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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.

Background Measurement of cortical γ-aminobutyric acid (GABA) and glutamate concentrations is possible using proton magnetic resonance spectroscopy. An initial report, using this technique, suggested that occipital cortex GABA concentrations are reduced in patients with major depressive disorder (MDD) relative to healthy comparison subjects. Objectives To replicate the GABA findings in a larger sample of MDD patients, to examine the clinical correlates of the GABA reductions in these subjects, and to examine other critical metabolite levels. Design Study for association. Setting Academic clinical research program. Participants The GABA measurements were made on 38 healthy control subjects and 33 depressed subjects. Interventions Occipital cortex metabolite levels were measured using proton magnetic resonance spectroscopy. Main Outcome Measures The levels of occipital cortex GABA, glutamate, N -acetylaspartate, aspartate, creatine, and choline-containing compounds, along with several measures of tissue composition, were compared between the 2 groups. Results Depressed subjects had significantly lower occipital cortex GABA concentrations compared with healthy controls ( P = .01). In addition, mean glutamate levels were significantly increased in depressed subjects compared with healthy controls ( P P = .009) and the percentage of white matter ( P = .04) in the voxel were also observed. An examination of a combined database including subjects from the original study suggests that GABA and glutamate concentrations differ among MDD subtypes. Conclusions The study replicates the findings of decreased GABA concentrations in the occipital cortex of subjects with MDD. It also demonstrates that there is a change in the ratio of excitatory-inhibitory neurotransmitter levels in the cortex of depressed subjects that may be related to altered brain function. Last, the combined data set suggests that magnetic resonance spectroscopy GABA measures may serve as a biological marker for a subtype of MDD.

Background There is increasing support for the hypothesis that gonadal steroids involved in the regulation of the human menstrual cycle modulate γ-aminobutyric acid (GABA) neuronal function. This study tests the hypothesis that cortical GABA neuronal function, reflected in brain GABA concentrations, fluctuates across the menstrual cycle in healthy women and those with premenstrual dysphoric disorder (PMDD) and that a menstrual cycle phase–dependent abnormality in brain GABA concentrations in women diagnosed as having PMDD would reflect altered central response to circulating gonadal and neuroactive steroids. Methods Fourteen healthy menstruating women and 9 women diagnosed as having PMDD were recruited from a women's behavioral health research program located at a university-based medical center. The women underwent serial proton magnetic resonance spectroscopic measurements of occipital cortex GABA levels across the menstrual cycle (primary outcome measure) and had blood drawn for gonadal hormone and neurosteroid levels determined on each scan day (secondary outcome measure). Results There was a significant group × phase interaction with most of the finding explained by the reduction in cortical GABA levels during the follicular phase in those with PMDD compared with healthy controls. Cortical GABA levels declined across the menstrual cycle in healthy women, whereas women with PMDD experienced an increase in cortical GABA levels from the follicular phase to the mid luteal and late luteal phases. Significant between-group differences in the relationship between hormones and GABA were observed for estradiol, progesterone, and allopregnanolone. Conclusions These data strongly suggest that the GABAergic system is substantially modulated by menstrual cycle phase in healthy women and those with PMDD. Furthermore, they raise the possibility of disturbances in cortical GABA neuronal function and modulation by neuroactive steroids as potentially important contributors to the pathogenesis of PMDD.