868
PubMed
Devaud  LLPurdy  RHFinn  DAMorrow  AL Sensitization of gamma-aminobutyric acidA receptors to neuroactive steroids in rats during ethanol withdrawal. J Pharmacol Exp Ther 1996;278510- 517
PubMed
Sanna  EMostallino  MBusonero  FTalani  GTranquilli  SMameli  MSpiga  SFollesa  PBiggio  G Changes in GABAA receptor gene expression associated with selective alterations in receptor function and pharmacology after ethanol withdrawal. J Neurosci 2003;2311711- 11724
PubMed
Kumar  SKralic  JO'Buckley  TGrobin  AMorrow  A Chronic ethanol consumption enhances internalization of alpha1 subunit-containing GABAA-receptors in cerebral cortex. J Neurochem 2003;86700- 708
PubMed Link to Article
Toneatto  ASobell  LSobell  MKozlowski  L Effect of cigarette smoking on alcohol treatment outcome. J Subst Abuse 1995;7245- 252
PubMed Link to Article
Daeppen  JBSmith  TDanko  GGordon  LLandi  NANurnberger  JI  JrBucholz  KKRaimo  ESchuckit  MA Clinical correlates of cigarette smoking and nicotine dependence in alcohol-dependent men and women. Alcohol Alcohol 2000;35171- 175
PubMed Link to Article
Gulliver  SKalman  DRohsennow  DColby  SEaton  CMonti  P Smoking and drinking among alcoholics in treatment: cross-sectional and longitudinal relationships. J Stud Alcohol 2000;61157- 163
PubMed
Madden  PHeath  AStarmer  GWhitfield  JMartin  N Alcohol sensitivity and smoking history in men and women. Alcohol Clin Exp Res 1995;191111- 1120
PubMed Link to Article
Buck  KHarris  R Benzodiazepine agonist and inverse agonist actions on GABAA operated chloride channels, I: acute effects of ethanol. J Pharmacol Exp Ther 1990;253706- 712
PubMed
Buck  KHarris  R Benzodiazepine agonist and inverse agonist actions on GABAA receptor-operated chloride channels, II: chronic effects of ethanol. J Pharmacol Exp Ther 1990;253713- 719
PubMed
Aubin  HLaureaus  CTilikete  SBarrucand  D Changes in cigarette smoking and coffee drinking after alcohol detoxification in alcoholics. Addiction 1999;94411- 416
PubMed Link to Article
O'Neill  ABrioni  J Benzodiazepine receptor mediation of the anxiolytic-like effect of (-)-nicotine in mice. Pharmacol Biochem Behav 1994;49755- 757
PubMed Link to Article
Breyer-Pfaff  UWiatr  GSteens  IGaertner  HMundle  GMann  K Elevated norharman plasma levels in alcoholic patients and controls resulting from tobacco smoking. Life Sci 1996;581425- 1432
PubMed Link to Article
Rommelspacher  HNanz  CBorbe  HOFehske  KJMuller  WEWollert  U 1-Methyl-beta-carboline (harmane), a potent endogenous inhibitor of benzodiazepine receptor binding. Naunyn Schmiedebergs Arch Pharmacol 1980;31497- 100
PubMed Link to Article
Cain  MWeber  RWGuzman  FCook  JMBarker  SARice  KCCrawley  JNPaul  SMSkolnick  P Beta-carbolines: synthesis and neurochemical and pharmacological actions on brain benzodiazepine receptors. J Med Chem 1982;251081- 1091
PubMed Link to Article
Rommelspacher  HMeier-Henco  MSmolka  MKloft  C The levels of norharman are high enough after smoking to affect monoamine oxidase B in platelets. Eur J Pharmacol 2002;441115- 125
PubMed Link to Article
Fowler  JSVolkow  NDWang  GJPappas  NLogan  JShea  CAlexoff  DMacGregor  RRSchlyer  DJZezulkova  IWolf  AP Brain monoamine oxidase A inhibition in cigarette smokers. Proc Natl Acad Sci U S A 1996;9314065- 14069
PubMed Link to Article
Fowler  JSVolkow  NDWang  GJPappas  NLogan  JMacGregor  RAlexoff  DShea  CSchlyer  DWolf  APWarner  DZezulkova  ICilento  R Inhibition of monoamine oxidase in the brains of smokers. Nature 1996;379733- 736
PubMed Link to Article
Fowler  JSVolkow  NDWang  GJPappas  NLogan  JMacGregor  RAlexoff  DWolf  APWarner  DCilento  RZezulkova  I Neuropharmacological actions of cigarette smoke: brain monoamine oxidase B (MAO B) inhibition. J Addict Dis 1998;1723- 24
PubMed Link to Article
Airaksinen  MMikkonen  E Affinity of beta-carbolines on rat brain benzodiazepine and opiate binding sites. Med Biol 1980;58341- 344
PubMed
Rommelspacher  HNanz  CBorbe  HFehske  KMuller  WWollert  U Benzodiazepine antagonism by harmane and other beta-carbolines in vitro and in vivo. Eur J Pharmacol 1981;70409- 416
PubMed Link to Article
May  TRommelspacher  HPawlik  M [2H]harman binding experiments, I: a reversible and selective radioligand for monoamine oxidase subtype A in the CNS of the rat. J Neurochem 1991;56490- 499
PubMed Link to Article
Mason  GFPetrakis  ILde Graaf  RAGueorguieva  RRuff  ECoric  VEpperson  CNRothman  DLKrystal  JH Cortical GABA levels and the recovery from alcohol dependence: relationship to neurotoxicity and tobacco smoking. Biol Psychiatry In press
Goddard  AMason  GRothman  DBehar  KKrystal  J Reduced cortical GABA neuronal response to benzodiazepine administration in panic disorder. Am J Psychiatry In press
Mason  GFAppel  MDeGraaf  RAPetrakis  IRuff  ERothman  DLKrystal  JH Reduction in cortical GABA levels over the first month of sobriety. Alcohol Clin Exp Res 2003;2756AAbstract 305
Epperson  CNO'Malley  SCzarkowski  KAGueorguieva  RJatlow  PSanacora  GRothman  DLKrystal  JHMason  GF Sex, GABA, and nicotine: the impact of smoking on cortical GABA levels across the menstrual cycle as measured with proton magnetic resonance spectroscopy. Biol Psychiatry 2005;5744- 48
Link to Article
Ueno  SWick  MYe  QHarrison  NHarris  R Subunit mutations affect ethanol actions on GABA(A) receptors expressed in Xenopus oocytes. Br J Pharmacol 1999;127377- 382
PubMed Link to Article
Malcolm  RMyrick  HBrady  KBallenger  J Update on anticonvulsants for the treatment of alcohol withdrawal. Am J Addict 2001;10 ((Suppl)) 16- 23
PubMed Link to Article
Krystal  JPetrakis  ITrevisan  LD'Souza  D NMDA receptor antagonism and the ethanol intoxication signal: from alcoholism risk to pharmacotherapy. Ann N Y Acad Sci 2003;1003176- 184
PubMed Link to Article

Figures

Place holder to copy figure label and caption
Figure 1.

Voxel-based analysis using statistical parametric mapping (SPM99; FIL, Wellcome Department of Imaging Neuroscience, University College of London, London, England) of F test of all effects for iodine I 123–labeled iomazenil regional distribution volume (VT; all F5,53>300). A, The projection views illustrate the regions where 123I-iomazenil regional distribution volume is altered (set-level P value = 0 for all clusters; height threshold F = 300.00; extent threshold k = 0 voxels) for the comparison illustrated in the design matrix, including group 1, all control subjects (10 nonsmokers and 5 smokers; scan numbers 1-15); group 2, smokers with alcohol dependence (AS) who were abstinent from alcohol for less than 1 week (n = 15; scan numbers 16-31); group 3, nonsmokers with alcohol dependence (ANS) who were abstinent from alcohol for less than 1 week (n = 8; scan numbers 32-38); group 4, AS who were abstinent from alcohol for less than 4 weeks (n = 14; scan numbers 39-52); and group 5, ANS who were abstinent from alcohol for less than 4 weeks (n = 6; scan numbers 53-58). B, Plot of the activity (fitted and adjusted responses for all effects) at the voxel with the highest F value, suggesting that the ANS who have been abstinent from alcohol for less than 1 week have higher uptake compared with all other groups. C, The region localization of significant clusters on mean 123I-iomazenil regional distribution volume maps of all study participants. D, Representative magnetic resonance image from a single subject.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

Voxel-based analysis (t test) demonstrating higher iodine I 123–labeled iomazenil uptake in nonsmokers with alcohol dependence who were abstinent from alcohol for less than 1 week compared with control subjects. A, The t statistic map (t53; height threshold t = 3.25; extent threshold k = 42 voxels) illustrates brain regions with higher 123I-iomazenil regional distribution volume in nonsmokers with alcohol dependence who were abstinent from alcohol for less than 1 week (n = 8) compared with control subjects (n = 15), as illustrated in the design matrix (group 3>group 1). (For explanation of groups and scan numbers, see Figure 1A legend.) B, Scatter plot illustrates the regional distribution volume (VT) centered around the mean at the voxel with the highest F value for controls (1 on the x-axis) and nonsmokers with alcohol dependence (3 on the x-axis). C, The region localization of significant clusters on mean 123I-iomazenil regional distribution volume maps of all study participants. D, Representative magnetic resonance image from a single subject.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 3.

Scatterplots illustrating individual iodine I 123–labeled iomazenil regional distribution volume (VT) values for region of interest analyses. Regional distribution volume (regional activity/free plasma parent) determined from the region of interest analyses for each individual subject is illustrated for the medial frontal cortex (A), anterior cingulate cortex (B), hippocampal-amygdala area (C), and cerebellum (D) for the healthy nonsmokers (HNS), healthy smokers (HS), nonsmokers with alcohol dependence (ANS) who were abstinent from alcohol for less than 1 week, smokers with alcohol dependence (AS) who were abstinent from alcohol for less than 1 week, ANS who were abstinent from alcohol for less than 4 weeks, and AS who were abstinent from alcohol for less than 4 weeks. The mixed-regression analysis suggested that when analyzed as a group, the ANS who were abstinent from alcohol for less than 1 week were greater in the total volume of distribution than HNS and HS, and when analyzed individually, this comparison was significant only in the hippocampal-amygdala area.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 4.

Graph illustrating the correlation between iodine I 123–labeled iomazenil uptake and the number of days since the last alcoholic drink was consumed. The correlation between the number of days since consuming the last alcoholic drink and individual 123I-iomazenil regional distribution volume (VT) values were plotted for the medial frontal cortex (mFC) and cerebellum (CB) for nonsmokers with alcohol dependence who were abstinent from alcohol for less than 1 week of abstinence (A) and smokers with alcohol dependence with less than 1 week of abstinence from alcohol (B). Note the significant correlation between 123I-iomazenil VT and the number of days since consuming the last alcoholic drink in the nonsmoker group and the lack of correlation in the smoker group.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 5.

Voxel-based analysis demonstrating the correlation between iodine I 123–labeled iomazenil regional distribution volume (VT) and the severity of alcohol withdrawal. Voxel-based correlation between the severity of alcohol withdrawal was determined using the Clinical Institute Withdrawal Assessment (CIWA) and 123I-iomazenil VT values for all subjects with alcohol dependence (n = 23) with less than 1 week of abstinence from alcohol. A, The t statistic map (t16; height threshold t = 3.69; extent threshold k = 42 voxels). Design matrix shows relationship between 7 clinical variables, where group 4 is the peak CIWA score; the scan numbers refer to the 23 smokers and nonsmokers with alcohol dependence who were abstinent from alcohol for less than 1 week. B, Plot of the activity (fitted and adjusted responses) at less than 1 week of abstinence from alcohol; distribution volumes (VT) are centered around the mean at the highest t statistic value. C, The region localization of significant clusters on mean 123I-iomazenil VT maps of all study participants. D, Representative magnetic resonance image from a single subject.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 1. Demographics and Smoking Characteristics of Healthy Nonsmokers, Healthy Smokers, Nonsmokers With Alcohol Dependence, and Smokers With Alcohol Dependence*
Table Graphic Jump LocationTable 2. Characteristics of Nonsmokers With Alcohol Dependence and Smokers With Alcohol Dependence*
Table Graphic Jump LocationTable 3. Benzodiazepine-Receptor Distribution Volume in Different Brain Regions of Subjects in Control and Alcohol-Dependent Groups*
Table Graphic Jump LocationTable 4. Correlation of Iodine I 123–Labeled Iomazenil Uptake in Subjects With Alcohol Dependence Who Were Abstinent From Alcohol for Less Than 1 Week

References

Davies  M The role of GABAA receptors in mediating the effects of alcohol in the central nervous system. J Psychiatry Neurosci 2003;28263- 274
PubMed
Grobin  AMatthews  DDevaud  LMorrow  A The role of GABA(A) receptors in the acute and chronic effects of ethanol. Psychopharmacology (Berl) 1998;1392- 19
PubMed Link to Article
Krystal  JTabakoff  B Ethanol abuse, dependence, and withdrawal: neurobiology and clinical implications. Davis  KCharney  DCoyle  JNemeroff  Ceds.Psychopharmacology A Fifth Generation of Progress. Philadelphia, Pa Lippincott Williams & Wilkins2002;1425- 1443
Sullivan  JSykora  KSchneiderman  JNaranjo  CSellers  E Assessment of alcohol withdrawal: the revised clinical institute withdrawal assessment for alcohol scale (CIWA-Ar). Br J Addict 1989;841353- 1357
PubMed Link to Article
Sullivan  JSwift  RLewis  D Benzodiazepine requirements during alcohol withdrawal syndrome: clinical implications of using a standardized withdrawal scale. J Clin Psychopharmacol 1991;11291- 295
PubMed Link to Article
Littleton  JLittle  H Current concepts of ethanol dependence. Addiction 1994;891397- 1412
PubMed Link to Article
Grobin  APapadeas  SMorrow  A Regional variations in the effects of chronic ethanol administration on GABA(A) receptors expression: potential mechanisms. Neurochem Int 2000;37453- 461
PubMed Link to Article
Morrow  AVanDoren  MPenland  SMatthews  D The role of GABAergic neuroactive steroids in ethanol action, tolerance and dependence. Brain Res Brain Res Rev 2001;3798- 109
PubMed Link to Article
Mihic  SYe  QWick  MKoltchine  VVKrasowski  MDFinn  SEMascia  MPValenzuela  CFHanson  KKGreenblatt  EPHarris  RAHarrison  NL Sites of alcohol and volatile anesthetic action on GABAA and glycine receptors. Nature 1997;389385- 389
PubMed Link to Article
Olsen  R Drug interactions at the GABA receptor-ionophore complex. Annu Rev Pharmacol Toxicol 1982;22245- 277
PubMed Link to Article
Gilman  SKoeppe  RAdams  KJohnson-Greene  DJunck  LKluin  KJBrunberg  JMartorello  SLohman  M Positron emission tomographic studies of cerebral benzodiazepine-receptor binding in chronic alcoholics. Ann Neurol 1996;40163- 171
PubMed Link to Article
Abi-Dargham  AKrystal  JAnjivel  SScanley  BEZoghbi  SBaldwin  RMRajeevan  NEllis  SPetrakis  ILSeibyl  JPCharney  DSLaruelle  MInnis  RB Alterations of benzodiazepine receptors in type II alcoholics measured with SPECT and [123I]iomazenil. Am J Psychiatry 1998;1551550- 1555
PubMed
Lingford-Hughes  AActon  PGacinovic  SSuckling  JBusatto  GFBoddington  SJBullmore  EWoodruff  PWCosta  DCPilowsky  LSEll  PJMarshall  EJKerwin  RW Reduced levels of GABA-benzodiazepine receptor in alcohol dependency in the absence of grey matter atrophy. Br J Psychiatry 1998;173116- 122
PubMed Link to Article
Lingford-Hughes  AActon  PGacinovic  SBoddington  SJCosta  DCPilowsky  LSEll  PJMarshall  EJKerwin  RW Levels of gamma-aminobutyric acid-benzodiazepine receptors in abstinent, alcohol-dependent women: preliminary findings from an 123I-iomazenil single photon emission tomography study. Alcohol Clin Exp Res 2000;241449- 1455
PubMed
Jalan  RTurjanski  NTaylor-Robinson  SKoepp  MJRichardson  MPWilson  JABell  JDBrooks  DJ Increased availability of central benzodiazepine receptors in patients with chronic hepatic encephalopathy and alcohol related cirrhosis. Gut 2000;46546- 552
PubMed Link to Article
Volkow  NWang  GHitzemann  RFowler  JSWolf  APPappas  NBiegon  ADewey  SL Decreased cerebral response to inhibitory neurotransmission in alcoholics. Am J Psychiatry 1993;150417- 422
PubMed
Volkow  NWang  G-JOverall  JHitzemann  RFowler  JSPappas  NFrecska  EPiscani  K Regional brain metabolic response to lorazepam in alcoholics during early and late alcohol detoxification. Alcohol Clin Exp Res 1997;211278- 1284
PubMed Link to Article
Tran  VSynder  SMajor  LHawley  R GABA receptors are increased in the brains of alcoholics. Ann Neurol 1981;9289- 292
PubMed Link to Article
Dodd  PThomas  GHarper  CKril  J Amino acid neurotransmitter receptor changes in cerebral cortex in alcoholism: effect of cirrhosis of the liver. J Neurochem 1992;591506- 1515
PubMed Link to Article
Kril  JDodd  PGundlach  ADavies  NWatson  WEJohnston  GAHarper  CG Necropsy study of GABA/benzodiazepine receptor binding sites in brain tissue from chronic alcoholic patients. Clin Exp Neurol 1988;25135- 141
PubMed
Freund  GBallinger  W Decrease of benzodiazepine receptors in frontal cortex of alcoholics. Alcohol 1988;5275- 282
PubMed Link to Article
Freund  GBallinger  W Loss of muscarinic and benzodiazepine neuroreceptors from hippocampus of alcohol abusers. Alcohol 1989;623- 31
PubMed Link to Article
Litton  JNeiman  JPauli  SFarde  LHindmarsh  THalldin  CSedvall  G PET analysis of [11C]flumazenil binding to benzodiazepine receptors in chronic alcohol dependent men and healthy controls. Psychiatry Res 1993;501- 13
PubMed Link to Article
Sobell  LCSobell  MB Timeline follow-back: a technique for assessing self-reported alcohol consumption. Litten  RZAllen  JPeds.Measuring Alcohol Consumption Psychosocial and Biochemical Methods Totowa, NJ Humana Press1992;41- 72
American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders; Fourth Edition.  Washington, DC American Psychiatric Association1994;
Fujita  MWoods  SVerhoeff  NAbi-Dargham  ABaldwin  RMZoghbi  SSSoares  JCJatlow  PAKrystal  JHRajeevan  NCharney  DSSeibyl  JPInnis  RB Changes of benzodiazepine receptors during chronic benzodiazepine administration in humans. Eur J Pharmacol 1999;368161- 172
PubMed Link to Article
Skinner  HAHorn  JL Alcohol Dependence Scale (ADS) User's Guide.  Toronto, Ontario Addiction Research Foundation of Ontario1984;
Tiffany  SSingleton  EHaertzen  CAHenningfield  JE The development of a cocaine craving questionnaire. Drug Alcohol Depend 1993;3419- 28
PubMed Link to Article
Heatherton  TKozlowski  LFrecker  RFagerstrom  K The Fagerstrom Test for Nicotine Dependence: a revision of the Fagerstrom Tolerance Questionnaire. Br J Addict 1991;861119- 1127
PubMed Link to Article
Pomerleau  CCarton  SLutzke  MFlessland  KPomerleau  O Reliability of the Fagerstrom Tolerance Questionnaire and the Fagerstrom Test for Nicotine Dependence. Addict Behav 1994;1933- 39
PubMed Link to Article
Hariharan  MVanNoord  TGreden  JF A high performance liquid chromatographic method for routine simultaneous determination of nicotine and cotinine in plasma. Clin Chem 1988;34724- 729
PubMed
Zoghbi  SBaldwin  RSeibyl  Jal-Tikriti  MSZea-Ponce  YLaruelle  MSybirska  EHWoods  SWGoddard  AWMalison  RTZimmerman  RCharney  DSSmith  EOHoffer  PBInnis  RB Pharmacokinetics of the SPECT benzodiazepine receptor radioligand [123I]iomazenil in human and nonhuman primates. Int J Rad Appl Instrum B 1992;19881- 888
PubMed Link to Article
Abi-Dargham  AGandelman  MZoghbi  SLaruelle  MBaldwin  RMRandall  PZea-Ponce  YCharney  DSHoffer  PBInnis  RB Reproducibility of SPECT measurement of benzodiazepine receptors in human brain with iodine-123-iomazenil. J Nucl Med 1995;36167- 175
PubMed
Rajeevan  NZubal  IRambsy  SZoghbi  SSeibyl  JInnis  R Significance of nonuniform attenuation correction in quantitative brain SPECT imaging. J Nucl Med 1998;391719- 1726
PubMed
Abi-Dargham  ALaruelle  MSeibyl  JRattner  ZBaldwin  RMZoghbi  SSZea-Ponce  YBremner  JDHyde  TMCharney  DSHoffer  PBInnis  RB SPECT measurement of benzodiazepine receptors in human brain with [123I]iomazenil: kinetic and equilibrium paradigms. J Nucl Med 1994;35228- 238
PubMed
Lancaster  JSummerlin  JRainey  LFreitas  CFox  P The Talairach Daemon: a database server for Talairach atlas labels. Neuroimage 1997;5S633
Lancaster  JWoldorff  MParsons  LLiotti  MFreitas  CSRainey  LKochunov  PVNickerson  DMikiten  SAFox  PT Automated Talairach atlas for functional brain mapping. Hum Brain Mapp 2000;10120- 131
PubMed Link to Article
Beer  HBlauenstein  PHasler  PDelaloye  BRiccabona  GBangerl  IHunkeler  WBonetti  EPPieri  LRichards  JG In vitro and in vivo evaluation of iodine-123-Ro16-0154: a new imaging agent for SPECT investigations of benzodiazepine receptors. J Nucl Med 1990;311007- 1014
PubMed
Johnson  EWoods  SMcBride  BBaldwin  RInnis  R Receptor binding characterization of 125I-Ro16-0154: potential probe for SPECT brain imaging. Life Sci 1990;471535- 1546
PubMed Link to Article
Innis  RAl-Tikriti  MZoghbi  SBaldwin  RMSybirska  EHLaruelle  MAMalison  RTSeibyl  JPZimmermann  RCJohnson  EW SPECT imaging of the benzodiazepine receptor: feasibility of in vivo potency measurements from stepwise displacement curves. J Nucl Med 1991;321754- 1761
PubMed
Innis  RZoghbi  SJohnson  EWoods  Sal-Tikriti  MBaldwin  RSeibyl  JMalison  RZubal  GCharney  DHeninger  GHoffer  P SPECT imaging of the benzodiazepine receptor in non-human primate brain with [123I]Ro 16-0154. Eur J Pharmacol 1991;193249- 252
PubMed Link to Article
Sybirska  EAl-Tikriti  MZoghbi  SBaldwin  RJohnson  EInnis  R SPECT imaging of the benzodiazepine receptor: autoradiographic comparison of receptor density and radioligand distribution. Synapse 1992;12119- 128
PubMed Link to Article
Odano  INakajima  TMiyashita  KTakahashi  NFujita  MNaritomi  HFurusawa  THayashi  SSakai  K In vivo autoradiographic benzodiazepine binding with 125I-iomazenil. Kaku Igaku 1993;30761- 767
PubMed
Dodd  PKril  JThomas  GWatson  WJohnston  GHarper  C Receptor binding sites and uptake activities mediating GABA neurotransmission in chronic alcoholics with Wernicke encephalopathy. Brain Res 1996;710215- 228
PubMed Link to Article
Pritchett  DLuddens  HSeeberg  P Type I and type II GABAA-benzodiazepine receptors produced in transfected cells. Science 1989;2451389- 1391
PubMed Link to Article
Lewohl  JHuygens  FCrane  DDodd  P GABAA receptor alpha-subunit proteins in human chronic alcoholics. J Neurochem 2001;78424- 434
PubMed Link to Article
Lewohl  JCrane  DDodd  P Expression of the alpha1, alpha2, and alpha3 isoforms of the GABAA receptor in human alcoholic brain. Brain Res 1997;751102- 112
PubMed Link to Article
Mitsuyama  HLittle  KSieghart  WDevaud  LMorrow  A GABAA receptor alpha1, alpha4, and alpha3 subunit mRNA and protein expression in the frontal cortex of human alcoholics. Alcohol Clin Exp Res 1998;22815- 822
PubMed
Montpied  PMorrow  AKaranian  JGinns  EMartin  BPaul  S Prolonged ethanol inhalation decreases gamma-aminobutyric acidA receptor alpha subunit mRNAs in the rat cerebral cortex. Mol Pharmacol 1991;39157- 163
PubMed
Mhatre  MTicku  M Chronic ethanol administration alters gamma-aminobutyric acid A receptor gene expression. Mol Pharmacol 1992;42415- 422
PubMed
Morrow  AHerbert  JMontpied  P Differential effects of chronic ethanol administration on GABA-A receptor alpha1 and alpha6 subunit mRNA levels in rat cerebellum. Mol Cell Neurosci 1992;3251- 258
Link to Article
Mhatre  MPena  GSieghart  WTicku  M Antibodies specific for GABAA receptor alpha subunits reveal that chronic alcohol treatment down-regulates alpha subunit expression in rat brain regions. J Neurochem 1993;611620- 1625
PubMed Link to Article
Devaud  LSmith  FGrayson  DMorrow  A Chronic ethanol consumption differentially alters the expression of gamma-aminobutyric acidA receptor subunit mRNAs in rat cerebral cortex: competitive, quantitative reverse transcriptase-polymerase chain reaction analysis. Mol Pharmacol 1995;48861- 868
PubMed
Devaud  LLPurdy  RHFinn  DAMorrow  AL Sensitization of gamma-aminobutyric acidA receptors to neuroactive steroids in rats during ethanol withdrawal. J Pharmacol Exp Ther 1996;278510- 517
PubMed
Sanna  EMostallino  MBusonero  FTalani  GTranquilli  SMameli  MSpiga  SFollesa  PBiggio  G Changes in GABAA receptor gene expression associated with selective alterations in receptor function and pharmacology after ethanol withdrawal. J Neurosci 2003;2311711- 11724
PubMed
Kumar  SKralic  JO'Buckley  TGrobin  AMorrow  A Chronic ethanol consumption enhances internalization of alpha1 subunit-containing GABAA-receptors in cerebral cortex. J Neurochem 2003;86700- 708
PubMed Link to Article
Toneatto  ASobell  LSobell  MKozlowski  L Effect of cigarette smoking on alcohol treatment outcome. J Subst Abuse 1995;7245- 252
PubMed Link to Article
Daeppen  JBSmith  TDanko  GGordon  LLandi  NANurnberger  JI  JrBucholz  KKRaimo  ESchuckit  MA Clinical correlates of cigarette smoking and nicotine dependence in alcohol-dependent men and women. Alcohol Alcohol 2000;35171- 175
PubMed Link to Article
Gulliver  SKalman  DRohsennow  DColby  SEaton  CMonti  P Smoking and drinking among alcoholics in treatment: cross-sectional and longitudinal relationships. J Stud Alcohol 2000;61157- 163
PubMed
Madden  PHeath  AStarmer  GWhitfield  JMartin  N Alcohol sensitivity and smoking history in men and women. Alcohol Clin Exp Res 1995;191111- 1120
PubMed Link to Article
Buck  KHarris  R Benzodiazepine agonist and inverse agonist actions on GABAA operated chloride channels, I: acute effects of ethanol. J Pharmacol Exp Ther 1990;253706- 712
PubMed
Buck  KHarris  R Benzodiazepine agonist and inverse agonist actions on GABAA receptor-operated chloride channels, II: chronic effects of ethanol. J Pharmacol Exp Ther 1990;253713- 719
PubMed
Aubin  HLaureaus  CTilikete  SBarrucand  D Changes in cigarette smoking and coffee drinking after alcohol detoxification in alcoholics. Addiction 1999;94411- 416
PubMed Link to Article
O'Neill  ABrioni  J Benzodiazepine receptor mediation of the anxiolytic-like effect of (-)-nicotine in mice. Pharmacol Biochem Behav 1994;49755- 757
PubMed Link to Article
Breyer-Pfaff  UWiatr  GSteens  IGaertner  HMundle  GMann  K Elevated norharman plasma levels in alcoholic patients and controls resulting from tobacco smoking. Life Sci 1996;581425- 1432
PubMed Link to Article
Rommelspacher  HNanz  CBorbe  HOFehske  KJMuller  WEWollert  U 1-Methyl-beta-carboline (harmane), a potent endogenous inhibitor of benzodiazepine receptor binding. Naunyn Schmiedebergs Arch Pharmacol 1980;31497- 100
PubMed Link to Article
Cain  MWeber  RWGuzman  FCook  JMBarker  SARice  KCCrawley  JNPaul  SMSkolnick  P Beta-carbolines: synthesis and neurochemical and pharmacological actions on brain benzodiazepine receptors. J Med Chem 1982;251081- 1091
PubMed Link to Article
Rommelspacher  HMeier-Henco  MSmolka  MKloft  C The levels of norharman are high enough after smoking to affect monoamine oxidase B in platelets. Eur J Pharmacol 2002;441115- 125
PubMed Link to Article
Fowler  JSVolkow  NDWang  GJPappas  NLogan  JShea  CAlexoff  DMacGregor  RRSchlyer  DJZezulkova  IWolf  AP Brain monoamine oxidase A inhibition in cigarette smokers. Proc Natl Acad Sci U S A 1996;9314065- 14069
PubMed Link to Article
Fowler  JSVolkow  NDWang  GJPappas  NLogan  JMacGregor  RAlexoff  DShea  CSchlyer  DWolf  APWarner  DZezulkova  ICilento  R Inhibition of monoamine oxidase in the brains of smokers. Nature 1996;379733- 736
PubMed Link to Article
Fowler  JSVolkow  NDWang  GJPappas  NLogan  JMacGregor  RAlexoff  DWolf  APWarner  DCilento  RZezulkova  I Neuropharmacological actions of cigarette smoke: brain monoamine oxidase B (MAO B) inhibition. J Addict Dis 1998;1723- 24
PubMed Link to Article
Airaksinen  MMikkonen  E Affinity of beta-carbolines on rat brain benzodiazepine and opiate binding sites. Med Biol 1980;58341- 344
PubMed
Rommelspacher  HNanz  CBorbe  HFehske  KMuller  WWollert  U Benzodiazepine antagonism by harmane and other beta-carbolines in vitro and in vivo. Eur J Pharmacol 1981;70409- 416
PubMed Link to Article
May  TRommelspacher  HPawlik  M [2H]harman binding experiments, I: a reversible and selective radioligand for monoamine oxidase subtype A in the CNS of the rat. J Neurochem 1991;56490- 499
PubMed Link to Article
Mason  GFPetrakis  ILde Graaf  RAGueorguieva  RRuff  ECoric  VEpperson  CNRothman  DLKrystal  JH Cortical GABA levels and the recovery from alcohol dependence: relationship to neurotoxicity and tobacco smoking. Biol Psychiatry In press
Goddard  AMason  GRothman  DBehar  KKrystal  J Reduced cortical GABA neuronal response to benzodiazepine administration in panic disorder. Am J Psychiatry In press
Mason  GFAppel  MDeGraaf  RAPetrakis  IRuff  ERothman  DLKrystal  JH Reduction in cortical GABA levels over the first month of sobriety. Alcohol Clin Exp Res 2003;2756AAbstract 305
Epperson  CNO'Malley  SCzarkowski  KAGueorguieva  RJatlow  PSanacora  GRothman  DLKrystal  JHMason  GF Sex, GABA, and nicotine: the impact of smoking on cortical GABA levels across the menstrual cycle as measured with proton magnetic resonance spectroscopy. Biol Psychiatry 2005;5744- 48
Link to Article
Ueno  SWick  MYe  QHarrison  NHarris  R Subunit mutations affect ethanol actions on GABA(A) receptors expressed in Xenopus oocytes. Br J Pharmacol 1999;127377- 382
PubMed Link to Article
Malcolm  RMyrick  HBrady  KBallenger  J Update on anticonvulsants for the treatment of alcohol withdrawal. Am J Addict 2001;10 ((Suppl)) 16- 23
PubMed Link to Article
Krystal  JPetrakis  ITrevisan  LD'Souza  D NMDA receptor antagonism and the ethanol intoxication signal: from alcoholism risk to pharmacotherapy. Ann N Y Acad Sci 2003;1003176- 184
PubMed Link to Article

Correspondence

CME
Also Meets CME requirements for:
Browse CME for all U.S. States
Accreditation Information
The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
Note: You must get at least of the answers correct to pass this quiz.
Your answers have been saved for later.
You have not filled in all the answers to complete this quiz
The following questions were not answered:
Sorry, you have unsuccessfully completed this CME quiz with a score of
The following questions were not answered correctly:
Commitment to Change (optional):
Indicate what change(s) you will implement in your practice, if any, based on this CME course.
Your quiz results:
The filled radio buttons indicate your responses. The preferred responses are highlighted
For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.
Submit a Comment

Multimedia

Some tools below are only available to our subscribers or users with an online account.

Web of Science® Times Cited: 25

Related Content

Customize your page view by dragging & repositioning the boxes below.

Articles Related By Topic
Related Collections
PubMed Articles
JAMAevidence.com

Users' Guides to the Medical Literature
Alcohol Abuse or Dependence

The Rational Clinical Examination
Make the Diagnosis: Alcohol Abuse