Massive Withdrawal Symptoms and Affective Vulnerability Are Associated with Variants of the CHRNA4 Gene in a Subgroup of Smokers

Peer reviewe

Altered Organization of GABAA Receptor mRNA Expression in the Depressed Suicide Brain

Inter-relationships ordinarily exist between mRNA expression of GABAA subunits in the frontopolar cortex (FPC) of individuals that had died suddenly from causes other than suicide. However, these correlations were largely absent in persons that had died by suicide. In the present investigation, these findings were extended by examining GABAA receptor expression patterns (of controls and depressed individuals that died by suicide) in the orbital frontal cortex (OFC), hippocampus, amygdala. locus coeruleus (LC) and paraventricular nucleus (PVN), all of which have been implicated in either depression, anxiety or stress responsivity. Using QPCR analysis, we found that in controls the inter-relations between GABAA subunits varied across brain regions, being high in the hippocampus and amygdala, intermediate in the LC, and low in the OFC and PVN. The GABAA subunit inter-relations were markedly different in persons that died by suicide, being reduced in hippocampus and amygdala, stable in the LC, but more coordinated in the OFC and to some extent in the PVN. It seems that altered brain region-specific inhibitory signaling, stemming from altered GABAA subunit coordination, are associated with depression/suicide. Although, it is unknown whether GABAA subunit re-organization was specifically tied to depression, suicide, or the accompanying distress, these data show that the coordinated expression of this transcriptome does vary depending on brain region and is plastic

Molecular pathway reconstruction and analysis of disturbed gene expression in depressed individuals who died by suicide

Molecular mechanisms behind the etiology and pathophysiology of major depressive disorder and suicide remain largely unknown. Recent molecular studies of expression of serotonin, GABA and CRH receptors in various brain regions have demonstrated that molecular factors may contribute to the development of depressive disorder and suicide behaviour. Here, we used microarray analysis to examine the expression of genes in brain tissue (frontopolar cortex) of individuals who had been diagnosed with major depressive disorder and died by suicide, and those who had died suddenly without a history of depression. We analyzed the list of differentially expressed genes using pathway analysis, which is an assumption-free approach to analyze microarray data. Our analysis revealed that the differentially expressed genes formed functional networks that were implicated in cell to cell signaling related to synapse maturation, neuronal growth and neuronal complexity. We further validated these data by randomly choosing (100 times) similarly sized gene lists and subjecting these lists to the same analyses. Random gene lists did not provide highly connected gene networks like those generated by the differentially expressed list derived from our samples. We also found through correlational analysis that the gene expression of control participants was more highly coordinated than in the MDD/suicide group. These data suggest that among depressed individuals who died by suicide, wide ranging perturbations of gene expression exist that are critical for normal synaptic connectively, morphology and cell to cell communication

Maternal bonding styles in smokers and non-smokers: a comparative study

BACKGROUND: Parental bonding has been implicated in smoking behavior, and the quality of maternal bonding (MB) has been associated with poor mental health and substance use. However, little is known about the association of MB and the smoking of the offspring. METHODS: In our study, 129 smokers and 610 non-smoker medical students completed the parental bonding instrument, which measures MB along two dimensions: care and overprotection. Four categories can be created by high and low scores on care and overprotection: optimal parenting (OP; high care/low overprotection); affectionless control (ALC; low care/high overprotection); affectionate constraint (AC; high care/high overprotection), and neglectful parenting (NP; low care/low overprotection). Nicotine dependence was assessed by the Fagerstrom Nicotine Dependence Test, exhaled CO level, and daily cigarette consumption (CPD). RESULTS: Higher CPD was significantly associated with lower overprotection (p = 0.016) and higher care (p = 0.023) scores. The odds for being a smoker were significantly higher in the neglectful maternal bonding style compared to the other rearing styles (p = 0.022). Besides, smokers showed significantly higher care and lower overprotection scores with the Mann-Whitney U-test than non-smokers, although these associations did not remain significant in multiple regression models. CONCLUSION: Our results indicate that focusing on early life relationship between patient and mother can be important in psychotherapeutic interventions for smoking. Registration trials retrospectively registered

Serotonin receptor subtype and p11 mRNA expression in stress-relevant brain regions of suicide and control subjects

Objective: Studies comparing people suffering from depression who commited suicide with control subjects have yielded inconsistent results regarding serotonin (5-HT) involvement in pathology, possibly owing to procedural factors. Our objective was to investigate which 5-HT receptor subtypes might be associated with depression and suicide, whether receptor differences vary across brain regions and whether they are moderated by sex. Methods: We assessed messenger ribonucleic acid (mRNA) expression of several 5-HT receptor subtypes and that of p11, a protein involved in the functional expression of 5-HT 1B, in several stress-relevant brain regions. Tissue was obtained soon after death, and RNA integrity and pH was confirmed to be appropriate. Brain tissue from suicide subjects suffering from depression and from control subjects who had died from other causes (10 men and 10 women in each condition) was obtained within 6.5 hours postmortem. Quantitative polymerase chain reaction analyses determined mRNA expression of 5-HT receptor subtypes and p11 within the frontopolar cortex, orbitofrontal cortex, hippocampus, amygdala and paraventricular nucleus. The 5-HT transporter (5-HTT) was also assessed in the raphe nucleus. Results: Differences of 5-HT1A, 5-HT1B and p11 mRNA expression between people who committed suicide and control subjects were relatively widespread, whereas 5-HT2A and 5-HT2C variations were restricted to the frontopolar cortex and amygdala. Within the dorsal raphe nucleus, neither 5-HT1A nor 5-HTT mRNA expression differed between those who committed suicide and control subjects. Conclusion: Several 5-HT receptor subtypes are associated with depression and suicide, but these receptor differences vary across brain regions and are moderated by sex

Association analysis of 5-HTTLPR variants, 5-HT2A receptor gene 102T/C polymorphism and migraine

It is well known that migraine has a strong genetic component, although the type and number of genes involved is not yet clear. There is evidence to suggest that serotonin-related genes participate in the pathogenesis of migraine. Previous studies have shown that gender differences influence the serotonergic neurotransmission and, in addition, the migraine prevalence is higher in females than males. Therefore, we investigated the functional polymorphism in the upstream regulatory region of the serotonin transporter gene (5-HTTLPR) and the 102T/C polymorphism of the 5-HT2A receptor gene in the Hungarian female population. These genes were analysed in 126 migraine sufferers (with or without aura)and 101 unrelated healthy controls using case control design. A borderline association (chi2 = 3.84, df = 1, p = 0.049; OR = 1.45, 95% CI = 1.00-2.12) between 5-HTTLPR short (S) allele and migraine was found. No significant difference between migraine sufferers and controls was observed for the 102T/C polymorphism of 5-HT2A receptor gene. Furthermore, there was no significant interaction between5-HTTLPR and 102T/C polymorphisms in our study population. In conclusion, our results support that the genetic susceptibility of migraine may be associated with a locus at or near the 5-HT transporter gene

Two-step cluster analysis of three phenotypic variables resulted in three significantly different clusters.

<p>Mean scores are represented as percentages of possible maximum points for each measurements. MNWS, Minnesota Nicotine Withdrawal Scale; ZSDS, Zung Self-Rating Depression Scale.</p

MNWS and ZSDS scores and CO levels of the three phenotypic clusters (C1, C2, C3) identified by two-step cluster analysis.

<p>MNWS, Minnesota Nicotine Withdrawal Scale; ZSDS, Zung Self-Rating Depression Scale; SD, standard deviation.</p

Haplotype association tests on C3 phenotypic cluster in GLM and HapScore tests.

<p>Allelic components of the presented haplotypes are rs3787138, rs1044396 and rs3787140 SNPs, respectively. ^a<i>p_model = 0.018</i>; GLM, general linear model.</p