Biomedical subjects

Ralitza Gueorguieva

Publications and source records attributed to Ralitza Gueorguieva.

At least 19 recordsLinked to original sources

PubMed2007

New insights into the efficacy of naltrexone based on trajectory-based reanalyses of two negative clinical trials.

BACKGROUND: The heterogeneity of clinical findings in studies evaluating the efficacy of naltrexone in the treatment of alcohol dependence has led to growing efforts to explore novel approaches to data analysis. The objective of this study was to identify distinct trajectories of daily drinking over time in two negative clinical trials and to determine whether naltrexone affected the probability to follow a particular trajectory. METHODS: The Veterans Affairs (VA) Cooperative Study #425 and the Women's Naltrexone Study failed to demonstrate efficacy on primary outcome variables. Separately for each study, we analyzed daily indicators of any drinking and heavy drinking using a semiparametric group-based approach. RESULTS: We estimated three distinct trajectories of daily drinking (both any and heavy drinking) which we described as "abstainer," "sporadic drinker," and "consistent drinker." Naltrexone doubled the odds of following the abstainer trajectory instead of the consistent drinker trajectory but did not significantly change the odds of following the abstainer trajectory as contrasted with the sporadic drinker trajectory. CONCLUSIONS: Naltrexone may have a clinically meaningful effect for alcohol-dependent patients with a high chance of consistent drinking, even in studies where it failed to show efficacy in planned analyses.

Adult↗

PubMed2006

Dopamine beta-hydroxylase gene (DbetaH) -1021C-->T influences self-reported paranoia during cocaine self-administration.

BACKGROUND: Variation in the gene for dopamine beta-hydroxylase (DbetaH) has been reported to associate with cocaine-induced paranoia as assessed by retrospective self-report. This association has yet to be tested prospectively. METHODS: Visual analog scale (VAS) ratings of paranoia were obtained in 31 cocaine users during three cocaine self-administration sessions (8, 16, and 32 mg/70 kg). Pharmacogenetic interactions between cocaine and a putative functional polymorphism in DbetaH (-1021C-->T) were assessed. RESULTS: VAS self-ratings showed significant or trend-level interactions of genotype and time during each session (p = .004, .09 and .003, respectively) with TT homozygotes endorsing greater paranoia over time than either CT or CC individuals. Interactions were significant at all doses in African Americans (n = 19; p = .02, .04 and .05). No other demographic or experimental variable distinguished genotypic groups. CONCLUSIONS: Results indicate that individuals homozygous for the 'very low-activity' T allele at DbetaH -1021C-->T show an increased propensity to paranoia over time during cocaine self-administration.

Adult↗

PubMed2006

Enhanced sensitivity to the euphoric effects of alcohol in schizophrenia.

The purpose of this study was to determine whether schizophrenia was associated with alterations in alcohol response that might explain the elevated risk for AUDs in this population. In a randomized, double-blind, placebo-controlled, counter-balanced 3 test day laboratory study, the effects of alcohol were compared in 23 subjects with schizophrenia (without any previous alcohol use disorder (AUD) but with some alcohol exposure) and in 14 healthy subjects matched for age, gender, education, and lifetime exposure to alcohol. Standard alcohol drinks in a scheduled design were administered to produce blood alcohol levels of 0, 0.02-0.04 mg%, or 0.06-0.08 mg%. Schizophrenia symptoms, perceptual alterations, stimulant and depressant subjective effects of alcohol, and 'high' were measured before alcohol administration and at several post-drug time points. Verbal learning and recall, vigilance and distractibility, and motor function were assessed once per test day. Relative to healthy subjects, subjects with schizophrenia reported greater euphoria and stimulatory effects in response to alcohol. Alcohol produced small transient increases in positive psychotic symptoms and perceptual alterations without affecting negative symptoms. Alcohol also impaired several aspects of immediate and delayed recall, and vigilance, and distractibility. Schizophrenia patients showed increased euphoric and stimulatory responses to alcohol. These exaggerated positive responses to alcohol doses may contribute to the increased risk for AUDs associated with schizophrenia. The absence of 'beneficial' effects of alcohol does not support a self-medication hypothesis of alcohol use in schizophrenia.

Adolescent↗

PubMed2006

Estradiol and tryptophan depletion interact to modulate cognition in menopausal women.

Despite an abundance of data in animals, there is little research in humans regarding how estrogen and serotonin (5-HT) may interact to influence cognition. Through the use of estrogen treatment (ET) and tryptophan depletion (TRP-D) in a within-subject design involving healthy menopausal women, we have manipulated both estrogen and 5-HT in order to evaluate their individual and joint effects. Although neither manipulation influenced visuospatial learning, a significant interaction suggested that estrogen exerted a protective effect on verbal memory, such that TRP-D impaired performance to a greater extent before the administration of ET. In consonance with this finding, ET was associated with a small, but positive mood effect on the day following active TRP-D. In addition, ET significantly improved letter-cued verbal fluency with and without TRP-D. Finally, time since last menstrual period was significantly associated with verbal memory scores, such that longer length of hypogonadism resulted in decreased verbal memory performance. These data support the interaction of estrogen and 5-HT in nonreproductive behavior in humans as well as highlight the role of ovarian steroids in cognition.

Affect↗

PubMed2006

Preliminary evidence of reduced occipital GABA concentrations in puerperal women: a 1H-MRS study.

RATIONALE: Childbirth is associated with rapid neuroendocrine fluctuations, which are thought to contribute to the phatogenesis of postpartum major depression (PPD). OBJECTIVES: The aim of this proton magnetic resonance spectroscopy (1H-MRS) study was two-fold; 1) to examine whether puerperium is associated with alterations in occipital cortex gamma-aminobutyric acid (GABA) concentrations and 2) to determine whether such alterations may be more prominent in women with PPD. MATERIALS AND METHODS: Nine women with PPD, 14 postpartum healthy controls, and ten healthy follicular phase females underwent 1H-MRS at 2.1 Tesla to measure occipital cortex GABA concentrations. Postpartum women were scanned within 6 months of delivery and prior to resumption of menstruation. Healthy non-puerperal controls, drawn from a historical sample, were scanned during the early to mid-follicular phase when ovarian hormone levels would be similar to those found in the puerperium. GABA data were analyzed using analysis of covariance, and regression models were used to explore the relationship between cortical GABA concentrations and blood levels of estradiol, progesterone, and neurosteroids. RESULTS: Cortical GABA and plasma allopregnanolone (ALLO) concentrations were reduced in both groups of postpartum women, regardless of PPD diagnosis, compared to healthy follicular phase women. There was no correlation between cortical GABA concentrations and estradiol, progesterone, ALLO, or pregnenolone (PREG). CONCLUSIONS: This study is the first to describe reductions in occipital cortex GABA levels in the postpartum period, a time of increased vulnerability to mood disturbances in women. The concomitant reduction in peripheral ALLO levels provides further evidence of alterations in the balance between cortical excitation and inhibition during the puerperium. Women with PPD may represent a subgroup of women who fail to adequately adapt to this alteration in the neuroendocrine milieu.

Adult↗

PubMed2006

Self-reported paranoia during laboratory "binge" cocaine self-administration in humans.

Cocaine-induced paranoia (CIP) has been extensively studied by retrospective interviews; however, only limited efforts have been made to further characterize CIP by human laboratory methods. We examined CIP in 28 healthy cocaine-dependent volunteers, who participated in 2-h, intravenous cocaine self-administration sessions at 8, 16, and 32 mg/70 kg doses, including 18 in a placebo-controlled design. Self-reports of paranoia showed significant main effects of cocaine dose (p=0.0002) and time (p=0.0003), and were statistically distinguishable from placebo at the two highest doses (16 and 32 mg). These effects were accounted for by a subgroup of vulnerable subjects in whom self-reports were consistent across dose and test-retest sessions. Subjects with CIP did not differ from those without CIP with respect to demographic, cocaine use, or cocaine self-administration variables. In conclusion, self-reports of CIP in the human lab are frequently endorsed, dose-dependent, and though variable between subjects, reproducible within subjects. Such methods may facilitate our understanding of the vulnerability to CIP in humans.

Adolescent↗

PubMed2006

Risk factors for cocaine-induced paranoia in cocaine-dependent sibling pairs.

OBJECTIVE: Cocaine-induced paranoia (CIP), an irrational intense suspicion of others, is a common manifestation of cocaine dependence. Both environmental and genetic factors are thought to play a role, but the specific nature of such contributions is poorly understood. METHODS: Demographic, diagnostic, and cocaine-use data were obtained from 420 cocaine-dependent, genetically confirmed, full-sibling pairs (N=840 subjects) interviewed with the Semi-Structured Assessment for Drug Dependence and Alcoholism (SSADDA). Probands with and without CIP were compared; then, factors associated with sibling CIP status were analyzed by logistic regression. Alcohol dependence, a known heritable phenotype, was analyzed as a positive control. RESULTS: Of 420 probands, 273 (65%) experienced CIP. Probands with CIP were more severely dependent upon cocaine, had an earlier age of onset, were more likely to smoke cocaine, and used cocaine less frequently during the preceding year. Independent analyses of siblings replicated two of the former (i.e., dependence severity and age of onset). Probands with CIP also had a non-significantly higher proportion of siblings with the trait (66% versus 59%). Probands with concurrent alcohol dependence were confirmed to have significantly higher rates of alcoholism among their siblings. CONCLUSIONS: Severity of cocaine dependence and age of onset appear to be important risk factors for CIP. Concordance for CIP between siblings did not emerge as significant in our analyses.

Adult↗

PubMed2006

Potentiation of low dose ketamine effects by naltrexone: potential implications for the pharmacotherapy of alcoholism.

The interplay of opiate and NMDA glutamate receptors may contribute to psychosis, cognitive function, alcoholism, and substance dependence. Ketamine and ethanol block the NMDA glutamate receptor. The purpose of this randomized double-blind, placebo-controlled human laboratory study was to evaluate whether the interactive effects of drugs acting at opiate and NMDA glutamate receptors might partially explain the efficacy of naltrexone for the treatment of alcoholism, that is, whether naltrexone 25 mg pretreatment would modulate ketamine effects in healthy human subjects. Two groups of healthy subjects were studied. An initial group (n=31) received a perception-altering subanesthetic dose of ketamine (bolus of 0.23 mg/kg over 1 min followed by a 60-min infusion of 0.58 mg/kg or saline bolus and infusion). A second group (n=24) completed the same testing procedures, but received a subperceptual ketamine dose (bolus 0.081 mg/kg over 10 min followed by an infusion of 0.4 mg/kg/h). Ketamine produced positive symptoms, negative symptoms, emotional discomfort, and cognitive effects as measured by the Positive and Negative Syndrome Scale (PANSS) in a dose-related fashion. The lower ketamine dose produced subjective effects similar to two standard ethanol drinks, whereas the higher ketamine dose produced effects similar to five standard drinks. Although naltrexone produced no significant behavioral effects, it significantly magnified the increase in the total PANSS score produced by the lower subperceptual dose of ketamine, but not the higher perception-altering dose of ketamine. These data suggest that the interplay of opiate receptor antagonism and NMDA receptor antagonism may be relevant to the protective effects of naltrexone on alcohol consumption via potentiation of dysphoric effects associated with the NMDA receptor antagonist effects of ethanol. However, these data suggest that at levels of NMDA receptor antagonism associated with heavy drinking, this protective effect of naltrexone on drinking is no longer present.

Adult↗

PubMed2006

Gelatin "shots" as a new method for alcohol administration in a laboratory setting.

BACKGROUND: This experiment was designed to compare gelatin "shots"-a new procedure for administering alcohol in a laboratory setting-to the alcohol beverage method. We proceeded to test whether the two methods were comparable in terms of alcohol absorption, metabolism, and effects on mood and whether gelatin "shots" were better than the beverage in disguising alcohol in a blind, placebo comparison. METHODS: Healthy volunteers participated in a two-phase trial. In the first phase they completed 2 days of testing during which the effects of alcohol-delivered in beverage (1 day) or gelatin "shots" (alternative day)-on blood and breathalyzer concentrations and mood were assessed. In the second phase participants completed 2 days of testing and were asked to identify if samples contained alcohol or placebo. The presentation of alcohol and placebo and the presentation of beverage or gelatin "shots" were random. RESULTS: In the first phase there was a significant time-by-condition interaction in the blood alcohol concentration. Two-and-a-half hours after the alcohol was administered, those given gelatin "shots" had slightly lower but statistically significant blood alcohol concentrations. There was a significant time effect for breathalyzer alcohol levels but no condition or condition-by-time interaction. There were no differences between the two methods on any of the subjective mood measures. In the second phase of the study there were differences in the ability to differentiate alcohol from placebo between the two conditions with significantly more participants making errors in the gelatin "shots" than in the beverage condition. CONCLUSIONS: Our findings indicate that gelatin "shots" are an effective method for delivering alcohol to humans in a laboratory setting. This method may be superior to the alcohol beverage mixture in a placebo-controlled design because gelatin "shots" mask the alcohol much better than a beverage and are easier to administer.

Affect↗

PubMed2005

Cortical gamma-aminobutyric acid levels and the recovery from ethanol dependence: preliminary evidence of modification by cigarette smoking.

BACKGROUND: Gamma-aminobutyric acid (GABA)ergic adaptations contribute to the neurobiology of ethanol dependence and withdrawal. Clinical data suggest that tobacco smoking attenuates alcohol withdrawal symptoms. This study's objective was to measure time-dependent cortical GABA levels with sobriety in ethanol-dependent patients with mild to moderate withdrawal severity, controlling for alcoholism-related neurotoxicity and smoking. METHODS: Proton magnetic resonance spectroscopy (MRS) was used to measure occipital cortical N-acetylaspartate (NAA), glutamate plus glutamine, and GABA in 12 ethanol-dependent men at approximately 1 week and 1 month of medication-free sobriety on an inpatient unit. Eight healthy men were studied once. The tissue composition of the MRS volume was determined. RESULTS: Adjusting for less white matter in patients, GABA differed insignificantly between ethanol-dependent patients (smokers plus nonsmokers) and healthy subjects. In early sobriety, nonsmoking patients had more GABA than did smoking patients, but by 1 month, GABA decreased in nonsmokers without changing in smokers. Smoking was associated with increased glutamate plus glutamine in patients and healthy subjects, adjusting for NAA levels. CONCLUSIONS: These data do not show that deficits in cortical GABA contribute directly to acute ethanol withdrawal. If smoking prevents withdrawal-related changes in cortical GABA systems, it may contribute to comorbidity of alcoholism and tobacco smoking.

Adult↗

PubMed2005

Preliminary evidence for medication effects on functional abnormalities in the amygdala and anterior cingulate in bipolar disorder.

RATIONALE: Abnormal amygdala and frontocortical responses to emotional stimuli are implicated in bipolar disorder (BD) and have been proposed as potential treatment targets. OBJECTIVES: The aim of this study was to investigate amygdala and frontocortical responses to emotional face stimuli in BD and the influences of mood-stabilizing medications on these responses. METHODS: Functional magnetic resonance imaging was performed while 17 BD participants (5 unmedicated) and 17 healthy comparison (HC) participants viewed faces with happy, sad, fearful, or neutral expressions. RESULTS: The group by stimulus-condition interaction was significant (p<0.01) for amygdala activation, with the greatest effects in the happy face condition. Relative to HC, amygdala increases were greater in unmedicated BD, but lower in medicated BD. Rostral anterior cingulate (rAC) activation was decreased in unmedicated BD compared to HC; however, BD participants taking medication demonstrated rAC activation similar to HC participants. CONCLUSIONS: Although the sample sizes were small, these preliminary results suggest that BD is associated with increased amygdala and decreased rAC response to emotional faces. The findings also provide preliminary evidence that mood-stabilizing medications may reverse abnormalities in BD in the response of an amygdala-frontal neural system to emotional stimuli.

Adult↗

PubMed2005

Riluzole augmentation in treatment-resistant obsessive-compulsive disorder: an open-label trial.

BACKGROUND: Most patients with obsessive-compulsive disorder (OCD) show only partial reduction of symptoms with standard therapy. Recent imaging data suggests glutamatergic dysfunction in the corticostriatal pathway in OCD. We investigated the efficacy of augmentation therapy with riluzole, a glutamate-modulating agent, in treatment-resistant OCD. METHODS: Thirteen patients aged between 18 and 65 years with a primary diagnosis of OCD that had proven resistant to standard treatment were treated with the addition of riluzole to their existing pharmacotherapy. Yale-Brown Obsessive Compulsive Scale (Y-BOCS), Hamilton Depression Inventory (HAM-D), and Hamilton Anxiety Inventory (HAM-A) scores were obtained weekly. RESULTS: Thirteen treatment-resistant OCD patients received riluzole 50 mg twice a day. Y-BOCS scores improved significantly over time. Of 13 patients, 7 (54%) demonstrated a >35% reduction in Y-BOCS scores, and 5 (39%) were categorized as treatment responders. HAM-D and HAM-A scores for the group also significantly improved over time. Riluzole was well tolerated with no serious adverse effects noted. CONCLUSIONS: Riluzole appears to have significant antiobsessional, antidepressant, and antianxiety properties. The addition of this agent may be of practical clinical benefit in patients with OCD.

Adult↗

PubMed2005

Temporoparietal transcranial magnetic stimulation for auditory hallucinations: safety, efficacy and moderators in a fifty patient sample.

BACKGROUND: Auditory hallucinations are often resistant to treatment and can produce significant distress and behavioral difficulties. A preliminary report based on 24 patients with schizophrenia or schizoaffective disorder indicated greater improvement in auditory hallucinations following 1-hertz left temporoparietal repetitive transcranial magnetic stimulation (rTMS) compared to sham stimulation. Data from the full 50-subject sample incorporating 26 new patients are now presented to more comprehensively assess safety/tolerability, efficacy and moderators of this intervention. METHODS: Right-handed patients experiencing auditory hallucinations at least 5 times per day were randomly allocated to receive either rTMS or sham stimulation. A total of 132 minutes of rTMS was administered over 9 days at 90% motor threshold using a double-masked, sham-controlled, parallel design. RESULTS: Hallucination Change Score was more improved for rTMS relative to sham stimulation (p = .008) as was the Clinical Global Impressions Scale (p = .0004). Hallucination frequency was significantly decreased during rTMS relative to sham stimulation (p = .0014) and was a moderator of rTMS effects (p = .008). There was no evidence of neurocognitive impairment associated with rTMS. CONCLUSIONS: Left temporoparietal 1-hertz rTMS warrants further study as an intervention for auditory hallucinations. Data suggest that this intervention selectively alters neurobiological factors determining frequency of these hallucinations.

Adult↗

PubMed2005

Delta-9-tetrahydrocannabinol effects in schizophrenia: implications for cognition, psychosis, and addiction.

BACKGROUND: Recent advances in the neurobiology of cannabinoids have renewed interest in the association between cannabis and psychotic disorders. METHODS: In a 3-day, double-blind, randomized, placebo-controlled study, the behavioral, cognitive, motor, and endocrine effects of 0 mg, 2.5 mg, and 5 mg intravenous Delta-9-tetrahydrocannabinol (Delta-9-THC) were characterized in 13 stable, antipsychotic-treated schizophrenia patients. These data were compared with effects in healthy subjects reported elsewhere. RESULTS: Delta-9-tetrahydrocannabinol transiently increased 1) learning and recall deficits; 2) positive, negative, and general schizophrenia symptoms; 3) perceptual alterations; 4) akathisia, rigidity, and dyskinesia; 5) deficits in vigilance; and 6) plasma prolactin and cortisol. Schizophrenia patients were more vulnerable to Delta-9-THC effects on recall relative to control subjects. There were no serious short- or long-term adverse events associated with study participation. CONCLUSIONS: Delta-9-tetrahydrocannabinol is associated with transient exacerbation in core psychotic and cognitive deficits in schizophrenia. These data do not provide a reason to explain why schizophrenia patients use or misuse cannabis. Furthermore, Delta-9-THC might differentially affect schizophrenia patients relative to control subjects. Finally, the enhanced sensitivity to the cognitive effects of Delta-9-THC warrants further study into whether brain cannabinoid receptor dysfunction contributes to the pathophysiology of the cognitive deficits associated with schizophrenia.

Adult↗

PubMed2005

A paradigm to investigate the self-regulation of cocaine administration in humans.

INTRODUCTION: Current laboratory paradigms of human cocaine administration generally dictate the timing of drug access in ways that may limit assessing aspects of cocaine-taking behavior. Patient-controlled analgesia (PCA) methods, which allow individuals less restricted access to narcotic (i.e., opiate) analgesics, have proven safe and clinically effective for self-regulated treatment of pain. The current study assessed the feasibility, safety, and validity of a model of ad libitum cocaine self-administration, in which participants self-selected the timing of cocaine infusions, using PCA techniques. METHODS: Eight nontreatment seeking, otherwise medically healthy, experienced cocaine users participated in a double-blind, placebo-controlled, escalating-dose regimen of intravenous cocaine (0, 8, 16, and 32 mg per 70 kg) on 4 test days, during which time participants had 2 h of access to cocaine via manual presses of a corded PCA pump button under a fixed ratio 1: time-out 5-min schedule. RESULTS: Procedures were well-tolerated by participants, and no significant adverse events were noted. Measures of cocaine self-administration (e.g., number of responses and interinfusion intervals) indicated a significant main effect of cocaine dose, consistent with predicted dose-response relationships (i.e., decreasing responses and increasing interinfusion intervals with increasing injection dose). Participants appeared to regulate their cocaine intake in a carefully controlled manner, using considerably less cocaine (about half) that permitted by pump loading, PCA parameters, and session duration. CONCLUSIONS: Data from this study support the validity of our PCA paradigm. Moreover, results suggest the apparent feasibility and safety of allowing experienced users to self-select the timing of cocaine infusions to intervals as short as 5 min. Such procedures may enhance our ability to identify effective pharmacological treatments for cocaine addiction.

Adult↗

PubMed2005

Absence of behavioral sensitization in healthy human subjects following repeated exposure to ketamine.

RATIONALE: Sensitization to the effects of N-methyl-D-aspartate (NMDA) glutamate receptor antagonists is robust in animals. However, the applicability of this model to humans is unclear because it currently rests on highly confounded retrospective studies of individuals who experienced protracted psychoses following repeated binges with NMDA receptor antagonists. OBJECTIVES: The purpose of the current study was to determine whether there was evidence of sensitization to the behavioral effects of ketamine in healthy human subjects with repeated exposure to this drug. METHODS: Data were studied from 295 healthy human subjects who participated in one or more of 11 separate studies that involved ketamine administration over 14 years. Positive and negative symptoms (Brief Psychiatric Rating Scale: BPRS), perceptual alterations (Clinician-Administered Dissociative States Scale: CADSS), and "high" and "anxiety" states (Visual Analog Scale: VAS) that were measured in all studies were included as outcome measures. RESULTS: After including the number of previous exposures, number of previous studies, and time since first exposure as variables, repeated exposure to ketamine did not result in increased behavioral responses, suggestive of behavioral sensitization. CONCLUSIONS: The current data do not provide evidence that repeated exposure to ketamine, albeit limited, is associated with sensitization to the behavioral effects of ketamine.

Adult↗

PubMed2005

Sex, GABA, and nicotine: the impact of smoking on cortical GABA levels across the menstrual cycle as measured with proton magnetic resonance spectroscopy.

BACKGROUND: Given that nicotine modulates amino acid neurotransmission, we sought to examine the impact of nicotine on cortical gamma-aminobutyric acid (GABA) levels in male and female smokers. METHODS: Healthy nicotine-dependent men (n = 10) and women (n = 6) underwent proton magnetic resonance spectroscopy (1H-MRS) to measure occipital cortex GABA concentrations. A subset of the smoking men (n = 5) underwent 1H-MRS scans before and after 48 hours of smoking abstinence, whereas each of the women were scheduled to undergo pre- and postabstinence scans during the follicular and luteal phases of one menstrual cycle. Healthy nonsmoking men (n = 7) and women (n = 13) underwent 1H-MRS for comparison. RESULTS: Short-term abstinence had no significant effect on cortical GABA concentrations in either men or women. There was, however, a significant effect of sex, diagnosis (smoker/nonsmoker), and menstrual cycle phase on cortical GABA levels, such that female smokers experienced a significant reduction in cortical GABA levels during the follicular phase and no cyclicity in GABA levels across the menstrual cycle, whereas cortical GABA levels were similar in smoking and nonsmoking men. CONCLUSIONS: Taken together with previous 1H-MRS data showing abnormalities in occipital cortex GABA concentrations in several affective disorders, our preliminary finding that nicotine modulation of GABA levels varies by sex provides a further rationale for investigating the impact of nicotine on central GABAergic function as a potential risk factor for women to experience depressive symptoms during smoking cessation.

Adult↗

PubMed2005

Cortical gamma-aminobutyric acid type A-benzodiazepine receptors in recovery from alcohol dependence: relationship to features of alcohol dependence and cigarette smoking.

CONTEXT: Adaptations in gamma-aminobutyric acid type A (GABA(A))-benzodiazepine receptors contribute to the neurobiology of human alcohol dependence and withdrawal. OBJECTIVE: To study GABA(A)-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: (123)I-iomazenil single-photon emission computed tomographic images were converted to units of distribution volume (regional activity/free (123)I-iomazenil) and were analyzed using voxel-based statistical parametric mapping and regions of interest analyses. The relationships between (123)I-iomazenil distribution volume, clinical features of alcohol dependence, and smoking status were evaluated. RESULTS: (123)I-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 (123)I-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 GABA(A)-benzodiazepine receptors associated with the recovery from alcohol dependence. Higher GABA(A)-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 GABA(A) receptor function with sobriety. Smoking may attenuate GABA(A) receptor adaptations associated with alcohol dependence and may contribute to the comorbidity between alcoholism and smoking.

Adult↗