| 51. |
- Lindfors, Charlotte, et al.
(författare)
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Hypothalamic mitochondrial dysfunction associated with anorexia in the anx/anx mouse
- 2011
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 108:44, s. 18108-18113
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Tidskriftsartikel (refereegranskat)abstract
- The anorectic anx/anx mouse exhibits disturbed feeding behavior and aberrances, including neurodegeneration, in peptidergic neurons in the appetite regulating hypothalamic arcuate nucleus. Poor feeding in infants, as well as neurodegeneration, are common phenotypes in human disorders caused by dysfunction of the mitochondrial oxidative phosphorylation system (OXPHOS). We therefore hypothesized that the anorexia and degenerative phenotypes in the anx/anx mouse could be related to defects in the OXPHOS. In this study, we found reduced efficiency of hypothalamic OXPHOS complex I assembly and activity in the anx/anx mouse. We also recorded signs of increased oxidative stress in anx/anx hypothalamus, possibly as an effect of the decreased hypothalamic levels of fully assembled complex I, that were demonstrated by native Western blots. Furthermore, the Ndufaf1 gene, encoding a complex I assembly factor, was genetically mapped to the anx interval and found to be down-regulated in anx/anx mice. These results suggest that the anorexia and hypothalamic neurodegeneration of the anx/anx mouse are associated with dysfunction of mitochondrial complex I.
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| 52. |
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| 53. |
- Linner, Love, et al.
(författare)
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Reboxetine modulates the firing pattern of dopamine cells in the ventral tegmental area and selectively increases dopamine availability in the prefrontal cortex
- 2001
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Ingår i: Journal of Pharmacology and Experimental Therapeutics. - 0022-3565 .- 1521-0103. ; 297:2, s. 540-546
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Tidskriftsartikel (refereegranskat)abstract
- Central dopaminergic neurons have been suggested to be involved in the pathophysiology of several psychiatric disorders, including depression, and appear to be modulated by noradrenergic activity both at the nerve terminal level and at the somatodendritic level. In recent years reboxetine, a selective noradrenaline reuptake inhibitor that differs from tricyclic anti-depressants by its low affinity for muscarinic, cholinergic and α1-adrenergic receptors, has been introduced clinically. In the present study the effect of reboxetine on the function of the mesolimbocortical dopamine system was investigated by means of single cell recording and microdialysis in rats following administration of reboxetine in doses that appear to yield clinically relevant plasma concentrations. Reboxetine (0.625-20 mg/kg intravenously) induced an increase in burst firing, but not in average firing frequency of dopamine (DA) cells in the ventral tegmental area (VTA). Moreover, reboxetine (0.15-13.5 mg/kg intraperitoneally) caused a significantly enhanced DA output in the medial prefrontal cortex, whereas no effect was observed in the nucleus accumbens. Local administration of reboxetine (333 μM, 60 min), by means of reversed microdialysis into these brain regions, caused a significant increase in DA output in both brain regions. However, local administration of reboxetine into the VTA (333 μM, 60 min) did not affect DA availability in these terminal areas. Our results imply that clinical treatment with reboxetine may result in facilitation of both prefrontal DA output and the excitability of VTA DA neurons, effects that may contribute to its antidepressant action, especially on drive and motivation.
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| 54. |
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| 55. |
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| 56. |
- Lonsdorf, Tina B, et al.
(författare)
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The COMTval158met polymorphism is associated with symptom relief during exposure-based cognitive-behavioral treatment in panic disorder
- 2010
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Ingår i: BMC Psychiatry. - : BioMed Central. - 1471-244X. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- Background: Cognitive behavioral therapy (CBT) represents a learning process leading to symptom relief and resulting in long-term changes in behavior. CBT for panic disorder is based on exposure and exposure-based processes can be studied in the laboratory as extinction of experimentally acquired fear responses. We have recently demonstrated that the ability to extinguish learned fear responses is associated with a functional genetic polymorphism (COMTval158met) in the COMT gene and this study was aimed at transferring the experimental results on the COMTval158met polymorphism on extinction into a clinical setting. Methods: We tested a possible effect of the COMTval158met polymorphism on the efficacy of CBT, in particular exposure-based treatment modules, in a sample of 69 panic disorder patients. Results: We present evidence that panic patients with the COMTval158met met/met genotype may profit less from (exposure-based) CBT treatment methods as compared to patients carrying at least one val-allele. No association was found with the 5-HTTLPR/rs25531 genotypes which is presented as additional material. Conclusions: We were thus able to transfer findings on the effect of the COMTval158met polymorphism from an experimental extinction study obtained using healthy subjects to a clinical setting. Furthermore patients carrying a COMT val-allele tend to report more anxiety and more depression symptoms as compared to those with the met/met genotype. Limitations of the study as well as possible clinical implications are discussed.
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| 57. |
- Lonsdorf, Tina B, et al.
(författare)
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The symptomatic profile of panic disorder is shaped by the 5-HTTLPR polymorphism
- 2009
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Ingår i: Progress in Neuro-psychopharmacology and Biological Psychiatry. - : Elsevier BV. - 0278-5846 .- 1878-4216. ; 33:8, s. 1479-1483
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Forskningsöversikt (refereegranskat)abstract
- The short allele of a functional polymorphism (5-HTTLPR) in the serotonin transporter (5-HTT) promoter is associated with reduced serotonin transporter expression, lower in vivo 5-HTT binding, higher neuroticism and amygdala reactivity as well as facilitated fear conditioning and is a candidate variant for panic disorder. However, case-control studies have consistently failed to show an association between 5-HTTLPR and panic disorder. As psychiatric disorders are broadly defined phenotypes merging different symptoms to syndromes, they may not be very well suited for genetic association studies. An alternative approach is to measure symptoms along continuous symptom dimensions which may more appropriately reflect their biological underpinnings and may reveal subpopulations within clinical diagnostic groups. We recorded the symptomatic profile in 73 in panic disorder patients using observer-rated instruments (Panic Disorder Severity Scale, PDSS; Montgomery-Asberg Depression Rating Scale, MADRS) and hypothesized more severe symptoms in patients carrying the 5-HTTLPR s-allele. We observed a strong association between bi- and triallelic 5-HTTLPR polymorphisms and the symptomatic profile. Carriers of the 5-HTTLPR s-allele suffered from most severe panic and depressive symptoms. Our data highlight the importance of defining appropriate phenotypes for psychiatric genetic studies and demonstrate that the 5-HTTLPR genotype may be related to the symptomatic profiles rather than to the vulnerability to develop panic disorder.
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| 58. |
- Louca Jounger, Sofia, et al.
(författare)
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Polymorphisms in the HTR2A and HTR3A Genes Contribute to Pain in TMD Myalgia
- 2021
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Ingår i: Frontiers in Oral Health. - : Frontiers Media S.A.. - 2673-4842. ; 2
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Tidskriftsartikel (refereegranskat)abstract
- Background: The aim of this study was to investigate if single nucleotide polymorphisms (SNPs) related to monoaminergic neurotransmission, in particular the serotonergic pathway, contribute to pain perception in patients with temporomandibular disorder (TMD) myalgia and if there is a correlation to jaw function as well as psychosocial factors such as stress, anxiety and depression.Materials and Methods: One hundred and seventeen individuals with TMD myalgia were included. A venous blood or saliva sample was taken for genetic analyses and genotyped regarding HTR2A (rs9316233) HTR3A (rs1062613), HTR3B (rs1176744), SERT (5-HTTLPR) and COMT (rs4680). A clinical examination according to Diagnostic Criteria for TMD (DC/TMD) was performed and axis II data (psychosocial factors) were compared between participants with different genotypes for each gene using Kruskall–Wallis test. The characteristic pain intensity (CPI) was tested for correlations to scores for the Perceived Stress Scale, Generalized Anxiety Disorder, and Patient Health Questionnaires using Spearman's rank correlation test with Bonferroni correction for multiple testing. To further explore data factor analysis was performed to identify latent factors associated to the outcome variables.Results: Participants carrying at least one copy of the rare allele of the HTR2A (rs9316233) and HTR3A (rs1062613) had higher CPI compared with the participants with the homozygous common genotype (P = 0.042 and P = 0.024, respectively). Correlation analyses showed several significant positive correlations between CPI on one hand, and self-reported psychosocial distress and jaw function on the other hand for several genotypes that mostly were weak to moderate. The factor analysis identified two latent variables. One was positively correlated to the HTR3B gene, jaw function and self-reported parafunctions, and the other was positively correlated to psychological distress and negatively correlated to SERT.Conclusion: Taken together, the polymorphism rs1062613 in the HTR3A gene contributes to pain intensity in TMD myalgia. This together with positive interactions between pain variables and psychological factors in genotypes strengthens that pain and psychological distress are related. Further research is needed to explore this as well as the influence of gene-to-gene interactions on pain and psychological distress.
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| 59. |
- Mendlewicz, Julien, et al.
(författare)
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Expanded RED products and loci containing CAG/CTG repeats on chromosome 17 (ERDA1) and chromosome 18 (CTG18.1) in trans-generational pairs with bipolar affective disorder
- 2004
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Ingår i: American Journal of Medical Genetics. - Hoboken : John Wiley & Sons. - 0148-7299 .- 1096-8628. ; 128B:1, s. 71-75
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Tidskriftsartikel (refereegranskat)abstract
- The purpose of the present study was to further test if expanded CAG repeats detected by the repeat expansion detection (RED) method in bipolar affective disorder (BPAD) are correlated with ERDA1 (17q21.3) and/or CTG18.1 (18q21.1) loci expansions, and changes of phenotype severity in successive generations (anticipation). The sample was designed to analyze ERDA1 and CTG18.1 expansions in trans-generational pairs of affected individuals (parent-offspring pairs: G1 and G2). Clinical and genetic information was available on 95 two-generations pairs. We found in our sample no one patient.
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| 60. |
- Montagnese, Sara, et al.
(författare)
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A pilot study of golexanolone, a new GABA-A receptor-modulating steroid antagonist, in patients with covert hepatic encephalopathy
- 2021
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Ingår i: Journal of Hepatology. - : Elsevier. - 0168-8278 .- 1600-0641. ; 75:1, s. 98-107
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Tidskriftsartikel (refereegranskat)abstract
- Background & Aims: Golexanolone is a novel small molecule GABA-A receptor-modulating steroid antagonist under development for the treatment of cognitive and vigilance disorders caused by allosteric over-activation of GABA-A receptors by neurosteroids. It restored spatial learning and motor coordination in animal models of hepatic encephalopathy (HE) and mitigated the effects of intravenous allopregnanolone in healthy adults in a dose-dependent fashion. Herein, we report data on the safety, pharmacokinetics (PK) and efficacy of golexanolone in adult patients with cirrhosis.Methods: Following single/multiple ascending dose studies, adults with Child-Pugh A/B cirrhosis and abnormal continuous reaction time (CRT) on screening were randomized to 3 weeks’ dosing with golexanolone (10, 40 or 80 mg BID) or placebo. CRT, psychometric hepatic encephalopathy score (PHES), animal naming test (ANT), Epworth sleepiness scale (ESS) and electroencephalogram (mean dominant frequency [MDF]; delta+theta/alpha+beta ratio [DT/AB]) were obtained at baseline, 10, and 21 days.Results: Golexanolone exhibited satisfactory safety and PK. Baseline characteristics were similar between the 12 and 33 patients randomized to placebo or golexanolone, respectively. By prespecified analyses, golexanolone was associated with directionally favourable changes vs. placebo in ESS (p = 0.047), MDF (p = 0.142) and DT/AB (p = 0.021). All patients also showed directionally favourable changes in CRT, PHES and ANT, but with no statistical difference between golexanolone and placebo. Post hoc analyses taking into account the variability and improvement in CRT, PHES and ANT observed between screening and baseline suggested an efficacy signal by cognitive measures as well.Conclusion: Golexanolone was well tolerated and associated with improvement in cognitive performance. These results implicate GABA-A receptor-modulating neurosteroids in the pathogenesis of HE and support the therapeutic potential of golexanolone.Lay summary: Many patients with cirrhosis experience subtle but disabling cognitive problems, including sleepiness and poor attention span, that impair their ability to be gainfully employed or carry out activities of daily living. This pilot study tested the hypothesis that these problems with cognition, for which there is no approved treatment, might be improved by an experimental drug, golexanolone, designed to normalize the function of receptors which inhibit brain function. The results of this study suggest that golexanolone is well tolerated and may improve cognition, as reflected by measures of sleepiness, attention span and brain wave activity, paving the way for future larger studies of this promising experimental drug.Clinical trial registration number: EudraCT 2016-003651-30.
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