Several genetic studies have revealed that bipolar disorders are linked with the chromosomal locus of 15q11-q13, where the gamma-aminobutyric acid (GABA) receptor alpha5 subunit gene (GABRA5) locates. GABA is one of the major neurotransmitters that may be involved in the pathogenesis of bipolar disorder. Five polymorphisms in the GABRA5 gene, -754C>T in the promoter region, IVS1-21G>A, IVS2-26T>A, (*)302C>T in 3'-UTR of exon 5, and a CA repeat polymorphism in the 3' flanking region were examined in a Japanese population. IVS1-21G>A exhibited significant differences in the distribution of the genotype and allele frequency in bipolar I disorder patients but not in bipolar II disorder patients, compared with control subjects. The haplotype analysis showed that IVS1-21G>A/IVS2-26A>T was associated with bipolar I disorder, and the IVS1-21A/IVS2-26T haplotype was a negative risk factor for susceptibility to the disorders (odds ratio: 0.57, 95% confidence interval: 0.44-0.73). These results suggest that the GABRA5 gene may confer susceptibility to bipolar I disorder.
"This region is organized in cluster with three of the GABA A receptor subunit genes (GABRB3, GABRA5 and GABRG3)  . Single nucleotide polymorphisms (SNPs) present in these genes have been associated in epilepsy susceptibility, drug resistance  , susceptibility to autistic  or with bipolar schizoaffective disorders  Specifically, GABRA5 was associated with bipolar I disorder   . In the mouse model, four lines of GABA A -receptor point mutated knock-in have attributed different diazepam pharmacological properties to different GABA A -receptor isoforms. "
[Show abstract][Hide abstract] ABSTRACT: The gabra5 gene is associated with pharmacological properties (myorelaxant, amnesic, anxiolytic) of benzodiazepines. It is tightly located (0.5 cM) close to the pink-eyed dilution (p) locus which encodes for fur color on mouse chromosome 7. We tested the putative role of the gabra5 gene in pharmacological properties of the full non specific agonist chlordiazepoxide (CDP), using behavioral and molecular approaches in mutated p/p mice and wild type F2 from crosses between two multiple markers inbred strain ABP/Le and C57BL/6By strain. From our results, using rotarod, light-dark box, elevated maze and radial arm maze tests, we demonstrate that p/p mice are more sensitive than WT to the sensory motor, anxiolytic and amnesic effect of CDP. This is associated with the presence of a haplotypic block on the murine chromosome 7 and with an up regulation of gabra5 mRNAs in hippocampi of p/p F2 mice.
Behavioural brain research 06/2012; 233(2):474-82. DOI:10.1016/j.bbr.2012.05.041 · 3.03 Impact Factor
"Polymorphisms in genes involved in regulating the dopamine system have been related to both behavioral disinhibition and alcohol problems (Limosin et al., 2003; Blum et al., 1990; Hopfer et al., 2005; Vanyukov et al., 1998). Genes involved in regulating the serotonergic and GABAergic systems have been related to behavioral disinhibition, anxiety and depression, and alcohol problems (Dick et al., 2006; Edenberg et al., 2004; Dick et al., 2004; Eley et al., 2004; Hill et al., 2002; Otani et al., 2005), and results from one molecular genetic study indicate that anxiety mediates the influence of GABRA2 on alcoholism (Enoch et al., 2006). These findings support the idea that behavioral disinhibition and behavioral inhibition/anxiety may serve as individual difference pathways for genetic influence on alcohol abuse and dependence (Gottesman and Gould, 2003). "
[Show abstract][Hide abstract] ABSTRACT: Behavioral disinhibition (externalizing/impulsivity) and behavioral inhibition (internalizing/anxiety) may contribute to the development of alcohol abuse and dependence. But tests of person-by-environment interactions in predicting alcohol use disorders are needed. This study examined the extent to which interactions between behavioral disinhibition, behavioral inhibition and family management during adolescence predict alcohol abuse and alcohol dependence at age 27.
This study used longitudinal data from a community sample of 808 men and women interviewed from ages 10 to 27 in the Seattle Social Development Project. Zero-order correlations followed by a series of nested regressions examined the relationships between individual characteristics (behavioral disinhibition and behavioral inhibition/anxiety) and environment (good vs. poor family management practices during adolescence) in predicting alcohol abuse and dependence criterion counts at age 27.
Behavioral disinhibition and poor family management predicted increased likelihood of both alcohol abuse and alcohol dependence at age 27. Behavioral inhibition/anxiety was unrelated to both outcomes. Youths high in behavioral disinhibition were at increased risk for later alcohol abuse and dependence only in consistently poorly managed family environments. In consistently well-managed families, high levels of behavioral disinhibition did not increase risk for later alcohol abuse or dependence.
Behavioral disinhibition increases risk for alcohol abuse and dependence in early adulthood only for individuals who experience poor family management during adolescence. Interventions seeking to reduce environmental risks by strengthening consistent positive family management practices may prevent later alcohol abuse and dependence among individuals at risk due to behavioral disinhibition.
Drug and alcohol dependence 03/2010; 110(1-2):62-9. DOI:10.1016/j.drugalcdep.2010.02.005 · 3.42 Impact Factor
"Altered brain GABA A receptor function may account for some of the neuropsychiatric problems associated with PWS as there is increasing evidence that GABA neuronal dysfunction is implicated in various psychiatric disorders including psychosis (Guidotti et al., 2000; van Kammen et al., 1998), mood disorders (Sanacora et al., 1999), anxiety disorders (Goddard et al., 2001), and autism (Blatt et al., 2001; Dhossche et al., 2002). Genetic studies also suggest that polymorphisms of a GABA A receptor subunit gene (GABRB3) or a gene near this locus increases susceptibility to catatonia (Stöber et al., 2000, 2002), bipolar disorder (Papadimitriou et al., 1998; Otani et al., 2005), and autism (Nurmi et al., 2003; Shao et al., 2003). GABRB3 has been associated with a subtype of autism with high levels of repetitive behaviors and stereotyped patterns (insistence on sameness ) (Shao et al., 2003) and with a subtype of autism with savant skills, a characteristic often associated with the development of special skills (O'Conner and Hermelin, 1991). "
[Show abstract][Hide abstract] ABSTRACT: The interest in neurosis sparked by psychoanalytical ideas and the segregation of the "feeble-minded" into special institutions may be the potent factors in the decline of catatonia. Likewise, the impact of Kanner's delineation of autism, and research into the stereotypies of mental retardation has tended to mute the earlier enthusiasm concerning the interrelationship between the functional psychoses and mental retardation. In fact, the clinical and research "hole" resembles a form of diagnostic sterilization reminiscent of the operative practices of the eugenics period. Reviewing the whole process in the light of critical science and historical understanding in services shows up areas of underdevelopment in services, research, and clinical acumen. Yet the potential for genuinely new discoveries is there provided we understand what really has gone before.T. Turner, M.D. (1989). Historically, autism, childhood schizophrenia, mental retardation, and other early-onset developmental disorders were thought to be connected (Earl, 1934; Turner, 1989). In 1943, Kanner isolated autism from other childhood disorders. This may have caused premature closure of the search for commonalities between autism, psychosis, mental retardation, and other early-onset neurodevelopmental disorders. However, research advances in these disorders offer an opportunity for re-evaluation. New findings reveal phenomenological, biochemical, and genetic areas of overlap. GABA dysfunction may provide a common risk factor in autism, Prader-Willi syndrome, and catatonia (Dhossche, 2004). In this chapter, evidence that GABA abnormalities are present in autism, Prader-Willi syndrome, and catatonia is reviewed. Implications for future research are described.
International Review of Neurobiology 02/2005; 71:189-216. DOI:10.1016/S0074-7742(05)71009-6 · 1.92 Impact Factor
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