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P.1.b.001 Association of NOS1 and NOS3 variants with the serotonergic marker loudness dependence of auditory evoked potentials
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P.1.b Basic neuroscience – Neuroanatomy and neurophysiology
allele and compared with the higher expressing LA allele. The distribution of allelic and genotype frequencies were in accordance with the Hardy-Weinberg equilibrium. We revealed no significant differences in allele and genotype distribution between suicide and control groups. In women there was a tendency of a lower frequency of the LS carriers in suicide group compared to that in control group (chi2 = 3.5; p = 0.06; OR = 0.62, 95% CI 0.38−1.02). Our findings indicate a possible contribution of the 5-HTT gene to susceptibility for suicidal behaviour in females only. References [1] Wendland JR, Martin BJ, Kruse et al, 2006, Simultaneous genotyping of four loci of human SLC6A4, with a reappraisal of 5-HTTLPR and rs25531. Molecular Psychiatry 11, 224–226.
P.1.b Basic neuroscience – Neuroanatomy and neurophysiology P.1.b.001 Association of NOS1 and NOS3 variants with the serotonergic marker loudness dependence of auditory evoked potentials W. Kawohl1 ° , I. Giegling2 , P. Mavrogiorgou3 , O. Pogarell2 , C. Mulert2 , U. Hegerl4 , D. Rujescu2 , G. Juckel3 . 1 Psychiatric University Hospital, Research Group Clinical and Experimental Psychopathology, Z¨urich, Switzerland; 2 University of Munich, Department of Psychiatry, Munich, Germany; 3 Ruhr-University Bochum, Department of Psychiatry, Bochum, Germany; 4 University of Leipzig, Department of Psychiatry, Leipzig, Germany Nitric oxide (NO) is a gaseous molecule with neurotransmitter properties that is involved in numerous functions in the central nervous system (CNS), the vascular system and also in macrophages(Snyder and Ferris, 2000). NO dynamics are determined by nitric oxide synthase (NOS) activity. Haplotypes of NOS1 and NOS3 genes have been shown to be associated with different psychiatric disorders such as schizophrenia and bipolar disorder due to modulating brain functioning. Therefore, the detection of other characteristics of nitrinergic transmission is desirable. A manifold interaction between NO and serotonin has been reported by different animal studies: NO signaling modulates serotonin release, postsynaptic serotonin response, and the reuptake of serotonin (Bryan-Lluka et al., 2004). Therefore, a functional marker of the serotonergic transmission, the loudness dependence of auditory evoked potentials (LDAEP) (Juckel et al., 1997), could be a promising marker of nitrinergic transmission as well. The aim of our study was to clarify the relationship between nitrinergic transmission and the LDAEP. In order to clarify the relationship between nitrinergic transmission and the LDAEP 95 healthy subjects (41 males, 54 females) were included and received auditory stimulation during 32-channel electrophysiological recording and blood drawing for genotyping of SNPs and haplotypesof NOS1 and NOS3 genes. The following SNPs (NOS-I: rs2682826, rs1353939, rs693534, rs2293049; NOS-III: rs2070744, rs1799983, rs891512) were genotyped. Additionally, 31 SNPs in genes spanning all chromosomes were included as genomic controls. An exploratory haplotype analysis of all investigated NOS1 SNPs (rs2682826-rs1353939-rs693534) showed an association of the haplotype C-G-G with lower loudness dependence scores (haplotype frequency = 0.411, haplotype score = −2.006, p = 0.045,
simulated p = 0.044). The haplotype analysis of all investigated NOS3 SNPs (rs2070744-rs1799983-rs891512) showed an association of the haplotype T-T-G with lower loudness dependence scores (haplotype frequency = 0.109, haplotype score = −2.095, p = 0.036, simulated p = 0.034). SNPs of both genes were significantly associated with lower LDAEP scores, too. Interestingly, haplotypes and SNP analysis of both NOS1 and NOS3 genes are associated with lower LDAEP scores. Thus, LDAEP-changes may serve as an easily accessible marker of nitrinergic neurotransmission. Further research is needed to fully clarify the relationship between nitrinergic transmission, the LDAEP and complex disorders such as schizophrenia and affective disorders. The findings support the hypothesis that the NO-system has an influence on the LDAEP via serotonergic functioning. To our knowledge, this interaction has not been demonstrated with a biomarker in humans yet. Haplotypes- and SNP-analysis of both NOS1 and NOS3 genes are, according to our findings, associated with lower LDAEP scores. Lower loudness dependence has been shown to be an epiphenomenon of higher serotonergic activity. A subsequent change of the LDAEP is plausible and supported by our findings. rs2070744 lies in the promoter region of NOS3, rs1799983 is functional in exon 8 and to an amino-acid-exchange (Glu298Asp). The consequences of the different variants on the NOS-activity are unclear. In case of lower LDAEP, a lower NOfunctioning can be assumed, whereas the complex property of the serotonergic system and the not fully clarified interaction on the cellular level must be taken into account. References [1] Bryan-Lluka LJ, Papacostas MH, Paczlowski FA, Wanstall JC, 2004, Nitric oxide donors inhibit 5-hydroxytryptamine (5-HT) uptake by the human 5-HT transporter (SERT). Br J Pharmacol 143, 63−70. [2] Juckel G, Molnar M, Hegerl U, Csepe V, Karmos G, 1997, Auditoryevoked potentials as indicator of brain serotonergic activity – first evidence in behaving cats. Biol Psychiatry 41, 1181−95. [3] Snyder SH, Ferris CD, 2000, Novel neurotransmitters and their neuropsychiatric relevance. Am J Psychiatry 157, 1738−51.
P.1.b.002 Platelet 3H-imipramine, 3H-paroxetine and 5-HT2 binding sites in bipolar disorder N. Custal1 ° , J.M. Crespo1 , S. Morchon2 , P. Rosel3 , V. Soria1 , R. Hern´andez1 , N. Cardoner1 , M. Urretavizcaya1 , J.M. Menchon1 , J. Vallejo1 . 1 University Hospital of Bellvitge, Psychiatry, Hospitalet del Llobregat, Spain; 2 University Hospital of Bellvitge, Preventive Medicine, Hospitalet del Llobregat, Spain; 3 University Hospital of Bellvitge, Biochemical Service, Hospitalet del Llobregat, Spain Introduction and purpose of the study: There is growing evidence that serotonergic neurotransmission plays an important role in the pathogenesis of bipolar disorder. Furthermore, as this neurotransmitter system represents an attractive putative target for therapeutic agents, several studies have attempted to uncover the biochemical factors mediating this mood disorder. However, nowadays its undergoing pathophysiology remains to be elucidated, due in part to methodological difficulties. The aim of the current study is to determine the presence of serotonergic differences between healthy subjects and bipolar patients by studying human platelet as a peripheral model of central serotonergic neurons. Subject sample and Method: We evaluated a sample of 70 untreated individuals diagnosed as having Bipolar Disorder
P.1.b Basic neuroscience – Neuroanatomy and neurophysiology
allele and compared with the higher expressing LA allele. The distribution of allelic and genotype frequencies were in accordance with the Hardy-Weinberg equilibrium. We revealed no significant differences in allele and genotype distribution between suicide and control groups. In women there was a tendency of a lower frequency of the LS carriers in suicide group compared to that in control group (chi2 = 3.5; p = 0.06; OR = 0.62, 95% CI 0.38−1.02). Our findings indicate a possible contribution of the 5-HTT gene to susceptibility for suicidal behaviour in females only. References [1] Wendland JR, Martin BJ, Kruse et al, 2006, Simultaneous genotyping of four loci of human SLC6A4, with a reappraisal of 5-HTTLPR and rs25531. Molecular Psychiatry 11, 224–226.
P.1.b Basic neuroscience – Neuroanatomy and neurophysiology P.1.b.001 Association of NOS1 and NOS3 variants with the serotonergic marker loudness dependence of auditory evoked potentials W. Kawohl1 ° , I. Giegling2 , P. Mavrogiorgou3 , O. Pogarell2 , C. Mulert2 , U. Hegerl4 , D. Rujescu2 , G. Juckel3 . 1 Psychiatric University Hospital, Research Group Clinical and Experimental Psychopathology, Z¨urich, Switzerland; 2 University of Munich, Department of Psychiatry, Munich, Germany; 3 Ruhr-University Bochum, Department of Psychiatry, Bochum, Germany; 4 University of Leipzig, Department of Psychiatry, Leipzig, Germany Nitric oxide (NO) is a gaseous molecule with neurotransmitter properties that is involved in numerous functions in the central nervous system (CNS), the vascular system and also in macrophages(Snyder and Ferris, 2000). NO dynamics are determined by nitric oxide synthase (NOS) activity. Haplotypes of NOS1 and NOS3 genes have been shown to be associated with different psychiatric disorders such as schizophrenia and bipolar disorder due to modulating brain functioning. Therefore, the detection of other characteristics of nitrinergic transmission is desirable. A manifold interaction between NO and serotonin has been reported by different animal studies: NO signaling modulates serotonin release, postsynaptic serotonin response, and the reuptake of serotonin (Bryan-Lluka et al., 2004). Therefore, a functional marker of the serotonergic transmission, the loudness dependence of auditory evoked potentials (LDAEP) (Juckel et al., 1997), could be a promising marker of nitrinergic transmission as well. The aim of our study was to clarify the relationship between nitrinergic transmission and the LDAEP. In order to clarify the relationship between nitrinergic transmission and the LDAEP 95 healthy subjects (41 males, 54 females) were included and received auditory stimulation during 32-channel electrophysiological recording and blood drawing for genotyping of SNPs and haplotypesof NOS1 and NOS3 genes. The following SNPs (NOS-I: rs2682826, rs1353939, rs693534, rs2293049; NOS-III: rs2070744, rs1799983, rs891512) were genotyped. Additionally, 31 SNPs in genes spanning all chromosomes were included as genomic controls. An exploratory haplotype analysis of all investigated NOS1 SNPs (rs2682826-rs1353939-rs693534) showed an association of the haplotype C-G-G with lower loudness dependence scores (haplotype frequency = 0.411, haplotype score = −2.006, p = 0.045,
simulated p = 0.044). The haplotype analysis of all investigated NOS3 SNPs (rs2070744-rs1799983-rs891512) showed an association of the haplotype T-T-G with lower loudness dependence scores (haplotype frequency = 0.109, haplotype score = −2.095, p = 0.036, simulated p = 0.034). SNPs of both genes were significantly associated with lower LDAEP scores, too. Interestingly, haplotypes and SNP analysis of both NOS1 and NOS3 genes are associated with lower LDAEP scores. Thus, LDAEP-changes may serve as an easily accessible marker of nitrinergic neurotransmission. Further research is needed to fully clarify the relationship between nitrinergic transmission, the LDAEP and complex disorders such as schizophrenia and affective disorders. The findings support the hypothesis that the NO-system has an influence on the LDAEP via serotonergic functioning. To our knowledge, this interaction has not been demonstrated with a biomarker in humans yet. Haplotypes- and SNP-analysis of both NOS1 and NOS3 genes are, according to our findings, associated with lower LDAEP scores. Lower loudness dependence has been shown to be an epiphenomenon of higher serotonergic activity. A subsequent change of the LDAEP is plausible and supported by our findings. rs2070744 lies in the promoter region of NOS3, rs1799983 is functional in exon 8 and to an amino-acid-exchange (Glu298Asp). The consequences of the different variants on the NOS-activity are unclear. In case of lower LDAEP, a lower NOfunctioning can be assumed, whereas the complex property of the serotonergic system and the not fully clarified interaction on the cellular level must be taken into account. References [1] Bryan-Lluka LJ, Papacostas MH, Paczlowski FA, Wanstall JC, 2004, Nitric oxide donors inhibit 5-hydroxytryptamine (5-HT) uptake by the human 5-HT transporter (SERT). Br J Pharmacol 143, 63−70. [2] Juckel G, Molnar M, Hegerl U, Csepe V, Karmos G, 1997, Auditoryevoked potentials as indicator of brain serotonergic activity – first evidence in behaving cats. Biol Psychiatry 41, 1181−95. [3] Snyder SH, Ferris CD, 2000, Novel neurotransmitters and their neuropsychiatric relevance. Am J Psychiatry 157, 1738−51.
P.1.b.002 Platelet 3H-imipramine, 3H-paroxetine and 5-HT2 binding sites in bipolar disorder N. Custal1 ° , J.M. Crespo1 , S. Morchon2 , P. Rosel3 , V. Soria1 , R. Hern´andez1 , N. Cardoner1 , M. Urretavizcaya1 , J.M. Menchon1 , J. Vallejo1 . 1 University Hospital of Bellvitge, Psychiatry, Hospitalet del Llobregat, Spain; 2 University Hospital of Bellvitge, Preventive Medicine, Hospitalet del Llobregat, Spain; 3 University Hospital of Bellvitge, Biochemical Service, Hospitalet del Llobregat, Spain Introduction and purpose of the study: There is growing evidence that serotonergic neurotransmission plays an important role in the pathogenesis of bipolar disorder. Furthermore, as this neurotransmitter system represents an attractive putative target for therapeutic agents, several studies have attempted to uncover the biochemical factors mediating this mood disorder. However, nowadays its undergoing pathophysiology remains to be elucidated, due in part to methodological difficulties. The aim of the current study is to determine the presence of serotonergic differences between healthy subjects and bipolar patients by studying human platelet as a peripheral model of central serotonergic neurons. Subject sample and Method: We evaluated a sample of 70 untreated individuals diagnosed as having Bipolar Disorder