OBJECTIVES: Adrenergic alpha 1 and 2 receptors work as pathways to control the serotonergic neuron moderation and mirtazapine acts as antagonist of these receptors. The adrenoreceptor alpha 1a (ADRA1A) gene, which encodes adrenergic alpha 1 receptor, has Arg347Cys genetic polymorphism and the polymorphism has strong relationship with many neuro-psychiatric diseases. In this study, we explored the relationship between ADRA1A R347C polymorphism and mirtazapine treatment response in Koreans with major depression. METHODS: 352 patients enrolled in this study, and the symptoms were evaluated by 17-item Hamilton Depression Rating (HAMD-17) scale. After 1, 2, 4, 8, and 12 weeks of mirtazapine treatment, the association between ADRA1A R347C polymorphism and remission/response outcomes was evaluated. RESULTS: Treatment response to mirtazapine was significantly better in T allele carriers than C allele homozygotes after 12 weeks of mirtazapine monotherapy. The percentile decline of HAMD-17 score in T allele carriers was larger than that of C allele homozygotes. ADRA1A R347C genotypes were not significantly associated with remission. CONCLUSIONS: The result showed that treatment response to mirtazapine was significantly associated with ADRA1A R347C genetic polymorphism. T allele carriers showed better treatment response than C allele homozygotes. It can be supposed that T allele carriers have a trend of better treatment response to mirtazapine monotherapy.
Alleles ; Depression* ; Depressive Disorder, Major ; Genotype ; Homozygote ; Humans ; Polymorphism, Genetic ; Serotonergic Neurons

OBJECTIVE: We investigated possible association between depressive disorders and BDNF Val66Met and 5-HTTLPR. Brain derived neurotrophic factor (BDNF) gene and serotonin transporter (SLC6A4) gene are promising candidate genes for depressive disorders. It has been suggested that BDNF promotes the survival and differentiation of serotonergic neurons and that serotonergic transmission exerts powerful control over BDNF gene expression. METHODS: Final analyses were performed on 186 patients with depressive disorders and 1032 controls. Val66Met polymorphism of BDNF gene and 5-HTTLPR polymorphism of serotonin transporter gene were genotyped and allele and genotypic associations on the diagnosis of depression and age at onset of depression were analyzed. RESULTS: The 5-HTTLPR was positively associated with depressive affected status in the total sample and in females (p=0.038 for allelewise, p=0.015 for genotype-wise associations), but, not in males. The BDNF Val66Met showed no association with depression. BDNF Val66Met and 5-HTTLPR alone were not associated with age at onset of depression. Additional analysis on the interaction between BDNF Val66Met and 5-HTTLPR found a significant association with age at onset of depression in the entire patient group. This association was also found in the female but not in the male patient group. None of the positive results survived Bonferroni correction for multiple testing. CONCLUSION: This result suggested that BDNF Val66Met and 5-HTTLPR may contribute to depressive disorders in a complex way and that the genetic effect could differ by gender. Further studies with large number of patients will be necessary.
Alleles ; Brain-Derived Neurotrophic Factor* ; Depression ; Depressive Disorder* ; Diagnosis ; Female ; Gene Expression ; Humans ; Male ; Polymorphism, Genetic ; Serotonergic Neurons ; Serotonin Plasma Membrane Transport Proteins

No abstract available.
Alcohol-Related Disorders/*epidemiology ; Crime/prevention & control/*statistics & numerical data ; Ethanol/pharmacology ; GABAergic Neurons/drug effects ; Humans ; Republic of Korea/epidemiology ; Serotonergic Neurons/drug effects ; Violence/statistics & numerical data

The rostral ventromedial medulla (RVM) is a prominent component of the descending modulatory system involved in the control of spinal nociceptive transmission. In the current study, we investigated melanocortin-4 receptor (MC4R) expression in the RVM, where the neurons involved in modulation of nociception reside. Using a line of mice expressing green fluorescent protein (GFP) under the control of the MC4R promoter, we found a large number of GFP-positive neurons in the RVM [nucleus raphe magnus (NRM) and nucleus gigantocellularis pars α (NGCα)]. Fluorescence immunohistochemistry revealed that approximately 10% of MC4R-GFP-positive neurons coexpressed tyrosine hydroxylase, indicating that they were catecholaminergic, whereas 50%-75% of those coexpressed tryptophan hydroxylase, indicating that they were serotonergic. Our findings support the hypothesis that MC4R signaling in RVM may modulate the activity of serotonergic sympathetic outflow sensitive to nociceptive signals, and that MC4R signaling in RVM may contribute to the descending modulation of nociceptive transmission.
Animals ; Female ; Male ; Medulla Oblongata ; cytology ; metabolism ; Mice ; Mice, Transgenic ; Neural Pathways ; cytology ; metabolism ; Neurons, Afferent ; cytology ; metabolism ; Nociception ; physiology ; Receptor, Melanocortin, Type 4 ; genetics ; metabolism ; Serotonergic Neurons ; metabolism ; Tyrosine 3-Monooxygenase ; metabolism

OBJECTIVE: The definite causes of obsessive-compulsive disorder (OCD) are still unknown. Evidences from familial, twin and segregation studies support the role of a genetic component in the etiology of OCD. There are growing evidences that OCD has specific neurochemical and neuroanatomical basis. It has been shown that serotonergic neurons play the predominant pathophysiological role in OCD. Recently, it has also been proposed that neurotransmitters other than serotonin play a role in the pathophysiology of OCD, and a series of studies have provided evidence that dopamine is involved in some OCD patients. Therefore, the aims of this study were to investigate the association between dopamine receptor D4 (DRD4) and OCD. METHODS: One hundred and fifteen OCD patients and 160 normal controls participated in this study. Genomic DNA was extracted from their blood. The genotypes and allele frequencies of the DRD4 polymorphism between OCD group and control group were compared. OCD patients were classified into early onset group (age of onset <17) and late onset group (age of onset > or =17) according to their onset age and the genotype and allele frequency were compared between two groups. Using principal component analysis, we had already derived 4 factors from 13 main contents of YBOCS checklist in the previous study and in this study, we investigated the association between these three factors and DRD4 genotypes. RESULTS: In this case-control study, we could find that the L-genotype frequencies of DRD4 were significantly higher in OCD than in normal control groups (chi2 test, p=0.04). There were no difference in genotype frequencies between early onset OCD group and late onset OCD group. In OCD group, patients with L-genotype had higher scores for the religious/somatic factor than the other groups (t test, p=0.009). CONCLUSIONS: The L-genotype of DRD4 may have negative effects on the development of OCD and religious/somatic factor of the obsessive-compulsive symptoms.
Age of Onset ; Case-Control Studies ; Checklist ; DNA ; Dopamine Plasma Membrane Transport Proteins ; Dopamine* ; Gene Frequency ; Genotype ; Humans ; Neurotransmitter Agents ; Obsessive-Compulsive Disorder* ; Principal Component Analysis ; Receptors, Dopamine* ; Serotonergic Neurons ; Serotonin

These experiments were performed to investigate the effect of photoperiod and melatonin on serotonergic immunoreactivity in rat brain stem. The animals were injected with melatonin (1 mg/kg, i.p.) after light and dark treatment. The results by immunohistochemical method were as follows; 1. Immunohistochemical serotonin intensity in brain stem (dorsal raphe nucleus of midbrain, nucleus tractus solitarius and dorsal raphe nucleus of vagus nerve in medulla) appeard weakly in medium in control group compared with light and dark treated group. It suggest that enhanced effect in single injection (light or dark) was canceled by complex mechanism when two factors (light and dark) bring about together. 2. Serotonin immunoreactive neurons in brain stem (dorsal raphe nucleus of midbrain, nucleus tractus solitarius and dorsal raphe nucleus of vagus nerve in medulla) were significantly increased in light and dark treated group compared with control group. These results show that serotonin pathways are more important in mediating the effects of retinally perceived light in the rat. 3. Serotonin immunoreactive neurons in brain stem (dorsal raphe nucleus of midbrain, nucleus tractus solitarius and dorsal raphe nucleus of vagus nerve in medulla) were incresesed in melatonin treated group compared with melatonin non-treated group in light and dark. These results indicated that melatonin injection during photo and dark period enhanced serotonergic neurons activity and then light control influenced the development of serotonergic systems in brain stem including dorsal raphe nucleus of midbrain, nucleus tractus solitarius and dorsal nucleus of vagus nerve in medulla.
Animals ; Brain Stem* ; Brain* ; Melatonin* ; Mesencephalon ; Negotiating ; Neurons ; Photoperiod* ; Raphe Nuclei ; Rats* ; Serotonergic Neurons ; Serotonin ; Solitary Nucleus ; Vagus Nerve

Alcohol abuse and cigarette smoking have been on the rise worldwide and it has been reported that alcohol and nicotine influence serotonergic neuronal activity in the dorsal raphe. Serotonin (5-hydroxytryptamine, 5-HT) has been implicated in the pathophysiology of various neuropsychiatric disorders. In the present study, the effects of alcohol and nicotine on the synthesis of 5-HT and the expression of tryptophan hydroxylase (TPH), the rate limiting enzyme of 5-HT synthesis, in the dorsal and median raphe of young rats were investigated via immunohistochemistry. The numbers of the 5-HT-positive and TPH-positive cells in raphe nuclei were reduced by alcohol and nicotine treatment, and these numbers were reduced more potently by co-administration of alcohol and nicotine. Based on the results, it can be suggested that the pathogenesis of alcohol- and nicotine-induced neuropsychological disorders involves alcohol- and nicotine-induced suppression of 5-HT synthesis and TPH expression in raphe, and that this may be of particular relevance in the consumption of alcohol and nicotine during adolescence.
Adolescent ; Alcoholism ; Animals ; Humans ; Immunohistochemistry ; Nicotine* ; Raphe Nuclei ; Rats* ; Serotonergic Neurons ; Serotonin* ; Smoking ; Tryptophan Hydroxylase* ; Tryptophan*

Tricyclic antidepressant clomipramine or selective serotonin reuptake inhibitors (SSRIs) have been commonly used for the treatment of premature ejaculation. In the present study, we analyzed the concentrations of serotonin and 5-hydroxyindoleacetic acid (5-HIAA) in the medial preoptic area (MPOA) of the hypothalamus by awakening animal microdialysis following administration of clomipramine and various SSRIs. We then compared the serotonin metabolism and clinical effects of clomipramine and SSRIs on premature ejaculation. Basal extracellular serotonin level in the MPOA was higher than other brain regions and it was significantly increased by clomipramine and the SSRIs. The rank order of the concentration of serotonin at the MPOA was clomipramine, sertraline, paroxetine and fluoxetine and the concentrations of 5-HIAA was vice versa. The changes in serotonin concentration at the MPOA appeared closely associated with the clinical effects of these drugs on premature ejaculation. These results suggest that the serotonergic neuronal activity in the MPOA may have an selective inhibitory influence on ejaculation, and the effects of clomipramine and SSRIs on erectile function are mainly mediated by MPOA of the hypothalamus.
Animals ; Brain ; Clomipramine ; Ejaculation ; Fluoxetine ; Hydroxyindoleacetic Acid ; Hypothalamus* ; Male ; Metabolism* ; Microdialysis ; Paroxetine ; Premature Ejaculation ; Preoptic Area ; Rats* ; Serotonergic Neurons ; Serotonin Uptake Inhibitors* ; Serotonin* ; Sertraline

Tryptophan hydroxylase (TPH), the rate-limiting enzyme in serotonin biosynthesis, is primarily expressed in serotonergic neurons of the raphe nuclei. Simple tandem repeat polymorphisms, typically one to four nucleotides long, are tandemly repeated several times and often characterized by many alleles. To identify the presence of polymorphic repeats, we sequenced the 5'-upstream region of the mouse TPH gene. For the detection of any allelic variants, polymerase chain reaction, nonisotopic single-strand conformation polymophism, and DNA sequencing analyses of the tandem repeat sequences were performed using genomic DNA extracted from 60 ICR mice. Two dinucleotide repeats, 5'-(AC/TG)22-3' and 5'-(GT/CA)17-3', were identified at approximately -5.7 kb and -3.4 kb upstream from the transcriptional initiation site of the mouse TPH gene, respectively. Minor allelic variants, 5'-(AC/TG)21-3' and 5'-(GT/CA)18-3', were observed in heterozygous pairs from 3 of 60 and 1 of 60 ICR mice, respectively. The identification of these microsatellites in the mouse TPH promoter raises the possibility that identical and/or other polymorphic sequences might exist in the upstream region of the human TPH gene.
Alleles ; Animals ; Dinucleotide Repeats* ; DNA ; Humans ; Mice* ; Mice, Inbred ICR ; Microsatellite Repeats ; Nucleotides ; Polymerase Chain Reaction ; Raphe Nuclei ; Sequence Analysis, DNA ; Serotonergic Neurons ; Serotonin ; Tandem Repeat Sequences ; Tryptophan Hydroxylase* ; Tryptophan*

This study was designed to clarify the cytotoxic effects of 5, 7-dihydroxytryptamine (5, 7-DHT) on the serotonergic neurons in the dorsal raphe nucleus, and to investigate the glial reaction during the neurodegenerative changes by light and electron microscopy. Adult male rats (Sprague-Dawley strain) weighing from 250 g to 350 g each were used as experimental animal. 5, 7-DHT (200 microgram dissolved in 0.9% NaCl) was injected into the lateral ventricle of the rat brain with the Hamiton syringe fixed on stereotaxic apparatus. The control rats were given with the similar volume of 0.9% NaCl. The rats were sacrified on the 1st, 3rd, 5th, 10th and 20th day after the injection of 5, 7-DHT. The results were as follows : The cytotoxicity of 5, 7-DHT resulted in severe neurodegenerations of the serotonergic neurons. Most degenerated cells mainly showed necrotic findings, but a few of them exhibited apoptotic features. That is, in early stage of this experiment, the degenerated cells showed edematic changes of cytoplasm, but their nuclei were relatively seen intact. In late stage, the cells showed dark degenerative changes both in their cytoplasm and nuclei. Thereafter the cells were autolysed or phagocytosed by neighboring glial cells. Based on the results, author thought that 5, 7-DHT act as a specific neurotoxin to serotonergic neurons in DRN, and induces severe neurodegenerative changes. The glial reactions in DRN are activated during the neurodegerative changes, and show characteristic patterns of glial reactions.
Adult ; Animals ; Brain ; Cytoplasm ; Humans ; Lateral Ventricles ; Male ; Microscopy, Electron ; Neuroglia ; Raphe Nuclei* ; Rats* ; Serotonergic Neurons* ; Syringes