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Articles by M. L Schwandt
Total Records ( 2 ) for M. L Schwandt
  S. G Lindell , M. L Schwandt , H Sun , J. D Sparenborg , K Bjork , J. W Kasckow , W. H Sommer , D Goldman , J. D Higley , S. J Suomi , M Heilig and C. S. Barr
 

Context  Neuropeptide Y (NPY) counters stress and is involved in neuroadaptations that drive escalated alcohol drinking in rodents. In humans, low NPY expression predicts amygdala response and emotional reactivity. Genetic variation that affects the NPY system could moderate stress resilience and susceptibility to alcohol dependence.

Objective  To determine whether functional NPY variation influences behavioral adaptation to stress and alcohol consumption in a nonhuman primate model of early adversity (peer rearing).

Design  We sequenced the rhesus macaque NPY locus (rhNPY) and performed in silico analysis to identify functional variants. We performed gel shift assays using nuclear extract from testes, brain, and hypothalamus. Levels of NPY in cerebrospinal fluid were measured by radioimmunoassay, and messenger RNA levels were assessed in the amygdala using real-time polymerase chain reaction. Animals were exposed to repeated social separation stress and tested for individual differences in alcohol consumption. Animals were genotyped for –1002 T > G, and the data were analyzed using analysis of variance.

Setting  National Institutes of Health Animal Center.

Subjects  Ninety-six rhesus macaques.

Main Outcome Measure  Behavior arousal during social separation stress and ethanol consumption.

Results  The G allele altered binding of regulatory proteins in all nuclear extracts tested, and –1002 T > G resulted in lower levels of NPY expression in the amygdala. Macaques exposed to adversity had lower cerebrospinal fluid NPY levels and exhibited higher levels of arousal during stress, but only as a function of the G allele. We also found that stress-exposed G allele carriers consumed more alcohol and exhibited an escalation in intake over cycles of alcohol availability and deprivation.

Conclusions  Our results suggest a role for NPY promoter variation in the susceptibility to alcohol use disorders and point to NPY as a candidate for examining gene x environment interactions in humans.

  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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