RESUMO
BACKGROUND: Studies of alcohol effects in rodents and in vitro implicate endogenous neuroactive steroids as key mediators of alcohol effects at GABA(A) receptors. We used a case-control sample to test the association with alcohol dependence (AD) of single nucleotide polymorphisms in the genes encoding two key enzymes required for the generation of endogenous neuroactive steroids: 5α-reductase, type I (5α-R), and 3α-hydroxysteroid dehydrogenase, type 2 (3α-HSD), both of which are expressed in human brain. METHODS: We focused on markers previously associated with a biological phenotype. For 5α-R, we examined the synonymous SRD5A1 exon 1 SNP rs248793, which has been associated with the ratio of dihydrotestosterone to testosterone. For 3α-HSD, we examined the nonsynonymous AKR1C3 SNP rs12529 (H5Q), which has been associated with bladder cancer. The SNPs were genotyped in a sample of 1,083 non-Hispanic Caucasians including 552 controls and 531 subjects with AD. RESULTS: The minor allele for both SNPs was more common among controls than subjects with AD: SRD5A1 rs248793 C-allele (χ(2)(1) = 7.6, p = 0.006) and AKR1C3 rs12529 G-allele (χ(2)(1) = 14.6, p = 0.0001). There was also an interaction of these alleles such that the "protective" effect of the minor allele at each marker for AD was conditional on the genotype of the second marker. CONCLUSIONS: We found evidence of an association with AD of polymorphisms in two genes encoding neuroactive steroid biosynthetic enzymes, providing indirect evidence that neuroactive steroids are important mediators of alcohol effects in humans.
Assuntos
3-Hidroxiesteroide Desidrogenases/genética , 3-Oxo-5-alfa-Esteroide 4-Desidrogenase/genética , Alcoolismo/genética , Variação Genética/genética , Hidroxiprostaglandina Desidrogenases/genética , Proteínas de Membrana/genética , Adulto , Alcoolismo/diagnóstico , Membro C3 da Família 1 de alfa-Ceto Redutase , Sequência de Bases , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Polimorfismo de Nucleotídeo Único , Adulto JovemRESUMO
BACKGROUND: Glutamate neurotransmission plays an important role in a variety of alcohol-related phenomena, including alcohol self-administration by both animals and humans. Because the risk for alcohol dependence (AD) is genetically influenced, genes encoding glutamate receptors are candidates to contribute to the risk for AD. We examined the role of variation in the 3' region of GRIK1, the gene that encodes the GluR5 receptor subunit of the kainic acid glutamate receptor, on risk for AD. We focused specifically on this gene because topiramate, a glutamate modulator that binds to the GluR5 subunit, has shown robust efficacy in the treatment of AD. METHODS: We genotyped 7 single nucleotide polymorphisms (SNPs) in the 3'-half of GRIK1, which includes 3 differentially spliced exons, in a sample of EA control subjects (n = 507) and subjects with AD (n = 1,057). RESULTS: We found nominally significant evidence of association to AD for 3 SNPs (rs2832407 in intron 9, rs2186305 in intron 17, and rs2832387 in the 3'UTR). Empirical p-value estimation revealed that only rs2832407 was significantly associated to phenotype (p = 0.043). DISCUSSION: These findings provide support for the hypothesis that variation in the 3' portion of the gene encoding the GluR5 kainate receptor subunit contributes to the risk for AD. Further research is needed to ascertain whether this SNP is itself functional or whether the association reflects linkage disequilibrium with functional variation elsewhere in the gene and whether this SNP moderates topiramate's effects in the treatment of AD.
Assuntos
Região 3'-Flanqueadora/genética , Alcoolismo/genética , Subunidades Proteicas/genética , Receptores de Ácido Caínico/genética , Adulto , Alcoolismo/diagnóstico , Feminino , Marcadores Genéticos/genética , Variação Genética/genética , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Subunidades Proteicas/química , Receptores de Ácido Caínico/química , Adulto JovemRESUMO
Stress plays a role in many psychiatric disorders that are characterized by deficits in prepulse inhibition (PPI), a form of sensorimotor gating. Corticotropin-releasing factor (CRF) is one of the most important neurotransmitters involved in behavioral components of the stress response, and central infusion of CRF decreases PPI in rodents. We recently demonstrated that restraint stress decreases PPI and attenuates the increase in PPI caused by repeated testing. To broaden our investigation into how restraint affects PPI, we subjected Wistar-Kyoto (WKY) and Brown Norway (BN) rats to 10 consecutive days of 2-hour restraint, or to brief handling, prior to assessing PPI. We next examined the effects of 1 or 10days of 2-hour restraint on plasma corticosterone levels in order to determine whether the endocrine response to stress parallels the behavioral effect of stress. Finally, we examined the effects of 1 or 10days of 2-hour restraint on CRF and CRF receptor gene expression in the amygdala, hippocampus, frontal cortex, and hypothalamus in order to determine whether a temporal pattern of gene expression parallels the change in the behavioral response to stress. The major findings of the present study are that 1) restraint stress attenuates the increase in PPI caused by repeated testing in both WKY and BN rats, and BN rats are more sensitive to the effects of restraint on PPI than WKY rats, 2) restraint-induced increases in corticosterone levels mirror the effect of restraint on PPI in WKY rats but not in BN rats, 3) laterality effects on gene expression were observed for the amygdala, whereby restraint increases CRF gene expression in the left, but not right, amygdala, and 4) some restraint-induced changes in CRF and CRF receptor gene expression precede changes in PPI while other changes coincide with altered PPI in a rat strain- and brain region-dependent manner.