Antidepressants in pregnancy: applying causal epidemiological methods to understand service-use outcomes in women and long-term neurodevelopmental outcomes in exposed children.

Background: Antidepressants are commonly prescribed during pregnancy, despite a lack of evidence from randomised trials on the benefits or risks. Some studies have reported associations of antidepressants during pregnancy with adverse offspring neurodevelopment, but whether or not such associations are causal is unclear. Objectives: To study the associations of antidepressants for depression in pregnancy with outcomes using multiple methods to strengthen causal inference. Design: This was an observational cohort design using multiple methods to strengthen causal inference, including multivariable regression, propensity score matching, instrumental variable analysis, negative control exposures, comparison across indications and exposure discordant pregnancies analysis. Setting: This took place in UK general practice. Participants: Participants were pregnant women with depression. Interventions: The interventions were initiation of antidepressants in pregnancy compared with no initiation, and continuation of antidepressants in pregnancy compared with discontinuation. Main outcome measures: The maternal outcome measures were the use of primary care and secondary mental health services during pregnancy, and during four 6-month follow-up periods up to 24 months after pregnancy, and antidepressant prescription status 24 months following pregnancy. The child outcome measures were diagnosis of autism, diagnosis of attention deficit hyperactivity disorder and intellectual disability. Data sources: UK Clinical Practice Research Datalink. Results: Data on 80,103 pregnancies were used to study maternal primary care outcomes and were linked to 34,274 children with at least 4-year follow-up for neurodevelopmental outcomes. Women who initiated or continued antidepressants during pregnancy were more likely to have contact with primary and secondary health-care services during and after pregnancy and more likely to be prescribed an antidepressant 2 years following the end of pregnancy than women who did not initiate or continue antidepressants during pregnancy (odds ratioinitiation 2.16, 95% confidence interval 1.95 to 2.39; odds ratiocontinuation 2.40, 95% confidence interval 2.27 to 2.53). There was little evidence for any substantial association with autism (odds ratiomultivariableregression 1.10, 95% confidence interval 0.90 to 1.35; odds ratiopropensityscore 1.06, 95% confidence interval 0.84 to 1.32), attention deficit hyperactivity disorder (odds ratiomultivariableregression 1.02, 95% confidence interval 0.80 to 1.29; odds ratiopropensityscore 0.97, 95% confidence interval 0.75 to 1.25) or intellectual disability (odds ratiomultivariableregression 0.81, 95% confidence interval 0.55 to 1.19; odds ratiopropensityscore 0.89, 95% confidence interval 0.61 to 1.31) in children of women who continued antidepressants compared with those who discontinued antidepressants. There was inconsistent evidence of an association between initiation of antidepressants in pregnancy and diagnosis of autism in offspring (odds ratiomultivariableregression 1.23, 95% confidence interval 0.85 to 1.78; odds ratiopropensityscore 1.64, 95% confidence interval 1.01 to 2.66) but not attention deficit hyperactivity disorder or intellectual disability; however, but results were imprecise owing to smaller numbers. Limitations: Several causal-inference analyses lacked precision owing to limited numbers. In addition, adherence to the prescribed treatment was not measured. Conclusions: Women prescribed antidepressants during pregnancy had greater service use during and after pregnancy than those not prescribed antidepressants. The evidence against any substantial association with autism, attention deficit hyperactivity disorder or intellectual disability in the children of women who continued compared with those who discontinued antidepressants in pregnancy is reassuring. Potential association of initiation of antidepressants during pregnancy with offspring autism needs further investigation. Future work: Further research on larger samples could increase the robustness and precision of these findings. These methods applied could be a template for future pharmaco-epidemiological investigation of other pregnancy-related prescribing safety concerns. Funding: This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (15/80/19) and will be published in full in Health Technology Assessment; Vol. 27, No. 15. See the NIHR Journals Library website for further project information.

About one in seven women experience depression during pregnancy. Left untreated, this may harm them and their unborn babies. However, the decision to take antidepressants during pregnancy is difficult because women often worry about the risks to their unborn baby. Research findings have been inconsistent, so women often do not have clear information to enable them to make informed decisions. We studied women's and children's outcomes after starting (compared with not starting) or continuing (compared with stopping) antidepressants in pregnancy. We used a large UK primary care database and several novel methods of analysis. We tracked 80,103 pregnancies of women with depression for up to 2 years after pregnancy. We also tracked 34,274 children from these pregnancies for at least 4 years to check for developmental outcomes. Women prescribed antidepressants were more likely than women not prescribed antidepressants to use general practice and mental health services during and after pregnancy, and to be prescribed antidepressants 2 years after pregnancy. This suggests that antidepressants were being prescribed to women with greater clinical need. Women who continued antidepressants in pregnancy had no higher likelihood than those who discontinued antidepressants of autism, attention deficit hyperactivity disorder or intellectual disability in their children. This should reassure women making the decision to continue taking their medications in pregnancy. Women who started antidepressants in pregnancy may possibly have had a slightly higher likelihood of autism in their children than those who did not start them. These findings were not seen in all analyses and were based on smaller numbers; therefore, they should be viewed with caution. Importantly, over 98 in every 100 children of women who initiated or continued antidepressants in pregnancy did not receive an autism diagnosis. The findings may help women and clinicians make informed decisions on treatment with antidepressants in pregnancy.

Reporte de un caso de tratamiento de gastroparesia pediátrica con prucaloprida: una terapia novedosa / A case report of prucalopride treatment in pediatric gastroparesis: a novel therapy

La prucaloprida acelera el vaciamiento gástrico en adultos con gastroparesia. No existen estudios con este medicamento en niños con gastroparesia. Se presenta un niño de 8 años que consultó por síntomas posprandiales de un mes de duración, con diagnóstico de gastroparesia por gammagrafía de vaciamiento gástrico. No mejoró con metoclopramida, domperidona, eritromicina y esomeprazol. Recibió prucaloprida durante dos períodos (durante 178 y 376 días) a dosis de 0,03-0,04 mg/kg/día. Presentó mejoría en el seguimiento con el índice cardinal de síntomas de gastroparesia y gammagrafías de vaciamiento gástrico. Por la buena respuesta, la prucaloprida podría ser una opción terapéutica en la gastroparesia pediátrica.

Prucalopride has been used in adults with gastroparesis, accelerating gastric emptying. There are no studies with this drug in gastroparetic children. An 8-year-old boy is presented who consulted for a month of postprandial symptoms, with a diagnosis of gastroparesis by gastric emptying scintigraphy. He did not improve with metoclopramide, domperidone, erythromycin, and esomeprazole. He received prucalopride for two periods (for 178 and 376 days) at doses: 0.03 - 0.04 mg/kg/day, presenting improvement in the follow-up with the cardinal gastroparesis symptom index and gastric emptying scintigraphy. Due to the good response, prucalopride may be a therapeutic option in pediatric gastroparesis.

A case report of prucalopride treatment in pediatric gastroparesis: a novel therapy. / Reporte de un caso de tratamiento de gastroparesia pediátrica con prucaloprida: una terapia novedosa.

Prucalopride has been used in adults with gastroparesis, accelerating gastric emptying. There are no studies with this drug in gastroparetic children. An 8-year-old boy is presented who consulted for a month of postprandial symptoms, with a diagnosis of gastroparesis by gastric emptying scintigraphy. He did not improve with metoclopramide, domperidone, erythromycin, and esomeprazole. He received prucalopride for two periods (for 178 and 376 days) at doses: 0.03 - 0.04 mg/ kg/day, presenting improvement in the follow-up with the cardinal gastroparesis symptom index and gastric emptying scintigraphy. Due to the good response, prucalopride may be a therapeutic option in pediatric gastroparesis.

La prucaloprida acelera el vaciamiento gástrico en adultos con gastroparesia. No existen estudios con este medicamento en niños con gastroparesia. Se presenta un niño de 8 años que consultó por síntomas posprandiales de un mes de duración, con diagnóstico de gastroparesia por gammagrafía de vaciamiento gástrico. No mejoró con metoclopramida, domperidona, eritromicina y esomeprazol. Recibió prucaloprida durante dos períodos (durante 178 y 376 días) a dosis de 0,03-0,04 mg/kg/ día. Presentó mejoría en el seguimiento con el índice cardinal de síntomas de gastroparesia y gammagrafías de vaciamiento gástrico. Por la buena respuesta, la prucaloprida podría ser una opción terapéutica en la gastroparesia pediátrica.

Role of 5-HT 1A and 5-HT 3 receptors in sevoflurane-induced cerebral neurotoxicity in aged rats / 中华麻醉学杂志

Objective:To preliminarily investigate the relationship between the mechanism of sevoflurane-induced cerebral neurotoxicity and receptors of 5-HT 1A and 5-HT 3 in aged rats. Methods:Twenty-four clean-grade healthy male Sprague-Dawley rats, aged 18-20 months, weighing 600-750 g, were divided into 3 groups ( n=8 each) using a random number table method: group C, group LS and group HS.In group C, group LS and group HS, 50% O 2, 1.5% sevoflurane plus 50% O 2 and 3% sevoflurane plus 50% O 2 were inhaled for 2 h, respectively.Open field test was performed at 1 day before inhalation of sevoflurane and at 1 day after the end of inhalation, the time spent in the central square, the number of crossing the grid and the number of standing on the back legs were recorded.The Morris water maze test was performed at 6 days before inhalation of sevoflurane and at 1 day after the end of inhalation, the escape latency, the total swimming distance and the number of crossing the platform were recorded.Immediately after the end of behavioral testing, the hippocampal tissues were obtained for determination of 5-HT 1A and 5-HT 3 receptors mRNA expression and the number of positive cells (using real-time reverse transcription-polymerase chain reaction assay and immunohistochemical method). Results:Compared with group C, the time spent in the central square was significantly prolonged, the number of crossing the grid and the number of standing on the back legs were decreased, the escape latency was prolonged, the total swimming distance was increased, the number of crossing platform was decreased, the mRNA expression of 5-HT 1A and 5-HT 3 was down-regulated, and the number of positive cells was decreased in HS group ( P<0.05). Conclusion:The mechanism of cerebral neurotoxicity induced by sevoflurane may be related to the down-regulation of the activities of 5-HT 1A and 5-HT 3 receptors in aged rats.

The study of 5-Hydroxytryptamine 2B receptor-nanodisc self-assembling and its ligand binding activity / 中国医师杂志

Objective To explore the application of nanodisc in functional and drug discovery research of G protein-coupled receptor (GPCR).Methods The purified recombinant 5-Hydroxytryptamine 2B receptor (5-HT2BR) was reconstituted into nanodisc complex.Sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) and size exclution chromatography were performed to evaluate the reconstitution reaction,followed by the use of surface plasmon resonance to validate the ligand-binding activity of 5-HT2BR after reconstitution.Results 5-HT2B R was effectively self-assembled into nanodisc while maintained its binding activity toward the antagonist SB204741.Conclusions The presented study provided potential application of 5-HT2B R-nanodisc for the development of subtype-selective drugs against 5-HT2B R and the fundamental of utilizing nanodisc for GPCR structural and functional studies as well as drug discovery.

Effect of Raw Atractylodes macrocephala on Motility and 5-HT4 Receptor in Small Intestine of Model Rats with Plateau Hypoxia / 胃肠病学

Background:Gastrointestinal dysmotility is commonly seen in individuals exposed to acute plateau hypoxia. Its pathogenic mechanism is still not clear and intervention study is rarely performed. Aims:To investigate the influence of plateau hypoxia on small intestinal motility of rats,its possible mechanism,and the intervention effect of raw Atractylodes macrocephala. Methods:Seventy Wistar rats were randomly divided into 7 groups:control group,two high altitude model groups(3 500 m and 5 000 m),trimebutine and raw Atractylodes macrocephala groups at 3 500 m or 5 000 m altitude. Rats in six experiment groups were placed in a hypobaric chamber mimicking 3 500 m or 5 000 m altitude and given trimebutine/ raw Atractylodes macrocephala/ saline intragastrically for 3 days. Then all the rats were lavaged with 2 mL ink and sacrificed 30 minutes later. The propulsion rate of ink in small intestine was measured,the pathological changes of small intestine tissue were examined,and the expression of 5-HT4 receptor was determined by immunohistochemistry. Results:Compared with control group,the propulsion rate of small intestine and immunopositive area of 5-HT4 receptor were reduced in model group at 3 500 m altitude,while those in model group at 5 000 m altitude were increased(P ﹤0. 05). Moderate-to-severe mucosal injury was observed in two model groups. In model rats treated with raw Atractylodes macrocephala,the abnormalities in small intestine propulsion and 5-HT4 receptor induced by high altitude(3 500 m and 5 000 m)returned to the control level(P ﹤ 0. 05),and the mucosal injury ameliorated simultaneously. Efficacy of raw Atractylodes macrocephala was prior to trimebutine,a positive control. Conclusions:Acute plateau hypoxia may induce small intestine dysmotility with diverse manifestations,and altitude is a crucial determinant in this process. Raw Atractylodes macrocephala can exert therapeutic effect on this dysmotility by modulating 5-HT4 receptor,and it is also effective in repairing mucosal injury.

Distribution of 5-HT3, 5-HT4, and 5-HT7 Receptors Along the Human Colon

BACKGROUND/AIMS: Several disorders of the gastrointestinal tract are associated with abnormal serotonin (5-HT) signaling or metabolism where the 5-HT3 and 5-HT4 receptors are clinically relevant. The aim was to examine the distribution of 5-HT3, 5-HT4, and 5-HT7 receptors in the normal human colon and how this is associated with receptor interacting chaperone 3, G protein coupled receptor kinases, and protein LIN-7 homologs to extend previous observations limited to the sigmoid colon or the upper intestine. METHODS: Samples from ascending, transverse, descending, and sigmoid human colon were dissected into 3 separate layers (mucosa, longitudinal, and circular muscles) and ileum samples were dissected into mucosa and muscle layers (n = 20). Complementary DNA was synthesized by reverse transcription from extracted RNA and expression was determined by quantitative or end point polymerase chain reaction. RESULTS: The 5-HT3 receptor subunits were found in all tissues throughout the colon and ileum. The A subunit was detected in all samples and the C subunit was expressed at similar levels while the B subunit was expressed at lower levels and less frequently. The 5-HT3 receptor E subunit was mainly found in the mucosa layers. All splice variants of the 5-HT4 and 5-HT7 receptors were expressed throughout the colon although the 5-HT4 receptor d, g, and i variants were expressed less often. CONCLUSIONS: The major differences in 5-HT receptor distribution within the human colon are in relation to the mucosa and muscular tissue layers where the 5-HT3 receptor E subunit is predominantly found in the mucosal layer which may be of therapeutic relevance.

Interação entre as vias de sinalização de receptores serotoninérgicos e Β-adrenérgicos em artéria femoral de ratos / Interaction between serotoninergic-and β-adrenergic receptors signaling pathways in rat femoral artery / Interacción entre las vías de señalización de receptores serotoninérgicos y β-adrenégicos en la arteria femoral de ratones

FUNDAMENTO: A doença coronária tem sido amplamente estudada em pesquisas cardiovasculares. No entanto, pacientes com doença arterial periférica (DAP) têm piores resultados em comparação àqueles com doença arterial coronariana. Portanto, os estudos farmacológicos com artéria femoral são altamente relevantes para a melhor compreensão das respostas clínicas e fisiopatológicas da DAP. OBJETIVO: Avaliar as propriedades farmacológicas dos agentes contráteis e relaxantes na artéria femoral de ratos. MÉTODOS: As curvas de resposta de concentração à fenilefrina contrátil (FC) e à serotonina (5-HT) e os agentes relaxantes isoproterenol (ISO) e forskolina foram obtidos na artéria femoral de ratos isolada. Para as respostas ao relaxamento, os tecidos foram contraídos com FC ou 5-HT. RESULTADOS: A potência de classificação na artéria femoral foi de 5-HT > FC para as respostas contráteis. Em tecidos contraídos com 5-HT, as respostas de relaxamento ao isoproterenol foram praticamente abolidas em comparação aos tecidos contraídos com FC. A forskolina, um estimulante da adenilil ciclase, restaurou parcialmente a resposta de relaxamento ao ISO em tecidos contraídos com 5-HT. CONCLUSÃO: Ocorre uma interação entre as vias de sinalização dos receptores β-adrenérgicos e serotoninérgicos na artéria femoral. Além disso, esta pesquisa fornece um novo modelo para estudar as vias de sinalização serotoninérgicas em condições normais e patológicas que podem ajudar a compreender os resultados clínicos na DAP.

BACKGROUND: Coronary heart disease has been widely studied in cardiovascular research. However, patients with peripheral artery disease (PAD) have worst outcomes compared to those with coronary artery disease. Therefore, pharmacological studies using femoral artery are highly relevant for a better understanding of the pathophysiologic responses of the PAD. OBJECTIVE: The aim of this study was to evaluate the pharmacologic properties of the contractile and relaxing agents in rat femoral artery. METHODS: Concentration response curves to the contractile phenylephrine (PE) and serotonin (5-HT) and the relaxing agents isoproterenol (ISO) and forskolin were obtained in isolated rat femoral artery. For relaxing responses, tissues were precontracted with PE or 5-HT. RESULTS: The order rank potency in femoral artery was 5-HT > PE for contractile responses. In tissues precontracted with 5-HT, relaxing responses to isoproterenol was virtually abolished as compared to PE-contracted tissues. Forskolin, a stimulant of adenylyl cyclase, partially restored the relaxing response to ISO in 5-HT-precontracted tissues. CONCLUSION: An interaction between β-adrenergic- and serotoninergic- receptors signaling pathway occurs in femoral artery. Moreover, this study provides a new model to study serotoninergic signaling pathway under normal and pathological conditions which can help understanding clinical outcomes in the PAD.

FUNDAMENTO: La enfermedad coronaria ha sido ampliamente estudiada en las investigaciones cardiovasculares. Sin embargo, los pacientes con enfermedad arterial periférica (EAP), tienen los peores resultados en comparación con aquellos con la enfermedad arterial coronaria. Por tanto, los estudios farmacológicos con la arteria femoral son extremadamente importantes para obtener una mejor comprensión de las respuestas clínicas y fisiopatológicas de la EAP. OBJETIVO: Evaluar las propiedades farmacológicas de los agentes contráctiles y relajantes en la arteria femoral de los ratones. MÉTODOS: Las curvas de concentración-respuesta a los agentes conctráctiles fenilefrina (FE) y a la serotonina (5-HT) y los agentes relajantes isoproterenol (ISO) y forskolina, se obtuvieron en la arteria femoral de ratones ya aislada. Para las respuestas a la relajación, los tejidos fueron contraídos con FE o 5-HT. RESULTADOS: La potencia de clasificación en la arteria femoral fue de 5-HT > FE para las respuestas contráctiles. En los tejidos contraídos con 5-HT, las respuestas de relajación al isoproterenol fueron prácticamente eliminadas en comparación con los tejidos contraídos con FE. La forskolina, un estimulante de la adenilil ciclasa, restauró parcialmente la respuesta de relajación al ISO en los tejidos contraídos con 5-HT. CONCLUSIÓN: Ocurre una interacción entre las vías de señalización de los receptores β-adrenérgicos y serotoninérgicos en la arteria femoral. Además, esa investigación suministra un nuevo modelo para estudiar las vías de señalización serotoninérgicas en condiciones normales y patológicas que puedan ayudar a comprender los resultados clínicos en la EAP.

Role of 5-HT5A receptors in activation of astroglia in the spinal dorsal horn in a rat model of neuropathic pain by vincristine / 中华麻醉学杂志

Objective To evaluate the role of 5-HT5A receptors (5-HT5A R) in activation of astroglia in the spinal dorsal horn in a rat model of neuropathic pain induced by vincristine. Methods Forty adult male SD rats weighing 180-200 g were randomly divided into 4 groups ( n = 10 each): control group (group C);neuropathic pain group (group P);Ad-X-HK group (group B) and Ad-5-HT5A-siRNA group (group S). Neuropathic pain was induced by repeated intraperitoneal (IP) injection of vincristine 0.1 mg/kg according to the method described by Weng et al in group P, B and S. On the 2nd day after the last IP injection, the animals received artificial cerebrospinal fluid, Ad-X-HK and Ad-5-HT5A-siRNA 25 μl administered intrathecally (IT) in group P, B and S respectively. Paw withdrawal threshold to mechanical stimulus was measured before and on the 7th day after IT administration. The animals were then sacrificed. The lumbar segment ( L4.5 ) of the spinal cord was removed for determination of 5-HT5A R and GFAP expression. Results Body weight and paw withdrawal threshold were significantly decreased after repeated IP vincristine administration in group P compared with group C. IT Ad-5-HT5A-siRNA reduced pain threshold further in group S compared with group P. Repeated IP vincristine significantly increased the expression of 5-HT5A R and GFAP in spinal dorsal horn, and IT Ad-5-HT5A-siRNA significantly decreased the expression of 5-HT5A R while increased the expression of GFAP in spinal dorsal horn in group S compared with group P. Conclusion 5-HT5AR is involved in the inhibition of astrocyte activation, resulting in reduction of vincristineinduced neuropathic pain.

Significance of physiologic changes of quantity of enterochromaffin cells and expression of 5-hydroxytryptamine receptor 3 (5-HT3R) in SD rats at different ages / 中华老年医学杂志

Objective To study the changes of intestinal transit rate, quantity of enterochromaffin cells and expressions of 5-hydroxytryptamine receptor 3 (5-HT3R) in SD rats at different ages, and to investigate the possible mechanism of gastrointestinal dysfunction in aged rats. Methods Eighty healthy SD rats were divided into five groups: three months age, nine months age, eighteen months age, twenty-four months age and thirty months age,and there were sixteen rats in each group. The intestinal transit rate was detected. Immunohistochemistry staining was used to test the quality of chromaffin cells in mucosa and submucosa of jejunum, ileum and colon and to detect the expressions of 5-HT3R in intestinal myenteric plexus. Results The intestinal transit rate was significantly lower in thirty months age group than in three months age group [(52.1±9.8)% vs. (67.2±13.5)%, t=7.013, P=0.001]. In thirty months age group, the quality of chromaffin cells in mucosa and submueosa of jejunum, ileum and colon were 11.1±3.0, 10.6±1.9, 10.2±4.3, respectively, which were reduced compared with three months age group (22.9±6.2, 25.8±7.1, 23.0±5.7, t=3. 640,3. 384,4. 154, all P<0.01). The expressions of 5-HT3R in myenteric plexus of jejunum and ileum were reduced in thirty months age group than in nine months age group [4.8±1.4, 9.3±4.2 vs. 8.9±1.5, 14.5±5.3;t=3.464, 3.003,all P<0.01]. The expression of 5-HT3R in colon myenteric plexus were 5.0±1.3 and 9.0±1.7 in thirty months age group and three months age group, respectively (t=4.549,P<0.001). Conclusions In aged rats, the intestinal transit rate, quantity of enterochromaffin cells and expressions of 5-HT3R are decreased with ageing, and the gastrointestinal dysfunction may be associated with the changing of the quantity of enterochromaffin cells and expressions of 5-HT3R in myenteric plexus.

Serotonin2A receptor binding potential in people with aggressive and violent behaviour.

OBJECTIVE: Indexes of brain serotonin2A (5-HT2A) density have never been investigated in a sample of humans with violent aggressive behaviour unbiased by medication use or current axis I psychiatric disorders. The objective of this study was to investigate prefrontal cortex 5-HT2A binding potential (BPND), an index of 5-HT2A density, in an unbiased sample of people with violent aggressive behaviour. METHODS: We used [18F] setoperone positron emission tomography to measure 5-HT2A BPND in the dorsolateral prefrontal cortex (primarily sampling Brodmann area 9) in 16 participants with violent aggressive behaviour and 16 healthy control participants. RESULTS: In people with violent aggressive behaviours, the slope of 5-HT2A BPND decline in the dorsolateral prefrontal cortex is 44% less than in healthy control participants (analysis of variance group by age interaction, p = 0.004). Prefrontal cortex 5-HT2A BPND was significantly lower in participants with more severe impulsivity and aggression (multiple linear regression with age and Barratt Impulsivity Scale [BIS] as predictor variables and regional 5-HT2A BPND as dependent variable; effect of BIS, dorsolateral prefrontal cortex: F1,13 = 7.95, p = 0.014). CONCLUSION: Lower prefrontal 5-HT2A BPND is related to violent aggression. Lower 5-HT2A BPND occurs at a younger age, when violent behaviour is more frequent, and is more prominent when impulsivity and aggression are more severe.

Serotonin1B heteroreceptor activation induces an antidepressant-like effect in mice with an alteration of the serotonergic system.

OBJECTIVE: We sought to demonstrate whether the specific activation of serotonin1B (5-HT1B) heteroreceptors by systemic or local administration of the selective 5-HT1B receptor agonist anpirtoline could mediate antidepressant-like effects in mice. METHODS: We confirmed the selectivity of action of anpirtoline in the forced swim test (FST) in 5-HT1B knockout mice. We then evaluated the behavioural effects of anpirtoline on 5-HT-lesioned (5,7-dihydroxytryptamine creatinine [5,7-DHT]) and 5-HT-depleted (p-CPA) mice. We estimated the depletion level and selectivity of action of 5,7-DHT and p-CPA by measuring the neurotransmitter levels and [3H]-citalopram binding. We investigated the antidepressant-like effect of anpirtoline when locally perfused in an area of the brain where the response is mainly attributable to presynaptic (cortex and hippocampus) or postsynaptic receptors (substantia nigra and caudate putamen). Furthermore, we evaluated the effect of the 5-HT1B receptor antagonist GR127935 on the activity of various antidepressants in the FST. RESULTS: Anpirtoline was devoid of effects in 5-HT1B receptor knockout mice. It induced a greater effect in p-CPA and 5,7-DHT pretreated mice compared with control subjects, suggesting that the antidepressant-like activity of anpirtoline mainly depends on 5-HT1B heteroreceptor stimulation (autoreceptors being destroyed by 5,7-DHT). This observation was confirmed by the results showing the antidepressant-like effect of anpirtoline when locally perfused in areas of the brain that contain postsynaptic receptors. The blockade of 5-HT1B receptors antagonizes the effect of selective serotonin reuptake inhibitors (SSRIs). CONCLUSION: Our results demonstrate that the antidepressant-like effect of SSRIs in the FST requires the activation of 5-HT1B heteroreceptors.

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 committed 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-HT(1A), 5-HT(1B) and p11 mRNA expression between people who committed suicide and control subjects were relatively widespread, whereas 5-HT(2A) and 5-HT(2C) variations were restricted to the frontopolar cortex and amygdala. Within the dorsal raphe nucleus, neither 5-HT(1A) 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 between serotonin 4 gene polymorphisms and attention deficit hyperactivity disorder comorbid or not comorbid disruptive behavioral disorder / 北京大学学报(医学版)

T were genotyped by restriction fragment length polymorphism analysis.Transmit/disequilibrium test and haplotype analysis were used to test the association of the three polymorphisms with ADHD comorbid or not comorbid DBD separately.Results:Haplotype T/G/T showed tendency of overtransmission(?2=3.470,P=0.062) to probands of ADHD with DBD, while haplotype C/G/T(?2=4.568,P=0.032) and C/G/C(?2=5.333,P=0.021) were undertransmitted to probands of ADHD without DBD,No biased transmissions of any allele were found in families with probands of ADHD with and without DBD.Conclusion:whether ADHD comorbid DBD or not comorbid DBD makes difference at the level of HTR4 gene polymrohisms.

In situ hybridization analysis of mRNA expression of 5-Hydroxytryptamine_4 receptor in intestinal mucosa mast cells / 北京大学学报(医学版)

Objective: To verify 5-HT4 receptor mRNA expression in intestinal mucosa mast cells (IMMC). Methods: IMMC was isolated from the whole intestines of normal rats by collagenase digestion and purified by percoll. In situ hybridization was performed to detect the expression of 5-HT4 receptor mRNA in IMMC. Results: Evidently positive staining was shown in the cytoplasm of IMMC. Conclusion: We have verified the expression of 5-HT4 receptor mRNA in IMMC for the first time and provided evidence for further research.

Association between serotonin 1D gene polymorphisms and attention deficit hyperactivity disorder comorbid or not comorbid disruptive behavior disorder / 北京大学学报(医学版)

G. The current results indicate that ADHD with DBD has more heritable backgrounds when compared with ADHD without DBD.

Association between serotonin 2C gene polymorphisms and attention deficit hyperactivity disorder comorbid or not comorbid with learning disorder / 北京大学学报(医学版)

Objective: To investigate the relationship between two HTR2C gene polymorphisms, that is C 759T and G 697C polymorphisms, and attention deficit hyperactivity disorder (ADHD) comorbid or not comorbid learning disorder (LD). Methods: Blood samples were taken from 189 trios with probands of ADHD comrbid LD (ADHD+LD) and 299 trios with probands of ADHD not comorbid LD (ADHD-LD). DNA was extracted and PCR was performed to amplify the fragments containing both C 759T and G 697C polymorphisms. Aci Ⅰ was used to detect different alleles of the two polymorphisms. Allele based and haplotype based TDT analysis were used to test the association of the two polymorphisms of HTR2C gene and ADHD-LD and ADHD+LD. Results: 759C(? 2= 6.961 , P =0.008), 697G(? 2=8.346, P =0.004), as well as 759C/ 697G haplotype were over transmitted(? 2=9.000, P = 0.002 7), while haplotype 759T/ 697C was under transmitted(? 2= 7.784 , P =0.005 3) to probands with ADHD-LD. No biased transmission of any allele and haplotype were found in families with probands of ADHD+LD. Conclusion: ADHD-LD and ADHD+LD are different at the level of HTR2C gene polymrohisms of C 759T and G 697C. HTR2C is related to ADHD-LD, while not related to ADHD+LD.

Binding capacity of 5-HT_(1A) receptor in central nervous system and hypertension in rats / 第二军医大学学报

40 weeks old SHR did not differ from that in slices of age matched WKY. B max was increased in the same brain region of SHR when compared to WKY. That rats of 4 5 weeks were in prehypertensive stage;rats of 10 12 weeks and above were at the stage of establishing hypertensive stage. Conclusion: The difference between SHR and normotensive rats in 5 HT 1A receptor binding in various brain regions may be related to the development of hypertension. When blood pressure changes,binding capacity of 5 HT 1A receptor in CNS changes accordingly.

Effects of 5-HT and Norepinephrine on the Neuronal Activities of the Nucleus Tractus Solitaril in Medullary Slices / 第二军医大学学报

The relationship between 5-HT receptor and a-adrenoceptor was investigated in rat medullary slice preparations. In 57 nucleus tractus solitarii (NTS) neurons, 47 (82.5%) responded to both serotonin (5-HT) and norepinephrine (NE). After synapse transmission was blocked by perfusion of artificial cerebrospinal fluid (ACSF) with low calcium and high magnesium, 5 in 8 neurons were still sensitive to both 5-HT and NE. On the other hand, 3 in 5 neurons responding only to 5-HT or NA were sensitive to both 5-HT and NE after the synapse transmission blockage. In some neurons which exhibited excitatory or inhibitory responses to 5-HT or NE alone, the responses were inversed when perfused with 5-HT and NE in combination. These results suggest that there may exist an inhibitory interaction between 5-HT receptors and a-adrenoceptors in NTS and that most 5-NT and a-adrenoceptors coexist in the same NTS neurons.