-
Association between a genetic variant in the serotonin transporter gene (SLC6A4) and suicidal behavior in patients with schizophrenia
Background:
The serotonin (5-hydroxytryptamin; 5-HT) system has a central role in the circuitry of cognition and emotions. Multiple lines of evidence suggest that genetic variation in the serotonin transporter gene (SLC6A4; 5-HTT) is associated with schizophrenia and suicidal behavior. In this study, we wanted to elucidate whether SLC6A4 variations is involved in attempted suicide among patients with schizophrenia in a Scandinavian case-control sample.
Methods:
Patients diagnosed with schizophrenia from three Scandinavian samples were assessed for presence or absence of suicide attempts, based on record reviews and interview data. Seven SLC6A4 single nucleotide polymorphisms (SNPs) were genotyped in 837 schizophrenia patients and 1,473 control individuals. Association analyses and statistical evaluations were performed with the program UNPHASED (version 3.0.9).
Results:
We observed an allele association between the SNP rs16965628, located in intron one of SLC6A4, and attempted suicide (adjusted P-value = 0.04), among patients with schizophrenia. No association was found to a diagnosis of schizophrenia, when patients were compared to healthy control individuals.
Conclusion:
The gene SLC6A4 appears to be involved in suicidal ideation among patients with schizophrenia. Independent replication is needed before more firm conclusions can be drawn.
-
Variation in regulator of G-Protein signaling 17 Gene (RGS17) is associated with multiple substance dependence diagnoses
Background:
RGS17 and RGS20 encode two members of the regulator of G-protein signaling RGS-Rz subfamily. Variation in these genes may alter their transcription and thereby influence the function of G protein-coupled receptors, including opioid receptors, and modify risk for substance dependence.
Methods:
The association of 13 RGS17 and eight RGS20 tag single nucleotide polymorphisms (SNPs) was examined with four substance [dependence diagnoses (alcohol (AD), cocaine (CD), opioid (OD) or marijuana (MjD)) in 1,905 African Americans (AAs: 1,562 cases and 343 controls) and 1,332 European Americans (EAs: 981 cases and 351 controls). Analyses were performed using both chi2 tests and logistic regression analyses that covaried sex, age, and ancestry proportion. Correlation of genotypes and mRNA expression levels was assessed by linear regression analyses.
Results:
Seven RGS17 SNPs showed a significant association with at least one of the four dependence traits after a permutation-based correction for multiple testing (0.003<=Pempirical<=0.037). The G allele of SNP rs596359, in the RGS17 promoter region, was associated with AD, CD, OD, or MjD in both populations (0.005<=Pempirical<=0.019). This allele was also associated with significantly lower mRNA expression levels of RGS17 in YRI subjects (P=0.002) and non-significantly lower mRNA expression levels of RGS17in CEU subjects (P=0.185). No RGS20 SNPs were associated with any of the four dependence traits in either population.
Conclusions:
This study demonstrated that variation in RGS17 was associated with risk for substance dependence diagnoses in both AA and EA populations.
-
Possible effect of norepinephrine transporter polymorphisms on methylphenidate-induced changes in neuropsychological function in attention-deficit hyperactivity disorder
Background:
Dysregulation of noradrenergic system may play important roles in pathophysiology of attention-deficit/hyperactivity disorder (ADHD). We examined the relationship between polymorphisms in the norepinephrine transporter SLC6A2 genes and attentional performance before and after medication in children with ADHD.
Methods:
Fifty-three medication-naive children with ADHD were genotyped and evaluated using the continuous performance test (CPT). After 8-weeks of methylphenidate treatment, these children were evaluated by CPT again. We compared the baseline CPT measures and the post-treatment changes in the CPT measures based on the G1287A and the A-3081T polymorphisms of SLC6A2.
Results:
There was no significant difference in the baseline CPT measures associated with the G1287A or A-3081T polymorphisms. After medication, however, ADHD subjects with the G/G genotype at the G1287A polymorphism showed a greater decrease in the mean omission error scores (p= 0.005) than subjects with the G/A or A/A genotypes, and subjects with the T allele at the A-3081T polymorphism (T/T or A/T) showed a greater decrease in the mean commission error scores (p= 0.004) than those with the A/A genotypes
Conclusions:
Our results provide evidence for the possible role of the G1287A and A-3081T genotypes of SLC6A2 in methylphenidate-induced improvement in attentional performance and support the noradrenergic hypothesis for the pathophysiology of ADHD.
-
Brain antioxidant markers, cognitive performance and acetylcholinesterase activity of rat: Efficiency of Sonchus asper
Background:
Sonchus asper (SA) is traditionally used as a folk medicine to treat mental disorders in Pakistan. The aim of this study was to investigate the effect of polyphenolic rich methanolic fraction of SA on cognitive performance, brain antioxidant activities and acetylcholinesterase activity in male rats.
Methods:
30 male Sprague-Dawley rats were equally divided into three groups in this study. Animals of group I (control) received saline (vehicle), group II received SA (50 mg/kg) body weight (b.w.), and group III treated with SA (100 mg/kg b.w.,) orally in dimethyl sulphoxide (DMSO) for 7 days. The effect of SA was checked on rat cognitive performance, brain antioxidatant and acetylcholinesterase activities. Evaluation of learning and memory was assessed by a step-through a passive avoidance test on day 6 after two habituation trials and an initial acquisition trial on day 5. Antioxidant potential was determined by measuring activities of superoxide dismutase (SOD), catalase (CAT), contents of thiobarbituric acid reactive substances (TBARS) and reduced glutathione (GSH) in whole-brain homogenates. Acetylcholinesterase (AChE) activity was determined by the colorimetric method.
Results:
Results showed that 100 mg/kg b.w., SA treated rats exhibited a significant improvement in learning and memory (step-through latency time). SA administration reduced lipid peroxidation products and elevated glutathione levels in the SA100-treated group. Furthermore, salt and detergent soluble AChE activity was significantly decreased in both SA-treated groups. Short-term orally supplementation of SA showed significant cognitive enhancement as well as elevated brain antioxidant enzymes and inhibited AChE activity.
Conclusion:
These findings stress the critical impact of Sonchus asper bioactive components on brain function.KeywordsSonchus asper, Cognitive performance, Acetylcholinesterase activity, Antioxidant enzymes
-
The gamma-aminobutyric acid type B (GABAB) receptor agonist baclofen inhibits morphine sensitization by decreasing the dopamine level in rat nucleus accumbens
Background:
Repeated morphine exposure can induce behavioral sensitization. There are evidences haveshown that central gamma-aminobutyric acid (GABA) system is involved in morphinedependence. However, the effect of a GABAB receptor agonist baclofen on morphineinducedbehavioral sensitization in rats is unclear.
Methods:
We used morphine-induced behavioral sensitization model in rat to investigate the effects ofbaclofen on behavioral sensitization. Moreover, dopamine release in the shell of the nucleusaccumbens was evaluated using microdialysis assay in vivo.
Results:
The present study demonstrated that morphine challenge (3 mg/kg, s.c.) obviously enhancedthe locomotor activity following 4-day consecutive morphine administration and 3-daywithdrawal period, which indicated the expression of morphine sensitization. In addition,chronic treatment with baclofen (2.5, 5 mg/kg) significantly inhibited the development ofmorphine sensitization. It was also found that morphine challenge 3 days after repeatedmorphine administration produced a significant increase of extracellular dopamine release innucleus accumbens. Furthermore, chronic treatment with baclofen decreased the dopaminerelease induced by morphine challenge.
Conclusions:
Our results indicated that gamma-aminobutyric acid system plays an important role in themorphine sensitization in rat and suggested that behavioral sensitization is a promising modelto study the mechanism underlying drug abuse.
-
DRD2 and PPP1R1B (DARPP-32) polymorphisms independently confer increased risk for autism spectrum disorders and additively predict affected status in male-only affected sib-pair families
Background:
The neurotransmitter dopamine (DA) modulates executive functions, learning, and emotional processing, all of which are impaired in individuals with autism spectrum disorders (ASDs). Our previous findings suggest a role for dopamine-related genes in families with only affected males.
Methods:
We examined two additional genes which affect DA function, the DRD2 and PPP1R1B (DARPP-32) genes, in a cohort of 112 male-only affected sib-pair families. Selected polymorphisms spanning these genes were genotyped and both family-based and population-based tests were carried out for association analysis. General discriminant analysis was used to examine the gene-gene interactions in predicting autism susceptibility.
Results:
There was a significantly increased frequency of the DRD2 rs1800498TT genotype (P = 0.007) in affected males compared to the comparison group, apparently due to over-transmission of the T allele (P = 0.0003). The frequency of the PPP1R1B rs1495099CC genotype in affected males was also higher than that in the comparison group (P = 0.002) due to preferential transmission of the C allele from parents to affected children(P = 0.0009). Alleles rs1800498T and rs1495099C were associated with more severe problems in social interaction (P = 0.0002 and P = 0.0016, respectively) and communication (P = 0.0004 and P = 0.0046), and increased stereotypic behaviours (P = 0.0021 and P = 0.00072). General discriminant analysis found that the DRD2 and PPP1R1B genes additively predicted ASDs (P = 0.00011; Canonical R = 0.26) and explain ~7% of the variance in our families. All findings remained significant following corrections for multiple testing.
Conclusion:
Our findings support a role for the DRD2 and PPP1R1B genes in conferring risk for autism in families with only affected males and show an additive effect of these genes towards prediction of affected status in our families.
-
Interaction between Serotonin Transporter and Serotonin Receptor 1 B genes polymorphisms may be associated with antisocial alcoholism
Background:
Several studies have hypothesized that genes regulating the components of the serotonin system, including serotonin transporter (5-HTTLPR) and serotonin 1 B receptor (5-HT1B), may be associated with alcoholism, but their results are contradictory because of alcoholism's heterogeneity. Therefore, we examined whether the 5-HTTLPR gene and 5-HT1B gene G861C polymorphism are susceptibility factors for a specific subtype of alcoholism, antisocial alcoholism in Han Chinese in Taiwan.
Methods:
We recruited 273 Han Chinese male inmates with antisocial personality disorder (ASPD) [antisocial alcoholism (AS-ALC) group (n = 120) and antisocial non-alcoholism (AS-N-ALC) group (n = 153)] and 191 healthy male controls from the community. Genotyping was done using PCR-RFLP.
Results:
There were no significant differences in the genotypic frequency of the 5-HT1B G861C polymorphism between the 3 groups. Although AS-ALC group members more frequently carried the 5-HTTLPR S/S, S/LG, and LG/LG genotypes than controls, the difference became non-significant after controlling for the covarying effects of age. However, the 5-HTTLPR S/S, S/LG, and LG/LG genotypes may have interacted with the 5-HT1B G861C C/C polymorphism and increased the risk of becoming antisocial alcoholism.
Conclusion:
Our study suggests that neither the 5-HTTLPR gene nor the 5-HT1B G861C polymorphism alone is a risk factor for antisocial alcoholism in Taiwan's Han Chinese population, but that the interaction between both genes may increase susceptibility to antisocial alcoholism.
-
Associations between a neurophysiological marker of central cholinergic activity and cognitive functions in young and older adults
Background:
The deterioration of the central cholinergic system in aging is hypothesized to underlie declines in several cognitive domains, including memory and executive functions. However, there is surprisingly little direct evidence regarding acetylcholine's specific role(s) in normal human cognitive aging.
Methods:
We used short-latency afferent inhibition (SAI) with transcranial magnetic stimulation (TMS) as a putative marker of cholinergic activity in vivo in young (n = 24) and older adults (n = 31).
Results:
We found a significant age difference in SAI, concordant with other evidence of cholinergic decline in normal aging. We also found clear age differences on several of the memory and one of the executive function measures. Individual differences in SAI levels predicted memory but not executive functions.
Conclusion:
Individual differences in SAI levels were better predictors of memory than executive functions. We discuss cases in which the relations between SAI and cognition might be even stronger, and refer to other age-related biological changes that may interact with cholinergic activity in cognitive aging.
-
Children with Usher syndrome: mental and behavioral disorders
Background:
Mental and behavioral disorders among adults with Usher syndrome have been discussed and reported in some case studies but no research has been reported on children with Usher syndrome.
Methods:
This article investigates the prevalence and characteristics of mental and behavioral disorders among 26 children, 3-17 years of age, with Usher syndrome.
Results:
Six of the 26 children were diagnosed with a mental or behavioral disorder (1 with schizophrenia and mild mental retardation, 1 with atypical autism and severe mental retardation, 1 with atypical autism and mild mental retardation, 1 with mild mental retardation, and 2 with conduct disorder). Another 3 children had had a mental or behavioral disorder previously in their childhood.
Conclusion:
Even though vision impairment first manifests in late childhood, some children with Usher syndrome seem to develop mental and behavioral disorders during childhood. The aetiology and treatment of mental and behavioral disorders among children with Usher syndrome are discussed. Children with Usher syndrome and their parents may need clinical support during early childhood to prevent development of mental and behavioral disorders.
-
A dual task priming investigation of right hemisphere inhibition for people with left hemisphere lesions
Background:
During normal semantic processing, the left hemisphere (LH) is suggested to restrict right hemisphere (RH) performance via interhemispheric suppression. However, a lesion in the LH or the use of concurrent tasks to overload the LH's attentional resource balance has been reported to result in RH disinhibition with subsequent improvements in RH performance. The current study examines variations in RH semantic processing in the context of unilateral LH lesions and the manipulation of the interhemispheric processing resource balance, in order to explore the relevance of RH disinhibition to hemispheric contributions to semantic processing following a unilateral LH lesion.
Methods:
RH disinhibition was examined for nine participants with a single LH lesion and 13 matched controls using the dual task paradigm. Hemispheric performance on a divided visual field lexical decision semantic priming task was compared over three verbal memory load conditions, of zero-, two- and six-words. Related stimuli consisted of categorically related, associatively related, and categorically and associatively related prime-target pairs. Response time and accuracy data were recorded and analyzed using linear mixed model analysis, and planned contrasts were performed to compare priming effects in both visual fields, for each of the memory load conditions.
Results:
Control participants exhibited significant bilateral visual field priming for all related conditions (p < .05), and a LH advantage over all three memory load conditions. Participants with LH lesions exhibited an improvement in RH priming performance as memory load increased, with priming for the categorically related condition occurring only in the 2- and 6-word memory conditions. RH disinhibition was also reflected for the LH damage (LHD) group by the removal of the LH performance advantage following the introduction of the memory load conditions.
Conclusions:
The results from the control group are consistent with suggestions of an age related hemispheric asymmetry reduction and indicate that in healthy aging compensatory bilateral activation may reduce the impact of inhibition. In comparison, the results for the LHD group indicate that following a LH lesion RH semantic processing can be manipulated and enhanced by the introduction of a verbal memory task designed to engage LH resources and allow disinhibition of RH processing.
|
