Interaction between polymorphisms in SLC6A4 and BDNF on major depressive disorder in a sample of the argentinean population / Interacción entre polimorfismos en SLC6A4 y BDNF en el trastorno depresivo mayor en una muestra de la población argentina

The dysfunction in the serotoninergic neurotransmission has been classically associated with major depressive disorder (MDD); however, other pathways and processes seem to have a role in this illness, such as neurogenesis and related molecules: the Brain-Derived Neurotrophic Factor (BDNF) and the Apolipoprotein E (APOE). There are many reports that indicate an association between certain polymorphism in these genes and MDD. The aim of our study was to analyze the possible association between MDD and polymorphisms in HTR2A (5-hydroxytryptamine receptor 2A), BDNF and APOE genes in a sample of the Argentinean population previously studied for 2 polymorphisms in SLC6A4 (Solute Carrier Family 6 Member 4) gene. Five polymorphisms were studied (rs6311 and rs6313 in HTR2A; rs429358 and rs7412 in APOE, and rs6265 in BDNF) in 95 MDD patients and 107 non-related controls. No statistically significant differences were observed between groups when analyzing the association with a single marker using logistic regression; however, when a possible combinatory effect of the polymorphisms (including previously studied polymorphisms in SLC6A4 gene) was analyzed using a dominant model for the risk alleles, the genotypes L/S_10/12_G/A (OR=3.57(95%CI=1.43-8.93); p=0.004, adjusted p-value=0.01) in SLC6A4 and BDNF genes and L/S_10/12_T/C_3/3_G/A in SLC6A4, HTR2A, APOE and BDNF genes (OR=5.99(95%CI=1.66-21.56); p=0.002, adjusted p-value=0.07), were more prevalent in patients than in controls (20%vs.6% and 15%vs.3%, respectively). Even though it is necessary to replicate these findings in a larger population, our results suggest a possible interaction between molecules involved in neurogenesis (BDNF and APOE), serotoninergic neurotransmission (SLC6A4 and HTR2A) and the pathogenesis of MDD. (AU)

La disfunción en la neurotransmisión serotoninérgica ha sido clásicamente asociada con el trastorno depresivo mayor (TDM); sin embargo, otras vías y procesos parecerían tener un rol en esta enfermedad, como la neurogénesis y moléculas asociadas: el factor neurotrófico derivado del cerebro (BDNF) y la apoliproteína E (APOE). Existen reportes en los que se establecen asociaciones entre polimorfismos en estos genes y el TDM. El objetivo de nuestro trabajo fue analizar la posible asociación entre el TDM y polimorfismos en los genes HTR2A (receptor 5-hidroxitriptamina 2A), BDNF y APOE en una muestra de la población argentina previamente estudiada para 2 polimorfismos en el gen SLC6A4 (transportador soluble familia 6 miembro 4). Se estudiaron 5 polimorfismos (rs6311 y rs6313 en HTR2A; rs429358 y rs7412 en APOE; rs6265 en BDNF) en 95 pacientes con TDM y 107 controles no relacionados. No se observaron diferencias significativas entre grupos al analizar la asociación por regresión logística con un único marcador; cuando se analizó el posible efecto combinatorio de polimorfismos (incluyendo los previamente estudiados para el gen SCL6A4) usando un modelo dominante para los alelos de riesgo, los genotipos L/S_10/12_G/A (OR=3,57(95%CI=1,43-8,93); p=0,004, valor-p-ajustado=0,01) en SLC6A4 y BDNF y L/S_10/12_T/C_3/3_G/A en SLC6A4, HTR2A, APOE y BDNF (OR=5,99(95%CI=1,66-21,56); p=0,002, valor-p-ajustado=0,07), fueron más prevalentes en pacientes que controles (20%vs.6% y 15%vs.3% respectivamente). Si bien es necesario replicar estos hallazgos en una población más grande, nuestros resultados sugieren una posible interacción entre moléculas involucradas en la neurogénesis (BDNF y APOE), la neurotransmisión serotoninérgica (SLC6A4 y HTR2A) y la patogenia de la depresión mayor. (AU)

Effect of 5-hydroxtryptamine on megakaryocytopoiesis--review / 中国实验血液学杂志

5-hydroxtryptamine (5-HT, serotonin) has been recognized not only as a neurotransmitter and vasoactive agent, but also as a growth factor. 5-HT mainly binds to 5-HT(2) receptors or 5-HT(1) receptors on cell surface to stimulate cell proliferation through Ras or MAPK pathway in many cell types. It has been reported that 5-HT stimulates megakaryocytopoiesis via 5-HT receptors. The possible mechanism of 5-HT on the proliferation and differentiation of megakaryocytes (MK) has been discussed in this review article. In early stage of megakaryocytopoiesis, 5-HT may bind to 5-HT(2B) receptor on megakaryocytes, and promotes their proliferation and differentiation. In the late stage, 5-HT may involve in the platelet release procedure by inducing nitric oxide (NO) synthesis via 5-HT(2A) receptors. 5-HT can also antagonize the apoptotic effect induced by thrombospondin-1 (TSP-1) which is a platelet alpha granule protein and has synergic effect with platelet-derived growth factor (PDGF) to enhance megakaryocytes proliferation. Therefore, 5-HT is likely to be an important substance in the feedback regulation of thrombopoiesis. In this review the 5-HT and its receptors, 5-HT as cell growth factor, pathway of 5-HT stimulating cell proliferation and influance of 5-HT on MK-progenitor cells were summarized.

Interaction of 5-HT2 and 5-HT3 receptor subtype in 5-HT-induced nociceptive responses in peripheral primary sensory nerve ending / 中国应用生理学杂志

<p><b>AIM</b>To study the correlation between 5-HT-induced pain response and the contribution by individual 5-HTR subtypes including 5-HT1R, 5-HT2R and 5-HT3R at the level of peripheral primary afferent.</p><p><b>METHODS</b>The experiments were done on acutely isolated trigeminal ganglion (TG) neurons using whole-cell patch clamp technique and the nociceptive effect was observed on behavior experiments by intraplantar injection of test drugs.</p><p><b>RESULTS</b>The majority of cells examined responded to 5-HT in a manner of concentration dependence (10(-6) - 10(-3) mol/) (61.4%, 54/88) and with a fast activating and rapid desensitizing inward current (I(5-HT)), which was thought to be mediated by the activation of 5-HT3R, since it could be blocked by 5-HT3R antagonist ICS 205930 and mimicked by 5-HT3R agonist 2-methyl-5-HT. It was found that I(5-HT) was potentiated by 5-HT2R agonist alpha-methyl-5-HT markedly, while 5-HT1R agonist R-(+)-UH 301 did not. In behavioral experiment performed on conscious rats, intraplantar injection of 5-HT(10(-5), 10(-4) and 10(-3) mol/L) induced an increment of cumulative lifting time first 20 min in a manner of concentration dependence. By dissociating 5-HTR subtypes using their corresponding antagonists (ICS and CYP) the potency order of hindpaw lifting time was identified as follows: 5-HT > 5-HT + ICS > 5-HT + CYP.</p><p><b>CONCLUSION</b>The results suggest that in 5-HT-induced nociceptive response at the primary sensory level 5-HT3R may play a role of initiation, but 5-HT2R mediates maintaining and modulatory effect in the processes of nociceptive information convey.</p>

5-HT2 receptor mediated the potentiation of GABA-activated current in the membrane of the dorsal root ganglion neurons of rat / 药学学报

<p><b>AIM</b>To explore the modulation of 5-HT on GABA-activated current (I(GABA)) in the membrane of rat dorsal root ganglion (DRG) neurons and its mechanism.</p><p><b>METHODS</b>Rat DRG neurons were isolated mechanically and enzymatically, on which whole-cell patch clamp recording and repatch technique for intracellular dialysis were performed.</p><p><b>RESULTS</b>In the majority of neurons examined (92.0%, 69/75) GABA induced a concentration-dependent inward current. In neurons sensitive to GABA preapplication of 5-HT produced potentiation effect (82.6% , 57/69) on I(GABA). Preapplication of 5-HT at concentrations of 1 x 10(-6), 1 x 10(-5), 1 x 10(-4) and 1 x 10(-3) mol x L(-1) potentiated I(GABA) by (35 +/- 8)% (n=8), (47 +/- 11)% (n=10), (65 +/- 17)% (n=9) and (75 +/- 18)% (n=11), respectively. This effect was mimicked by alpha-methyl-5-HT (1 x 10(-6) mol x L(-1)), a specific 5-HT2 receptor agonist, and reversed by cyproheptadine, a selective 5-HT2 receptor antagonist. The potentiation of I(GABA) by 5-HT was irrespective to whether the I(5-HT) presents or not in a subset of neurons. The concentration-response curves for GABA before and after pretreatment with 5-HT manifested the same threshold value and similar EC50 (2.0 x 10(-5) and 1.9 x 10(-5) mol x L(-1), respectively) , while the maximal value of I(GABA) for the latter was 33.6% higher than that for the former. Intracellular dialysis with GDP-beta-S or H-7 abolished the potentiation of I(GABA) by 5-HT, while H-9 did not.</p><p><b>CONCLUSION</b>5-HT can potentiate GABA-activated current via PKC-dependent phosphorylation of GABA(A) receptor following the activation of 5-HT2 receptor.</p>

A Case of Delayed Risperidone-induced Neuroleptic Malignant Syndrome / 신경정신의학

Risperidone is a relatively new antipsychotic agent. It is often referred to as 'atypical', because it has a mechanism of action that blocks post synaptic dopamine-2 and serotonin-2 receptors, it is associated with fewer extrapyramidal side effects, it is not yet associated with tardive dyskinesia, and it may have some efficacy on negative symptoms of schizophrenia. In despite of its 'atypical' nature, there are already more than 15 reports of risperidone-induced neuroleptic malignant syndrome. Only one case of risperidone-induced NMS was reported recently in Korea. We report one case of delayed risperidoneinduced neuroleptic malignant syndrome in young male patient and review the related articles.

A Comparative Study of Clinical Effects and Changes of Plasma HVA and 5-HIAA on Risperidone vs Haloperidol in Chronic Schizophrenic Patients / 대한정신약물학회지

OBJECTIVES: This study was designed to compare risperidone(as an atypical antipsychotic) with haloperidol(as a typical antipsychotic), so we examined the clinical effects and changes of plasma HVA, 5-HIAA & HVA/5-HIAA ratio after 8 week of risperidone or haloperidol trial. METHOD: Twenty-six male chronic schizophrenic patients were treated for 8 weeks with risperidone(N=14) and haloperidol(N=12). The duration of wash-out period was 14 days. The psychopathologic assessment was chechked by Positive and Negative Syndrome Scale(PANSS) and plasma HVA & 5-HIAA was measured by High Performance Liquid Chromatography(HPLC) with electrochemical detector. The checking points were just before drug trial and 1st, 2nd, 4th, and 8th week(total 5 times). RESULTS: 1) Risperidone trial group were more improved than haloperidol tiral group in PANSS scores(total, positive, negative and general psychopathy). 2) Changes of plasma HVA and 5-HIAA in the risperidone and haloperidol trial group were not statistically different. But because baseline 5-HIAA of risperidone trial group was higher than that of haloperidol trial group, the increase of haloperidol trial group would be more. 3) There was significant difference in changes of HVA/5-HIAA ratio between risperidone and haloperidol trial group. But the change of HVA compared with 5-HIAA in risperidone trial group was higher than that of haloperidol trial group. CONCLUSION: These results revealed that risperidone was more effective in clinical symptoms, and suggest that cause of these results may be due to blocking both of dopamine D2 receptors and serotonin 5-HT2 receptors of risperidone.

Effect of Acute and Chronic Treatment with Risperidone on the Serotonin and Dopamine Receptors in the Rat Brain / 대한핵의학회잡지

The therapeutic efficacy of antipsychotic drugs is generally attributed to their ability to block dopamine D2 receptors. Classical D2 antagonists are not effective to treat negative symptoms and produce extrapyramidal side effects. On the other hand, atypical antipsychotic agents ameliorate negative symptoms without producing extra-pyramidal side effects, and it is reported to be associated with blockade of serotonin 5-HT2 receptors. The purpose of this study was to evaluate the effect of risperidone on neuroreceptors in the rat brain by quantitative autoradiography method. In acute treatment group, risperidone was injected into peritoneal cavity of male Wistar rats with dose of 0, 0.1, 0.25, 0.5, 1,0 and 2.0mg/kg in each Group(5/group), and they were decapitated after 2 hours. In chronic treatment group, risperidone was injected with dose of 0, 0.1, and 1mg/kg(I.P.) for 21 days and decapitated after 24 hours following last treatment. The effect of risperodone on the binding of [3H]spiperone to 5-HT2 and D2 receptors were analysed in 4 discrete regions of the striatum, nucleus accumbens, and frontal cortex by quantitative autoradiography. Acute treatment with risperidone reduced cortical 5-HT2 specific [3H]spiperone binding to 32% of vehicle-treated control. Subcortical 5-HT2 specific [3H]spiperone binding was not affected at all dose groups whereas a significant reduction (57%) in D2 specific [3H]spiperone binding was observed in risperidone treated group at doses of l-2mg/kg. Chronic treatment with risperidone produced a decrease in the maximal number of cortical 5-HT2 receptors to 51% and 46% of control in 0.1mg/kg & 1mg/kg treated group respectively. In conclusion, risperidone is a cortical serotonin receptor antagonist with relatively weak antagonistic action on dopamine receptors. These effects on neuroreceptors may explain the therapeutic effect of risperidone as a atypical antipsychotic agents.

Distribution of Serotonin-2 Receptor in the Superior Collicullus of the Adult Rat: A Radioarutographic Study

The superior colliculus is a laminated structure that consisted with superficial and deep layers in the roof of midbrain and the center of visual information and sensorimotor intergration. The deep layers of the mammalian superior colliculus are concerned with generation of eye movements. Serotonin is a neurotransmitter of the central nervous system and its binding sites can be classified into serotonin-1 receptor, serotonin-2 receptor and serotonin-3 receptor according to their pharmacological characteristics. The serotonin-2 receptors in the human brain presents in the motor cortex(area 4 of Brodmann) which role for the control of ocular motor activity and in the primary and secondary visual areas(areas 17 and 18 of Brodmann). Some of them presents in the limbic system role for the control of emotive activity, memory and other limbic functions. We performed this experiment to identify the anatomical distribution of the serotonergic nerve terminals in the superior colliculus of the rat by microscopicautography. It has been demonstrated that the serotonin-2 receptors of the superior colliculus are concerned with generation of saccade eye movements.