The MTHFR C677T Variant Is Associated With Responsiveness to Disulfiram Treatment for Cocaine Dependency.
The MTHFR C677T Variant is Associated with Responsiveness to Disulfiram Treatment for Cocaine Dependency.
Filed under: Addiction Rehab
Front Psychiatry. 2012; 3: 109
Spellicy CJ, Kosten TR, Hamon SC, Harding MJ, Nielsen DA
Objective: Disulfiram is a one of the few pharmacotherapies for cocaine addiction that shows promise. Since disulfiram and cocaine both affect levels of global methylation we hypothesized the MTHFR gene, whose product is involved in supplying methyl groups for DNA and protein methylation, may be associated with responsiveness to disulfiram in cocaine-dependent individuals. Methods: Sixty-seven cocaine-dependent patients were stabilized on methadone for 2?weeks and then randomized into disulfiram (250?mg/day, N?=?32) and placebo groups (N?=?35) for 10?weeks. Patients were genotyped for the MTHFR (rs1801133, also known as C677T) polymorphism and the data was evaluated for association with cocaine-free urines in the disulfiram or placebo groups. Data from patients that completed all 10?weeks of the study (N?=?56) were analyzed using repeated measures analysis of variance (ANOVA), corrected for population structure. Results: The CT or TT MTHFR genotype group (N?=?32) dropped from 73 to 52% cocaine-positive urines on disulfiram (p?=?0.0001), while the placebo group showed no treatment effect. The CC MTHFR genotype group (N?=?24) showed a smaller, but still significant, reduction in cocaine-positive urines on disulfiram compared to placebo; 81-69% (p?=?0.007). Conclusion: This study indicates that a patient’s MTHFR genotype may be used to identify individuals who might show improved response to disulfiram treatment for cocaine dependence. Clinical Trial: Pharmacogenetics of Disulfiram for Cocaine, clinicaltrials.gov/ct2/show/NCT00149630, NIDA-18197-2, NCT00149630.
HubMed – addiction
Effects of blast-induced neurotrauma on the nucleus accumbens.
Filed under: Addiction Rehab
J Neurosci Res. 2013 Jan 18;
Sajja VS, Galloway M, Ghoddoussi F, Kepsel A, Vandevord P
Blast-induced neurotrauma (BINT) leads to deterioration at the cellular level, with adverse cognitive and behavioral outcomes. The nucleus accumbens (NAC) plays an important role in reward, addiction, aggression, and fear pathways. To identify the molecular changes and pathways affected at an acute stage in the NAC, this study focused on a time course analysis to determine the effects of blast on neurochemical and apoptotic pathways. By using a rodent model of BINT, acute damage to the NAC was assessed by proton magnetic resonance spectroscopy ((1) H-MRS), high-performance liquid chromatography, immunohistochemistry, and Western blotting. The results demonstrated ongoing neuroprotective effects from elevated levels of Bcl-2, an antiapoptotic marker, at 24 hr and N-acetyl aspartate glutamate at 48 hr following blast exposure. Selective loss of serotonin levels at 24 hr, increased levels of inflammation (elevated glycerophosphocholine at 48 and 72 hr), and increased levels of glial fibrillary acidic protein were also observed at 24 and 48 hr, leading to disruptive energy status. Furthermore, active cell death was indicated by the increased levels of the apoptotic marker Bax, decreased actin levels, and signs excitotoxicity (glutamate/creatine). In addition, increased evels of caspase-3, an apoptotic marker, confirm active cell death in NAC. It is hypothesized that blast overpressure causes inflammation and neurochemical changes that trigger apoptosis in NAC. This cascade of events may lead to stress-related behavioral outcomes and psychiatric sequelae. © 2013 Wiley Periodicals, Inc.
HubMed – addiction
Translational Research in Nicotine Dependence.
Filed under: Addiction Rehab
Cold Spring Harb Perspect Med. 2013 Jan 18;
Turner JR, Gold A, Schnoll R, Blendy JA
Nicotine addiction accounts for 4.9 million deaths each year. Furthermore, although smoking represents a significant health burden in the United States, at present there are only three FDA-approved pharmacotherapies currently on the market: (1) nicotine replacement therapy, (2) bupropion, and (3) varenicline. Despite this obvious gap in the market, the complexity of nicotine addiction in addition to the increasing cost of drug development makes targeted drug development prohibitive. Furthermore, using combinations of mouse and human studies, additional treatments could be developed from off-the-shelf, currently approved medication lists. This article reviews translational studies targeting manipulations of the cholinergic system as a viable therapeutic target for nicotine addiction.
HubMed – addiction
A Bivariate Mann-Whitney Approach for Unraveling Genetic Variants and Interactions Contributing to Comorbidity.
Filed under: Addiction Rehab
Genet Epidemiol. 2013 Jan 17;
Wen Y, Schaid DJ, Lu Q
Although comorbidity among complex diseases (e.g., drug dependence syndromes) is well documented, genetic variants contributing to the comorbidity are still largely unknown. The discovery of genetic variants and their interactions contributing to comorbidity will likely shed light on underlying pathophysiological and etiological processes, and promote effective treatments for comorbid conditions. For this reason, studies to discover genetic variants that foster the development of comorbidity represent high-priority research projects, as manifested in the behavioral genetics studies now underway. The yield from these studies can be enhanced by adopting novel statistical approaches, with the capacity of considering multiple genetic variants and possible interactions. For this purpose, we propose a bivariate Mann-Whitney (BMW) approach to unravel genetic variants and interactions contributing to comorbidity, as well as those unique to each comorbid condition. Through simulations, we found BMW outperformed two commonly adopted approaches in a variety of underlying disease and comorbidity models. We further applied BMW to datasets from the Study of Addiction: Genetics and Environment, investigating the contribution of 184 known nicotine dependence (ND) and alcohol dependence (AD) single nucleotide polymorphisms (SNPs) to the comorbidity of ND and AD. The analysis revealed a candidate SNP from CHRNA5, rs16969968, associated with both ND and AD, and replicated the findings in an independent dataset with a P-value of 1.06 × 10(-03) .
HubMed – addiction
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