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Articles by R Spanagel
Total Records ( 3 ) for R Spanagel
  J Mutschler , A Bilbao , C von der Goltz , C Demiralay , H Jahn , K Wiedemann , R Spanagel and F. Kiefer
 

Aims: Preclinical and clinical data suggest an involvement of atrial natriuretic peptides (ANP) in alcohol-associated psychopathology. We now present first data on alcohol drinking behaviour in mice lacking a functional natriuretic peptide-A (NPR-A) receptor. Methods: NPR-A–/– and wild-type mice were given a free choice between water and increasing concentrations of alcohol (2–16%). A forced swim stress was performed thereafter on three consecutive days to investigate stress-induced alcohol drinking. Additionally, neurobehavioural alcohol withdrawal response was investigated following 14 days of forced-alcohol intake. Results: Whereas basal alcohol intake did not differ between NPR-A mutants and wild-type littermates, NPR-A mutants showed an increased stress-induced alcohol intake and aggravated neurobehavioural symptoms of alcohol withdrawal. Conclusions: Mice lacking a functional NPR-A receptor represent a useful model to study the role of the ANP system in alcohol-associated pathology. To study the role of the natriuretic NPR-A gene for the modulation of risk of alcohol-related disorders, NPR-A-related polymorphisms should be targeted in clinical studies.

  J Treutlein , S Cichon , M Ridinger , N Wodarz , M Soyka , P Zill , W Maier , R Moessner , W Gaebel , N Dahmen , C Fehr , N Scherbaum , M Steffens , K. U Ludwig , J Frank , H. E Wichmann , S Schreiber , N Dragano , W. H Sommer , F Leonardi Essmann , A Lourdusamy , P Gebicke Haerter , T. F Wienker , P. F Sullivan , M. M Nothen , F Kiefer , R Spanagel , K Mann and M. Rietschel
 

Context  Alcohol dependence is a serious and common public health problem. It is well established that genetic factors play a major role in the development of this disorder. Identification of genes that contribute to alcohol dependence will improve our understanding of the mechanisms that underlie this disorder.

Objective  To identify susceptibility genes for alcohol dependence through a genome-wide association study (GWAS) and a follow-up study in a population of German male inpatients with an early age at onset.

Design  The GWAS tested 524 396 single-nucleotide polymorphisms (SNPs). All SNPs with P < 10–4 were subjected to the follow-up study. In addition, nominally significant SNPs from genes that had also shown expression changes in rat brains after long-term alcohol consumption were selected for the follow-up step.

Setting  Five university hospitals in southern and central Germany.

Participants  The GWAS included 487 male inpatients with alcohol dependence as defined by the DSM-IV and an age at onset younger than 28 years and 1358 population-based control individuals. The follow-up study included 1024 male inpatients and 996 age-matched male controls. All the participants were of German descent.

Main Outcome Measures  Significant association findings in the GWAS and follow-up study with the same alleles.

Results  The GWAS produced 121 SNPs with nominal P < 10–4. These, together with 19 additional SNPs from homologues of rat genes showing differential expression, were genotyped in the follow-up sample. Fifteen SNPs showed significant association with the same allele as in the GWAS. In the combined analysis, 2 closely linked intergenic SNPs met genome-wide significance (rs7590720, P = 9.72 x 10–9; rs1344694, P = 1.69 x 10–8). They are located on chromosome region 2q35, which has been implicated in linkage studies for alcohol phenotypes. Nine SNPs were located in genes, including the CDH13 and ADH1C genes, that have been reported to be associated with alcohol dependence.

Conclusions  This is the first GWAS and follow-up study to identify a genome-wide significant association in alcohol dependence. Further independent studies are required to confirm these findings.

  J. C Umhau , R Momenan , M. L Schwandt , E Singley , M Lifshitz , L Doty , L. J Adams , V Vengeliene , R Spanagel , Y Zhang , J Shen , D. T George , D Hommer and M. Heilig
 

Context  Acamprosate is approved for the treatment of alcoholism, but its mechanism of action remains unclear. Results of animal studies suggest that a persistent hyperglutamatergic state contributes to the pathogenesis of alcoholism and that acamprosate may exert its actions by intervening in this process. Human translation of these findings is lacking.

Objective  To examine whether acamprosate modulates indices of central glutamate levels in recently abstinent alcohol-dependent patients as measured using proton nuclear magnetic resonance spectroscopy (1H-MRS).

Design  A 4-week, double-blind, placebo-controlled, randomized controlled experimental medicine study, with 1H-MRS measures obtained on days 4 and 25.

Setting  An inpatient research unit at the NIH Clinical Center.

Patients  Thirty-three patients who met the DSM-IV criteria for alcohol dependence and who were admitted for medically supervised withdrawal from ongoing alcohol use.

Intervention  Four weeks of acamprosate (initial oral loading followed by 1998 mg daily) or matched placebo, initiated at the time of admission.

Main Outcome Measures  The glutamate to creatine ratio as determined using single-voxel 1H-MRS in the anterior cingulate. Exploratory neuroendocrine, biochemical, and behavioral outcomes were also collected, as were safety- and tolerability-related measures.

Results  There was a highly significant suppression of the glutamate to creatine ratio across time by acamprosate (time x treatment interaction: F1,29 = 13.5, P < .001). Cerebrospinal fluid levels of glutamate obtained in a subset of patients 4 weeks into abstinence were uncorrelated with the MRS measures and unaffected by treatment but were strongly correlated (R2 = 0.48, P < .001) with alcohol dependence severity. Other exploratory outcomes, including repeated dexamethasone–corticotropin-releasing hormone tests, and psychiatric ratings were unaffected. Among tolerability measures, gastrointestinal symptoms were significantly greater in acamprosate-treated individuals, in agreement with the established profile of acamprosate.

Conclusion  The MRS measures of central glutamate are reduced across time when acamprosate therapy is initiated at the onset of alcohol abstinence.

Trial Registration  clinicaltrials.gov Identifier: NCT00106106

 
 
 
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