No association between two polymorphisms at the 5HT2A gene and bipolar affective puerperal psychosis

OBJECTIVE: To examine whether variation at two common polymorphisms, T102C and -1438AG, of the serotonin 2A gene (5HT2A) are involved in the puerperal triggering mechanism of bipolar affective puerperal psychosis. METHOD: A total of 242 parous women diagnosed with bipolar disorder were genotyped for the two polymorphisms. Of these, 165 women had experienced a manic or psychotic episode, according to DSM-IV criteria, within 6 weeks of childbirth (the puerperal psychosis group). The comparison group comprised of 77 parous women who had not experienced psychiatric disturbance following childbirth. RESULTS: No significant differences between genotype or allelic frequencies were found between the two groups for either polymorphism. CONCLUSION: The results indicate that variation at two common polymorphisms of the 5HT2A gene does not appear to play a major role in the development of bipolar affective puerperal psychosis.     

Endogenous cannabinoid,anandamide, acts as a noncompetitive inhibitor on 5-HT3 receptor-mediated responses in Xenopus oocytes

The cloned 5-HT3 receptor from NCB-20 neuroblastoma cells was expressed in Xenopus oocytes and the effect of the endogenous cannabinoid ligand, anandamide, was investigated on the function of this receptor. The oocytes expressing the cloned 5-HT3 receptors were voltage-clamped at -70 mV. Anandamide, at the concentration range of 0.1-100 microM, reversibly inhibited 1 microM 5-HT induced currents. The inhibition of 5-HT induced currents by anandamide was concentration-dependent with an EC50 of 3.7 microM and slope value of 0.94. This inhibitory effect was not dependent on the membrane potential and anandamide did not have an effect on the reversal potential of 5-HT-induced currents. In the presence of 10 microM anandamide, the maximum 5-HT-induced response was also inhibited and the respective EC50 values were 3.4 microM and 3.1 microM in the absence and presence of anandamide, indicating that anandamide acts as a noncompetitive antagonist on 5-HT3 receptors. CB1 receptor antagonist SR-141716A (1 microM) and pertussis toxin (5 microg/ml) did not cause a significant change on the inhibition of 5-HT responses by anandamide. The effect of anandamide was not changed by preincubating the oocytes with 0.2 mM 8-Br-cAMP, a membrane-permeable analog of cAMP, or Sp-cAMPS (0.1 mM), a membrane-permeable protein kinase A activator. These results suggest that the effect of anandamide is independent of the activation of cAMP pathway and not mediated by the activation of PTX sensitive G-proteins. In conclusion, we demonstrated that the endogenous cannabinoid anandamide inhibits the function of 5-HT3 receptors expressed in Xenopus oocytes in a cannabinoid-receptor independent and noncompetitive manner.     

5-HT(3) receptors and neurotransmitter release in the CNS: a nerve ending story?

Serotonin (5-HT) 5-HT₃ receptors are ligand-gated ion channels, which are generally thought to be involved in the presynaptic modulation of neurotransmitter release. However, analysis of published data reveals that most of the evidence for the alleged presynaptic role of 5-HT₃ receptors in modulating CNS neurotransmitter release is not compelling. Nevertheless, 5-HT₃ receptors are present in nerve terminals from some brain regions. The increased basic knowledge of the cellular physiology of central 5-HT₃ receptor ligand-gated ion channels provides opportunities for a detailed characterization of the specific presynaptic effects of 5-HT₃ receptors. Such reconsideration is required for the full appreciation of the functional role of 5-HT₃ receptors in the CNS.     

Synthesis and in vivo evaluation of [O‐methyl‐11C] 2‐(4‐methoxyphenyl)‐N‐(4‐methylbenzyl)‐N‐(1‐methyl‐ piperidin‐4‐yl)acetamide as an imaging probe for 5‐HT2A receptors

2‐(4‐Methoxyphenyl)‐N‐(4‐methylbenzyl)‐N‐(1‐methylpiperidin‐4‐yl)acetamide (AC90179, 4 ), a highly potent and selective competitive 5‐HT_2A antagonist, was labeled by [¹¹C]‐methylation of the corresponding desmethyl analogue 5 with [¹¹C]methyl triflate. The precursor molecule 5 for radiolabeling was synthesized from p‐tolylmethylamine in three steps with 46% overall yield. [¹¹C]AC90179 was synthesized in 30 min (30 ± 5% yield, EOS) with a specific activity of 4500 ± 500 Ci/mmol and >99% chemical and radiochemical purities. Positron emission tomography studies in anesthetized baboon revealed that [¹¹C] 4 Penetrates the blood–brain barrier (BBB) with a rapid influx and efflux of the tracer in all brain regions. Due to lack of tracer retention or specific binding, [¹¹C] 4 cannot be used as PET ligand for imaging 5‐HT_2A receptors. Copyright © 2006 John Wiley & Sons, Ltd.     

中药专业实验室建设初探

在对上海中医药大学中药学院实验教学改革试点工作回顾和分析的基础上,认为中药专业的实践教学改革应该从转变教学观念和中药专业课程体系改革为先导,通过实验课单列,推进“渐进板块教育模式”等改革措施,改革实验室管理体制和运行机制,逐步将其建设成为承担实验教学、科学研究和社会服务的开放式实验室。     

Hippocampal asymmetry in the behavioral responses to the 5-HT1A receptor agonist 8-OH-DPAT

The present study examined the behavioral responses of rats to unilateral and bilateral injections of the selective serotonin 1A (5-HT1A)-receptor agonist 8-hydroxydipropylaminotetralin hydrobromide (8-OH-DPAT) 1 μg into the hippocampal CA1 area of male Wistar rats. 8-OH-DPAT increased locomotor activity, which was most pronounced with injections into the left hippocampus. The agonist impaired learning and memory (shuttle-☐), especially when injected into the right hippocampus. The elevated plus-maze experiments showed that neither left nor right nor bilateral hippocampal injections of 8-OH-DPAT produced any anxiogenic effect. However, with Vogel's conflict test, right injections of 8-OH-DPAT produced anxiety. The present study has revealed hippocampal asymmetry in the behavioral responses to the 5-HT1A-receptor agonist 8-OH-DPAT.     

Developmental exposure to terbutaline and chlorpyrifos: pharmacotherapy of preterm labor and an environmental neurotoxicant converge on serotonergic systems in neonatal rat brain regions

Developmental exposure to unrelated neurotoxicants can nevertheless produce similar neurobehavioral outcomes. We examined the effects of developmental exposure to terbutaline, a tocolytic beta2-adrenoceptor agonist used to arrest preterm labor, and chlorpyrifos (CPF), a widely used organophosphate pesticide, on serotonin (5HT) systems. Treatments were chosen to parallel periods typical of human developmental exposures, terbutaline (10 mg/kg) on postnatal days (PN) 2-5 and CPF (5 mg/kg) on PN11-14, with assessments conducted on PN45, comparing each agent alone as well as sequential administration of both. Although neither treatment affected growth or viability, each elicited similar alterations in factors that are critical to the function of the 5HT synapse: 5HT1A receptors, 5HT2 receptors, and the presynaptic 5HT transporter (5HTT). Either agent elicited global increases in 5HT receptors and the 5HTT in brain regions possessing 5HT cell bodies (midbrain, brainstem) as well as in the hippocampus, which contains 5HT projections. For both terbutaline and CPF, males were affected more than females, although there were some regional disparities in the sex selectivity between the two agents. Both altered 5HT receptor-mediated cell signaling, suppressing stimulatory effects on adenylyl cyclase and enhancing inhibitory effects. When animals were exposed sequentially to both agents, the outcomes were no more than additive and, for many effects, less than additive, suggesting convergence of the two agents on a common set of developmental mechanisms. Our results indicate that 5HT systems represent a target for otherwise unrelated neuroteratogens.     

Behavior of new type of rock wool (HT wool) in lungs after exposure by nasal inhalation in rats

Objectives Previous types of rock wool has been recently replaced with high-temperature wool (HT wool). HT wool is characterized by a chemical composition with a higher concentration of Al₂O₃ and a lower concentration of SiO₂, lower biopersistence, and a higher melting point than previous types of rock wool. To evaluate the safety of HT wool, an asbestos substitute, we examined the biopersistence of HT wool in the lungs, based on changes in fiber count according to the length and fiber size (length and width), by performing a nose-only inhalation exposure study in rats. Methods Male Fischer 344 rats were exposed to fibers at the target exposure concentration of 30 mg/m³ continuously for 3 hours daily for 5 consecutive days. Rats were sacrificed shortly after exposure, and 1, 2, and 4 weeks after exposure, and their lung tissues were incinerated at a low temperature. Then, fiber counts and sizes in the lungs were analyzed using a phase contrast microscope. Results The fiber count in the lungs 4 weeks after exposure significantly decreased from the baseline value (shortly after exposure). The half-life of fibers calculated from the approximation curve was 34 days for all fibers and 11 days for fibers longer than 20 μm. Conclusions Both the length and width significantly decreased 4 weeks after exposure, probably because fibers were ingested by alveolar macrophages, discharged to outside of the body by mucociliary movement, or lysed by body fluid. In future studies, it is necessary to examine the long-term persistence of fibers in the lungs.     

The role of hypothalamic serotonin (5HT) before ovulation in immature rats treated with pregnant mare serum (PMS).

(1) PCPA methyl ester (10 mg/rat i.p.) inhibits induced ovulation in immature rats treated with pregnant mare serum (PMS). It also suppresses the preovulatory surges of LH and FSH, but not those of oestradiol or progesterone. (2) There is an increase in hypothalamic 5HT levels in the aftermoon and hypothalamic 5HIAA levels in the evening of the two days studied (days 28 and 29 of life). This occurs whether or not PMS was given on day 27. (3) The antiovulatory effects of PCPA are only seen when it is given on the afternoon or evening of the day before the pre-ovulatory gonadotrophin surge, i.e. on day 28 over the period of raised hypothalamic 5HT metabolism. (4) PCPA reduces 5HT metabolism in the hypothalamus within 2 hr of administration and its anti-ovulatory effect can be overcome by 5-hydroxytryptophan. This indicates that hypothalamic 5HT activity is essential for the gonadotrophin surge. (5) The anti-ovulatory effect of PCPA can be overcome by progesterone, LH and FSH but not oestradiol.     

Reduction in 5-HT1A receptor density, 5-HT1A mRNA expression, and functional correlates for 5-HT1A receptors in genetically defined aggressive rats

The present experiments tested the hypothesis that one of the critical mechanisms underlying genetically defined aggressiveness involves brain serotonin 5-HT1A receptors. 5-HT1A receptor density, the receptor mRNA expression in brain structures, and functional correlates for 5-HT1A receptors identified as 8-OH-DPAT-induced hypothermia and lower lip retraction (LLR) were studied in Norway rats bred for 59 generations for the lack of aggressiveness and for high affective aggressiveness with respect to man. Considerable differences between the highly aggressive and the nonaggressive rats were shown in all three traits. A significant decrease in B(max) of specific receptor binding of [3H]8-OH-DPAT in the frontal cortex, hypothalamus, and amygdala and a reduction in 5-HT1A receptor mRNA expression in the midbrain of aggressive rats were found. 5-HT1A receptor agonist 8-OH-DPAT (0.5 mg/kg, i.p.) produced a distinct hypothermic reaction in nonaggressive rats and did not affect significantly the body temperature in aggressive rats. Similar differences were revealed in 8-OH-DPAT-induced LLR: LLR was expressed much more in nonaggressive than in aggressive animals. Additionally, 8-OH-DPAT (0.5 mg/kg i.p.) treatment significantly attenuated the aggressive response to man. The results demonstrated an association of aggressiveness with reduced 5-HT1A receptor expression and function, thereby providing support for the view favoring the idea that brain HT1A receptor contributes to the genetically defined individual differences in aggressiveness.