Changes in the pattern of suicides and suicide attempt admissions in relation to the COVID-19 pandemic.

The consequences of the current COVID-19 pandemic for mental health remain unclear, especially regarding the effects on suicidal behaviors. To assess changes in the pattern of suicide attempt (SA) admissions and completed suicides (CS) in association with the COVID-19 pandemic. As part of a longitudinal study, SA admissions and CS are systematically documented and analyzed in all psychiatric hospitals in Frankfurt/Main (765.000 inhabitants). Number, sociodemographic factors, diagnoses and methods of SA and CS were compared between the periods of March-December 2019 and March-December 2020. The number of CS did not change, while the number of SA significantly decreased. Age, sex, occupational status, and psychiatric diagnoses did not change in SA, whereas the percentage of patients living alone while attempting suicide increased. The rate and number of intoxications as a SA method increased and more people attempted suicide in their own home, which was not observed in CS. Such a shift from public places to home is supported by the weekday of SA, as the rate of SA on weekends was significantly lower during the pandemic, likely because of lockdown measures. Only admissions to psychiatric hospitals were recorded, but not to other institutions. As it seems unlikely that the number of SA decreased while the number of CS remained unchanged, it is conceivable that the number of unreported SA cases increased during the pandemic. Our data suggest that a higher number of SA remained unnoticed during the pandemic because of their location and the use of methods associated with lower lethality.

Efficacy of Varenicline in Patients With Severe Alcohol Dependence: A Pilot Double-Blind Randomized and Controlled Study.

PURPOSE/BACKGROUND: Varenicline has proven its efficacy in the treatment of nicotine dependence, and there is also evidence that it could be helpful in the treatment of alcohol dependence. In our pilot study, we investigated the feasibility and acceptability of varenicline for the treatment of a population of patients with severe alcohol dependence and multiple somatic comorbidities after alcohol detoxification. METHODS/PROCEDURES: We conducted a phase II, double-blind, placebo-controlled randomized trial of daily oral varenicline versus a placebo in alcohol-dependent men and women after alcohol detoxification (n = 28). Following our study protocol, somatic conditions and adverse events were thoroughly monitored and several study end points were investigated (percentage of abstinent days for both alcohol and nicotine, number of standardized drinks and cigarettes per day, days of heavy drinking). FINDINGS/RESULTS: Compared with the placebo, varenicline did not have more side effects and did not provoke more adverse events. Patients in the varenicline group did not show a significantly higher percentage of alcohol abstinent days or fewer heavy drinking days. A trend significance was found for a reduced number of standard drinks per day (P = 0.06) in the varenicline group. IMPLICATIONS/CONCLUSIONS: In this pilot trial, varenicline was shown to be well tolerated by our study population of severely alcohol-dependent patients with somatic conditions. Varenicline did not sustain alcohol abstinence or reduce the number of heavy drinking days, but it did reduce the daily amount of alcohol consumed.

Acute effect of intravenously applied alcohol in the human striatal and extrastriatal D2 /D3 dopamine system.

Investigations on the acute effects of alcohol in the human mesolimbic dopamine D2 /D3 receptor system have yielded conflicting results. With respect to the effects of alcohol on extrastriatal D2 /D3 dopamine receptors no investigations have been reported yet. Therefore we applied PET imaging using the postsynaptic dopamine D2 /D3 receptor ligand [18 F]fallypride addressing the question, whether intravenously applied alcohol stimulates the extrastriatal and striatal dopamine system. We measured subjective effects of alcohol and made correlation analyses with the striatal and extrastriatal D2 /D3 binding potential. Twenty-four healthy male µ-opioid receptor (OPRM1)118G allele carriers underwent a standardized intravenous and placebo alcohol administration. The subjective effects of alcohol were measured with a visual analogue scale. For the evaluation of the dopamine response we calculated the binding potential (BPND ) by using the simplified reference tissue model (SRTM). In addition, we calculated distribution volumes (target and reference regions) in 10 subjects for which metabolite corrected arterial samples were available. In the alcohol condition no significant dopamine response in terms of a reduction of BPND was observed in striatal and extrastriatal brain regions. We found a positive correlation for 'liking' alcohol and the BPND in extrastriatal brain regions (Inferior frontal cortex (IFC) (r = 0.533, p = 0.007), orbitofrontal cortex (OFC) (r = 0.416, p = 0.043) and prefrontal cortex (PFC) (r = 0.625, p = 0.001)). The acute alcohol effects on the D2 /D3 dopamine receptor binding potential of the striatal and extrastriatal system in our experiment were insignificant. A positive correlation of the subjective effect of 'liking' alcohol with cortical D2 /D3 receptors may hint at an addiction relevant trait.

Association of VMAT2 gene polymorphisms with alcohol dependence.

Alcohol-related diseases cause significant harm in the western world. Up to 65 % of the phenotypic variance is genetically determined. Few candidate genes have been identified, comprising ADH4, ALDH2, COMT, CRHR1, DAT (SLC6A3), GABRA2 and MAOA. While abnormalities in the dopaminergic mesolimbic reward system are considered important mediators of alcoholism, studies analyzing variants of dopamine receptors showed conflicting results. Other modulators of the reward system are synaptosomal genes. Among candidate genes, polygenic variants of the Vesicular Monamine Transporter 2 (VMAT2) gene locus associated with alterations of drinking behavior were published. These variants comprise single nucleotide polymorphisms (SNPs) within the promoter region and the open reading frame. In this study, we confirm the association of VMAT2 SNP rs363387 (allelic association: p = 0.015) with alcohol dependence. This SNP defines several haplotypes including up to four SNPs (minimal p = 0.0045). In addition, numeric effects in the subgroups of males and patients with positive family history were found. We suggest that several rs363387 T-allele containing haplotypes increase the risk of alcohol dependence (OR 1.53), whereas G-allele containing haplotypes confer protection against alcohol dependence. Taken together, there is supporting evidence for a contribution of VMAT2 gene variants to phenotypes of alcohol dependence.

Possible association between OPRM1 genetic variance at the 118 locus and alcohol dependence in a large treatment sample: relationship to alcohol dependence symptoms.

BACKGROUND: Several lines of evidence from previous research indicate that opioid receptors play an important role in ethanol reinforcement and alcohol dependence (AD) risk. Conflicting results were reported on the role of the mu-opioid receptor (OPRM1) polymorphism A118G (Asn40Asp, rs1799971) in the development of alcoholism. METHODS: We investigated a total number of 1,845 alcohol-dependent subjects recruited from inpatient facilities in Germany and 1,863 controls for the mu-opioid receptor (OPRM1) polymorphism using chi-square statistics. RESULTS: An association between the OPRM variant and AD was detected (p = 0.022), in recessive (AA vs. GA/GG) and co-dominant (AA vs. GA) models of inheritance. An association between the OPRM variant and the DSM-IV criterion "efforts to cut down or could not" (p = 0.047) was found, but this did not remain significant after the correction for multiple testing. CONCLUSIONS: The results indicate that this functional OPRM variant is associated with risk of AD and these findings apply to more severe AD, although the association is only nominally significant.

Broad disruption of brain white matter microstructure and relationship with neuropsychological performance in male patients with severe alcohol dependence.

AIMS: In the last years, refined magnetic resonance diffusion tensor imaging (DTI) methods have become available to study microstructural alterations in the human brain. We investigated to what extent white matter tissue abnormalities are present in male patients after chronic, excessive alcohol consumption and if these alterations are correlated with measures of alcohol consumption and neuropsychological performance. METHODS: Twenty-four detoxified adult male patients with severe alcohol dependence and 23 healthy male control subjects were included in the study. Neuropsychological tests were assessed for executive function, attention, memory and visuospatial function. DTI was acquired and preprocessing of the data was performed using tract-based spatial statistics. Group differences of fractional anisotropy (FA) as well as correlation analyses with neuropsychological measures and drinking history were calculated. RESULTS: Performance in alcoholic patients was significantly poorer in tests of non-verbal reasoning and attention. In detoxified alcoholic patients, lower FA was primarily found in the body of the corpus callosum, but these findings did not correlate directly with behavioral measures. However, executive and psychomotor performance (Trail-Making Test) correlated significantly with FA in right anterior cingulate and left motor areas. CONCLUSION: These findings provide further evidence for reduced integrity of interhemispheric connections in male patients with severe alcohol dependence, and neurocognitive performance was in part correlated with FA.

Prefrontal and striatal dopamine D2/D3 receptors correlate with fMRI BOLD activation during stopping.

D2-like dopamine receptors in animals and humans have been shown to be linked to impulsive behaviors that are highly relevant for several psychiatric disorders. Here, we investigate the relationship between the fronto-striatal D2/D3 dopamine receptor availability and response inhibition in a selected population of healthy OPRM1 G-allele carriers. Twenty-two participants successively underwent blood-oxygen level dependent functional magnetic resonance imaging (fMRI) while performing a stop-signal task and a separate positron emission tomography (PET) scan. Striatal and extrastriatal D2/D3 dopamine receptor availability was measured using the radiotracer [18F]fallypride. Caudate D2/D3 dopamine receptor availability positively correlated with stopping-related fronto-striatal fMRI activation. In addition, right prefrontal D2/D3 dopamine receptor availability correlated positively with stopping-related striatal fMRI BOLD signal. Our study partially replicates previous findings on correlations between striatal D2/D3 dopamine receptor availability and response inhibition in a population selected for its genetic determination of dopamine response to alcohol and as a modulator of impulse control via the endogenous opioid system. We confirm the important role of D2/D3 dopamine receptor availability in the fronto-striatal neural circuit for response inhibition. Moreover, we extend previous findings suggesting that dopamine receptor availability in the right inferior frontal cortex, a crucial region of the stopping network, is also strongly associated with stopping-related striatal fMRI activity in healthy OPRM1 G-allele carriers.

Impulsiveness and venturesomeness in German smokers.

INTRODUCTION: Cigarette smoking is a behavior, which is influenced by genetic, demographic, and psychological factors. A large body of research has examined the association of cigarette smoking variables with individual differences in personality traits. The aim of the current study was to replicate the findings of higher self-reported impulsivity in smokers compared with never-smokers in a German sample using Eysenck´s construct of impulsivity. Furthermore, it was intended to further the knowledge about associations between different self-reported impulsivity components and different smoking variables. METHODS: We used the Impulsiveness-Venturesomeness-Empathy questionnaire (I7) to measure self-reported impulsiveness and venturesomeness and the Temperament and Character Inventory (TCI) to measure novelty seeking (NS) in a sample of 82 nicotine-dependent smokers and 119 never-smokers. RESULTS: Smokers scored higher on impulsiveness, venturesomeness, and NS than never-smokers independent of age, gender, and years of education. We found a significant association between venturesomeness, impulsiveness and smoking status in daily smokers. CONCLUSIONS: In summary, this study provides evidence that impulsiveness and venturesomeness as well as the novelty-seeking subscale extravagance are significantly associated with smoking status in a German sample of female and male smokers compared with never-smokers.

Dopamine D2/D3 receptor availability and venturesomeness.

The construct of impulsivity is considered as a major trait of personality. There is growing evidence that the mesolimbic dopamine system plays an important role in the modulation of impulsivity and venturesomeness, the two key components within the impulsivity-construct. The aim of the present study was to explore an association between trait impulsivity measured with self-assessment and the dopaminergic neurotransmission as measured by positron emission tomography (PET) in a cohort of healthy male subjects. In vivo D2/D3 receptor availability was determined with [(18)F]fallypride PET in 18 non-smoking healthy subjects. The character trait impulsivity was measured using the Impulsiveness-Venturesomeness-Empathy questionnaire (I7). Image processing and statistical analysis was performed on a voxel-by-voxel basis using statistical parametric mapping (SPM) software. The I7 subscale venturesomeness correlated positively with the D2/D3 receptor availability within the left temporal cortex and the thalamus. Measures on the I7 subscale impulsiveness and empathy did not correlate with the D2/D3 receptor availability in any brain region investigated. Our results suggest the involvement of extrastriatal dopaminergic neurotransmission in venturesomeness, a component of impulsivity.

Severity of dependence modulates smokers' neuronal cue reactivity and cigarette craving elicited by tobacco advertisement.

Smoking-related cues elicit craving and mesocorticolimbic brain activation in smokers. Severity of nicotine dependence seems to moderate cue reactivity, but the direction and mechanisms of its influence remains unclear. Although tobacco control policies demand a ban on tobacco advertising, cue reactivity studies in smokers so far have not employed tobacco advertisement as experimental stimuli. We investigated whether tobacco advertisement elicits cue reactivity at a behavioral (subjective craving) and a neural level (using functional magnetic resonance imaging) in 22 smokers and 21 never-smokers. Moreover, we studied the influence of severity of dependence on cue reactivity. In smokers, tobacco advertisement elicited substantially more craving than control advertisement whereas never-smokers reported no cue induced craving. Surprisingly, neuronal cue reactivity did not differ between smokers and never-smokers. Moderately dependent smokers' craving increased over the course of the experiment, whereas highly dependent smokers' craving was unaffected. Moderately dependent smokers' brain activity elicited by tobacco advertisement was higher in the amygdala, hippocampus, putamen and thalamus compared with highly dependent smokers. Furthermore, limbic brain activation predicted picture recognition rates after the scanning session, even in never-smokers. Our findings show that tobacco advertisement elicits cigarette craving and neuronal cue reactivity primarily in moderately dependent smokers, indicating that they might be particularly responsive towards external smoking-related cues. On the other hand, neuronal cue reactivity and cigarette craving in highly dependent smokers is more likely triggered by internal cues such as withdrawal symptoms. Tobacco advertisement seems to likewise appeal to smokers and non-smokers, clarifying the potential danger especially for young non-smokers.

Association of ADH4 genetic variants with alcohol dependence risk and related phenotypes: results from a larger multicenter association study.

Genetic variants of the alcohol-metabolizing enzyme ADH4, located on chromosome 4q22-4q23, have been related to alcohol dependence (AD) risk in previous research. The aim of this association study in a large multicenter sample of alcohol-dependent individuals and controls is to confirm ADH4 single nucleotide polymorphism (SNP) and haplotype association with AD and relevant related phenotypes. One thousand, six hundred and twenty-two (1622) inpatient subjects and 1469 control subjects with DSM-IV. AD from four addiction treatment centres were included. Characteristics of AD and related phenotypes including alcohol withdrawal, Cloninger's type I and II and first ages of drinking, regular drinking and AD onset were obtained using standardized structured interviews. After subjects were genotyped for 2 ADH4 polymorphisms, single SNP case-control and haplotype analyses were conducted. Both variants--rs1800759 and rs1042364--and the A-A and C-G haplotypes were significantly related to AD across samples. Furthermore, associations with AD-related phenotypes and subtypes revealed a potential protective influence of this haplotype. This study confirms the significant relationship of ADH4 variants with AD and related phenotypes. While the rs1800759 and rs1042364 A-A haplotype had a potential protective influence on the risk for several AD-related phenotypes, this effect is rather small compared to functional variants of other alcohol or acetaldehyde-metabolizing enzymes like ALDH2*2 or ADH1B*2.

Disturbed structural connectivity is related to inattention and impulsivity in adult attention deficit hyperactivity disorder.

Inattention and impulsivity are the most prominent clinical features of attention deficit hyperactivity disorder (ADHD) in adulthood. Structural and functional neuroimaging studies of subjects with ADHD have demonstrated abnormalities in several brain areas, including fronto-striatal and fronto-cerebellar networks. Mostly, these studies were based on volumetric measurements and have been conducted in children. We investigated white matter (WM) integrity and correlation with measures of attention and impulsivity in adult patients with ADHD adopting diffusion tensor imaging (DTI). N = 37 (21 males) never-medicated adult patients with ADHD combined subtype and N = 34 (16 males) healthy controls were investigated. ADHD diagnosis (DSM-IV) was assessed with clinical interviews and rating scales, subjects also underwent a large neuropsychological test battery including tests of attention and impulsivity. DTI was acquired, and group differences of fractional anisotropy (FA) and mean diffusivity (MD) as well as correlation analyses with measures of attentional performance and impulsivity were calculated using voxel-based analyses. In adult patients with ADHD, we found reduced FA as well as higher MD bilaterally in orbitomedial prefrontal WM and in the right anterior cingulate bundle, while elevated FA was present bilaterally in temporal WM structures. Measures of attention were correlated with DTI parameters in the right superior longitudinal fasciculus, whereas measures of impulsivity were correlated with FA in right orbitofrontal fibre tracts. This is the first DTI study demonstrating disturbed structural connectivity of the frontal-striatal circuitry in adult patients with ADHD. Moreover, a direct correlation between WM integrity and measures of attention and impulsivity is shown.

Human dopamine receptor D2/D3 availability predicts amygdala reactivity to unpleasant stimuli.

Dopamine (DA) modulates the response of the amygdala. However, the relation between dopaminergic neurotransmission in striatal and extrastriatal brain regions and amygdala reactivity to affective stimuli has not yet been established. To address this issue, we measured DA D2/D3 receptor (DRD2/3) availability in twenty-eight healthy men (nicotine-dependent smokers and never-smokers) using positron emission tomography with [18F]fallypride. In the same group of participants, amygdala response to unpleasant visual stimuli was determined using blood oxygen level-dependent (BOLD) functional magnetic resonance imaging. The effects of DRD2/3 availability in emotion-related brain regions and nicotine dependence on amygdala response to unpleasant stimuli were examined by multiple regression analysis. We observed enhanced prefrontal DRD2/3 availability in those individuals with higher amygdala response to unpleasant stimuli. As compared to never-smokers, smokers showed an attenuated amygdala BOLD response to unpleasant stimuli. Thus, individuals with high prefrontal DRD2/3 availability may be more responsive toward aversive and stressful information. Through this mechanism, dopaminergic neurotransmission might influence vulnerability for affective and anxiety disorders. Neuronal reactivity to unpleasant stimuli seems to be reduced by smoking. This observation could explain increased smoking rates in individuals with mental disorders.

Risk gene variants for nicotine dependence in the CHRNA5-CHRNA3-CHRNB4 cluster are associated with cognitive performance.

Recent studies strongly support an association of the nicotinic acetylcholine receptor gene cluster CHRNA5-CHRNA3-CHRNB4 with nicotine dependence (ND). However, the precise genotype-phenotype relationship is still unknown. Clinical and epidemiological data on smoking behavior raise the possibility that the relevant gene variants may indirectly contribute to the development of ND by affecting cognitive performance in some smokers who consume nicotine for reasons of "cognition enhancement." Here, we tested seven single nucleotide polymorphisms (SNPs) rs684513, rs637137, rs16969968, rs578776, rs1051730, rs3743078, rs3813567 from the CHRNA5-CHRNA3-CHRNB4 gene cluster for association with ND, measures of cognitive performance and gene expression. As expected, we found all SNPs being associated with ND in three independent cohorts (KORA, NCOOP, ESTHER) comprising 5,561 individuals. In an overlapping sample of 2,186 subjects we found three SNPs (rs16969968, rs1051730, rs3743078) being associated with cognitive domains from the Wechsler-Adult-Intelligence Scale (WAIS-R)-most notably in the performance subtest "object assembly" and the verbal subtest "similarities." In a refined analysis of a subsample of 485 subjects, two of these three SNPs (rs16969968, rs1051730) were associated with n-back task performance/Continuous Performance Test. Furthermore, two CHRNA5 risk alleles (rs684513, rs637137) were associated with CHRNA5 mRNA expression levels in whole blood in a subgroup of 190 subjects. We here report for the first time an association of CHRNA5-CHRNA3-CHRNB4 gene variants with cognition possibly mediating in part risk for developing ND. The observed phenotype-genotype associations may depend on altered levels of gene expression. © 2010 Wiley-Liss, Inc.

Detection times for urinary ethyl glucuronide and ethyl sulfate in heavy drinkers during alcohol detoxification.

AIMS: Ethyl glucuronide (EtG) and ethyl sulfate (EtS) are conjugated ethanol metabolites formed in low amounts after alcohol consumption. Compared with ethanol, EtG and EtS are excreted in urine for a prolonged time, making them useful as sensitive alcohol biomarkers. This study determined the detection times for EtG and EtS in alcoholic patients undergoing alcohol detoxification. METHODS: Alcohol-dependent patients (n = 32) with an initial alcohol concentration >or=1 g/L based on breath testing were followed during detoxification. Urine samples for determination of EtG, EtS, ethanol and creatinine were collected on admission to the hospital and thereafter once daily for several days. EtG and EtS measurements were performed by liquid chromatography-mass spectrometry (LC-MS) and EtG also using an immunochemical assay (DRI-EtG EIA, ThermoFisher/Microgenics). RESULTS: The detection time for urinary EtG was weakly correlated (r = 0.434, P = 0.013) with the initial alcohol concentration (range 1.0-3.4 g/L). For EtG, the individual time range until return to below the applied cut-off limit (<0.5 mg/L) was approximately 40-130 h (median 78) with a similar time course observed for EtS. After correction for urine dilution, the time until an EtG/creatinine ratio <0.5 mg/g was approximately 40- 90 h (median 65). The detection times after an estimated zero ethanol concentration were approximately 30-110 h (median 66) for EtG and approximately 30- 70 h (median 56) for EtG/creatinine. The EtG results by LC-MS and the immunoassay were in good agreement. CONCLUSIONS: During alcohol detoxification, EtG and EtS remained detectable in urine for several days. The detection times showed wide inter-individual variations, also after adjusting values for urine dilution and to the estimated times for a completed ethanol elimination.

No association of alcohol dependence with SLC6A5 and SLC6A9 glycine transporter polymorphisms.

To determine whether glycine transporter polymorphisms are associated with alcoholism, three genetic variants of SLC6A5 and two polymorphisms of SLC6A9 were genotyped in 463 German non-alcoholic controls and 644 German alcohol-dependent subjects. Association was investigated employing chi-square statistics and haplotype analysis. There was a significant association between the SLC6A5 polymorphism (rs1443547) and alcohol dependence as alcoholic individuals had a lower rate of AG-allele (chi(2) = 6.048, P = 0.049, d.f. = 2), which did not remain significant after correction for multiple testing. There was no association between SLC6A9 glycine transporter polymorphisms and alcohol dependence, and also none in haplotype analysis.

Association of low striatal dopamine d2 receptor availability with nicotine dependence similar to that seen with other drugs of abuse.

OBJECTIVE: All drugs of abuse induce a phasic dopamine release within the striatum that does not undergo habituation. Prolonged substance consumption impairs the natural function of the mesolimbic dopamine system, as shown by a decrease in the availability of striatal dopamine 2 (D(2)) receptors in patients suffering from cocaine, heroin, amphetamine, and alcohol dependence. However, it is unclear whether similar changes can also be observed in heavy-smoking nicotine-dependent smokers. METHOD: In vivo D(2)/D(3) receptor availability was determined with [ (18)F]fallypride positron emission tomography in 17 heavy-smoking nicotine-dependent subjects and in 21 age-matched never-smoking comparison subjects. The smokers were scanned twice: first, during a period of usual consumption and second, 24 hours after smoking cessation. RESULTS: Independent of the withdrawal status, the nicotine-dependent smokers displayed significantly less availability of D(2)/D(3) receptors within the bilateral putamen functionally covering parts of the dorsal striatum, as compared to the never-smoking subjects. Nicotine craving under the consumption condition correlated positively with D(2)/D(3) receptor availability within the ventral striatum but negatively with D(2)/D(3) receptor availability within the anterior cingulate and inferior temporal cortex. CONCLUSIONS: Similar to other types of substance abuse, nicotine dependence is associated with low availability of dorsal striatal D(2)/D(3) receptors. In contrast to previous findings on abstinent alcohol-dependent patients, nicotine craving seems to be maintained by a region-specific shift in D(2)/D(3) receptor availabilities, with higher availability within the ventral striatum but lower availability within the anterior cingulate and inferior temporal cortex.

Mpdz is a quantitative trait gene for drug withdrawal seizures.

Physiological dependence and associated withdrawal episodes can constitute a powerful motivational force that perpetuates drug use and abuse. Using robust behavioral models of drug physiological dependence in mice, positional cloning, and sequence and expression analyses, we identified an addiction-relevant quantitative trait gene, Mpdz. Our findings provide a framework to define the protein interactions and neural circuit by which this gene's product (multiple PDZ domain protein) affects drug dependence, withdrawal and relapse.

Tiagabine does not attenuate alcohol-induced activation of the human reward system.

RATIONALE: The rewarding effects of ethanol and other drugs of abuse are mediated by activation of the mesolimbic dopamine system. Recent neuroimaging studies in primates and humans suggest that cocaine-induced dopamine stimulation might be diminished by drugs augmenting gamma-aminobutyric acid A (GABA-A) receptor function such as the GABA transaminase inhibitor vigabatrin. OBJECTIVES: The objective of this study was to test the property of the selective GABA transporter 1 (GAT1) inhibitor tiagabine to block ethanol-induced activation of the mesolimbic reward system in an i.v. ethanol challenge. MATERIALS AND METHODS: Twenty nonaddicted healthy volunteers underwent an i.v. ethanol challenge after 1 week of tiagabine (15 mg/day) administration. Neuronal activation was measured using [(18)F]-fluoro-deoxyglucose positron emission tomography (PET). RESULTS: Tiagabine did not prevent ethanol-induced stimulation of the mesolimbic reward system but augmented ethanol-induced hypometabolism within areas of the visual system and the cerebellum. Tiagabine alone also decreased neuronal metabolism within parts of the right temporal cortex that are highly enriched with GABA-ergic neurons. CONCLUSIONS: Our ethanol challenge imaging study does not provide supporting evidence that the GAT1 inhibitor tiagabine diminishes the rewarding effects of ethanol. Further PET imaging studies using established anticraving compounds, such as the mu-opioid receptor antagonist naltrexone and antiepileptic drugs affecting the GABA-ergic system more broadly, will provide additional important insights on the interaction between the GABA-ergic and the brain reward system in vivo and the suitability of GABA-ergic drugs as anticraving compounds.

Confirmation of association of the GABRA2 gene with alcohol dependence by subtype-specific analysis.

OBJECTIVES: Three recent studies revealed a haplotypic association of alcohol dependence with the gene encoding the alpha2 subunit of the gamma-aminobutyric acid type A (GABAA) receptor (GABRA2). The present study examined whether variation of the GABRA2 gene confers susceptibility to different subtypes of alcohol dependence in the German population. METHODS: A total of 257 German alcohol-dependent patients and 88 healthy population controls were genotyped for six single-nucleotide polymorphisms covering the middle part and the 3' end of GABRA2. Allelic, genotypic and haplotypic comparisons were done for subgroups of alcohol-dependent patients with a presumed high genetic load. RESULTS: The overall alcohol-dependent patients vs. control group comparison confirmed positive allelic association for five of six single-nucleotide polymorphisms mapping from intron 3 to the 3' end of GABRA2 (P=0.01-0.02). Haplotype analysis revealed two common haplotypes accounting for approximately 90% of the chromosomes within the patients and controls. The less frequent haplotype was significantly more prevalent among the alcohol-dependent patients (45%) than among the controls [29%; odds ratio (OR)=1.97, 95% confidence interval (CI): 1.30-2.96]. The strength of association increased, if the subsets of alcohol-dependent patients with a positive family history (OR=2.60, 95% CI: 1.63-4.13), withdrawal seizures (OR=2.22, 95% CI: 1.30-3.79) or an early onset (OR=2.19, 95% CI: 1.24-3.88) were analyzed. CONCLUSIONS: Although our study was limited by the number of cases being larger than the number of controls, the results confirm GABRA2 as a susceptibility gene for alcohol dependence in the German population. We found a consistent increase of the susceptibility effect in alcohol-dependent patients with a presumed strong genetic predisposition.