JL13 has clozapine-like actions on thermoregulatory cutaneous blood flow in rats: Involvement of serotonin 5-HT1A and 5-HT2A receptor mechanisms

Clozapine is an effective atypical antipsychotic agent, with serious side effects. JL13 [5-(4-methylpiperazin-1-yl)-8-chloropyrido[2,3-b][1,5]benzoxazepine] is a potential new atypical antipsychotic, structurally modified from clozapine to resist oxidation so as to reduce haematological and cardiological side effects. To assess the potential clinical potency of JL13 we tested its action in a newly described animal model based on the ability of clozapine-like agents to affect brain mechanisms controlling sympathetic outflow to thermoregulatory cutaneous vascular beds.     

《信息与文献 参考文献著录规则》（GB/T 7714—2015）部分条款解读

【目的】促进业界对GB/T 7714—2015《信息与文献参考文献著录规则》的准确理解和快速掌握。【方法】通过文献阅读、对比研究等方法,分析2015版修订的背景,并对其中的术语修订、中文人名的著录、新增的文献标识类型与“数字唯一标识符”等进行解读,对主要修订条款进行了列表汇总。【结果】肯定2015版成就的同时,分析其中存在的部分问题:术语提出的科学依据、与国际惯例是否一致、示例以及语言文字的疏漏等。【结论】2015版在术语的提出以及与国际惯例的一致性上,应采取更为科学客观的态度,同时应进一步完善示例及语言文字的表达。     

正常人及2型糖尿病患者下肢动脉弹性的相关危险因素分析

目的 应用血管回声跟踪(echo-tracking,ET)技术研究影响正常人及2型糖尿病患者下肢动脉弹性的相关危险因素.方法 选取30例正常人和68例2型糖尿病患者,应用ET技术检测股总动脉、腘动脉弹性指标:僵硬度指数(β).比较正常对照组及糖尿病组一般情况及生化指标的差异,并对影响β值的相关危险因素如年龄、血压、血脂指标采用简单线性回归及多无线性回归方法进行分析.结果 正常对照组及糖尿病组股总动脉、腘动脉的β值与年龄、收缩压有良好的相关性(P<0.05).糖尿病组股总动脉的β值与甘油三酯、低密度脂蛋白、载脂蛋白B、脂蛋白a有良好的相关性(P<0.05),胭动脉的β值与血脂指标相关性不明显(P>0.05).结论 2型糖尿病患者随着年龄、血压、血脂的升高,动脉僵硬度增加,弹性减低.     

氟西汀和氟哌啶醇对DOI诱导头部抽动的小鼠模型的作用

目的：建立并评价拟抽动秽语综合征动物模型,探讨氟西汀和氟哌啶醇对该动物模型的作用。方法：将40只小鼠随机分为实验组和对照组,实验组小鼠腹腔注射DOI建立抽动秽语综合征小鼠模型,对照组注射生理盐水。应用高效液相－电化学法检测脑纹状体内多巴胺及其代谢产物高香草酸的含量。将80只小鼠随机分为4组,分别注射氟西汀、氟哌啶醇、氟西汀加氟哌啶醇和等体积生理盐水,每组取10只给药20 min后注射DOI,通过急性实验观察药物的作用;另外10只给药21 d后注射DOI,通过慢性实验观察药物的作用。结果：与对照组比,DOI诱导的头部抽动小鼠纹状体内多巴胺和高香草酸含量降低（58.16±14.51 ng/mg vs 45.00±11.24 ng/mg,12.82±2.66 ng/mg vs 10.54±1.86 ng/mg,均 P<0.05）。无论是急性实验还是慢性实验,与生理盐水组相比,预先应用氟哌啶醇的小鼠注射DOI后抽动行为显著减少（P<0.05）,预先应用氟西汀的小鼠注射DOI后抽动行为无明显改变（P>0.05）。结论：DOI诱导的头部抽动小鼠脑内多巴胺神经递质含量减少,可部分模拟抽动秽语综合征病人的神经生化和行为学改变。氟哌啶醇可抑制DOI诱导的小鼠抽动行为,氟西汀无明显作用。［中国当代儿科杂志,2007,9（5）：469-472］     

Cessation of chronic nicotine administration enhances wet-dog shake responses to 5-HT2 receptor stimulation in rats

RATIONALE: The involvement of central serotonergic systems has been hypothesized clinically to contribute to nicotine withdrawal symptoms. However, involvement of the serotonin2 (5-HT(2)) receptor system in nicotine withdrawal is not clear. OBJECTIVES: The changes in wet-dog shake responses induced by (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI), a selective 5-HT(2) receptor agonist, following nicotine cessation was investigated in rats. METHODS: DOI (1 mg/kg SC) was administered 24 h after the final treatment of saline or nicotine (0.5 mg/kg per day SC) for 7 or 21 days. RESULTS: Cessation of nicotine administration for 7 or 21 days increased DOI-induced wet-dog shake responses. A single administration of nicotine (0.5 mg/kg SC) had no effect on DOI-induced wet-dog shakes. The enhancement by the cessation of nicotine treatment for 7 days was abolished by coadministration of nicotine. Mecamylamine (3 mg/kg IP), a nicotinic receptor antagonist, precipitated DOI-induced wet-dog shake responses in rats chronically treated with nicotine but not with saline. CONCLUSIONS: These findings suggest that cessation of chronic nicotine produced increased sensitivity to 5-HT(2) receptor systems, and that the 5-HT(2) receptor systems may be involved in the nicotine withdrawal symptoms.     

Pharmacological characterization of serotonin receptor subtypes involved in vasopressin and plasma renin activity responses to serotonin agonists

Serotonergic drugs with 5-HT₂ receptor agonist properties have been suggested to increase plasma vasopressin concentration, blood pressure (BP) and plasma renin activity (PRA). To study whether these actions are mediated by the same or different receptors, we used three potent 5-HT agonists with different structures and receptor binding profiles. All drugs were administered i.v. to conscious, unrestrained rats. The selective agonist, 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI), which has high affinity for 5-HT₂ receptors, caused marked increases in BP and PRA but no change in plasma vasopressin concentrations. The 5-HT_1C agonist, m-chlorophenylpiperazine (m-CPP), which also binds to other 5-HT receptors, caused moderate increases in BP and PRA and significantly elevated plasma vasopressin concentrations. The 5-HT_1A agonist, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), did not increase any of these parameters. BP and PRA elevations paralleled each other after all drugs, while vasopressin responses were clearly different. Vasopressin responses to m-CPP were entirely antagonised by the 5-HT₁/5-HT₂ antagonist metergoline, partially by the 5-HT₂/5-HT_1C antagonists ritanserin and LY 53857, but not by the 5-HT₂ antagonist ketanserin. Ritanserin, LY53857 and ketanserin all very effectively blocked BP responses to m-CPP. These findings suggest that BP and PRA but not vasopressin responses are mediated by 5-HT₂ receptors. Vasopressin secretion is mediated by 5-HT₁ receptors, most likely by 5-HT_1C receptors.     

Potentiation of DOI-induced forward locomotion in rats by (−)-pindolol pretreatment

Summary The present experiments were undertaken in order to examine mechanisms of action for reported interactions between the -blocker (–)-pindolol and serotonergic agents. It was found that pretreatment with (–)-pindolol (2mg kg^–1 s.c.) potentiated the stereotyped forward locomotion induced by the 5-HT_2a/c receptor agonist DOI (0.125–1.0mg kg^–1 s.c.) in rats observed in an open-field arena. This (–)-pindolol/DOI-induced stereotyped forward locomotion was fully antagonized by the 5-HT_2a/c receptor antagonist ritanserin (2mg kg^–1 s.c.), suggesting that (–)-pindolol enhances serotonin release, resulting i.a. in postsynaptic 5-HT_2a/c receptor activation. This effect by (–)-pindolol is in all probability indirect since this compound lacks affinity for 5-HT_2a/c receptors, and could be explained by reported antagonism of inhibitory serotonergic somato-dendritic 5-HT_1a autoreceptors, although other possibilities related to 5-HT_1b receptors or -adrenoceptors can not be excluded at this time. Furthermore, (–)-pindolol treatment also enhanced 5-HTP-induced (12.5–100 mg kg^–1 i.p.) effects on spontaneous motor activity. These effects, however, were of smaller magnitude, and less consistent than those seen in combination with DOI.     

Brain structures implicated in the four-plate test in naïve and experienced Swiss mice using injection of diazepam and the 5-HT2A agonist DOI

Four-plate test-retest (FPT-R) is a useful tool to study aversive memory and abolishment of benzodiazepine effects in experienced mice to four-plate test (FPT), namely one-trial tolerance. In the present study, we have used local injections paradigm, in order to localize structures implied in anxiolytic-like effects of two drugs in naïve and experienced mice: a benzodiazepine, diazepam that is only active in naïve mice; and a 5-HT_2A/2C agonist, DOI that exert its anxiolytic-like effect both in naïve and experienced mice. Periacqueductal grey substance, three sub-regions of hippocampus (CA1, CA2 and CA3) and two nuclei of amygdala (BLA and LA) have been studied. Local injections did not cause any modifications of ambulatory activity. DOI injections elicit anxiolytic-like effects only when injected into CA2, in naïve and experienced mice. Diazepam had an anxiolytic-like effect in naïve mice, only when injected into lateral nucleus of amygdala; and in experienced mice when injected into PAG. These results help us to better understand the way of action of these two compounds and the structures functionally involved in their effects and in one-trial tolerance (OTT).     

Activation of adenosine1 (A1) receptors suppresses head shakes induced by a serotonergic hallucinogen in rats

Modulation of glutamatergic neurotransmission by metabotropic glutamate2/3 (mGlu2/3) receptor agonists effectively treats seemingly diverse neuropsychiatric illness such as generalized anxiety disorder and schizophrenia. Activation of adenosine A₁ heteroceptors, like mGlu2 autoreceptors, decreases glutamate release in the medial prefrontal cortex (mPFC) and other limbic brain regions. Previously, we have reported electrophysiological, neurochemical and behavioral evidence for interactions between the 5-hydroxytryptamine_2A (5-HT_2A) and mGlu2/3 receptors in the mPFC. The present studies were designed to investigate the effects in rats of adenosine A₁ receptor activation/blockade on a behavior modulated by 5-HT_2A receptor activation/blockade in the mPFC: head shakes induced in the rat by phenethylamine hallucinogens. An adenosine A₁ receptor agonist, N⁶-cyclohexyladenosine (CHA) suppressed head shakes induced by activation of 5-HT_2A receptors with the phenethylamine hallucinogen (±)-2,5-dimethoxy-4-iodoamphetamine hydrochloride (DOI). An adenosine A1 receptor antagonist, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), enhanced DOI-induced head shakes and blocked the suppressant action of an adenosine A₁ receptor agonist on DOI-induced head shakes. Thus, the pattern of activity for an agonist and antagonist at the adenosine A1 receptor with respect to modulating DOI-induced head shakes is similar to the pattern observed with mGlu2/3 receptor agonists and antagonists. These novel observations with an adenosine A₁ receptor agonist suggest that this pharmacological action could contribute to antipsychotic effects in addition to thymoleptic effects.     

Direct and indirect 5-HT receptor agonists produce gender-specific effects on locomotor and vertical activities in C57 BL/6J mice

It is well established that the dopamine (DA) and serotonin (5-HT) systems have extensive and complex interactions. However, the effects of specific 5-HT receptor agonists on traditionally DA-related behaviors remain unclear. Our goal in these studies was to characterize the effects of 5-HT receptor agonists on measures of locomotor activity and vertical rearing. The SSRIs fluoxetine and citalopram produced significant decreases in locomotor activity and vertical rearing at the highest doses used with females significantly more sensitive to citalopram. The 5-HT_1A agonist 8-OH-DPAT and the 5-HT_2C agonist MK 212 significantly decreased activity in both male and female mice, with females more sensitive to 8-OH-DPAT. In contrast, the 5-HT_1B agonist RU 24969 and the 5-HT_2A agonist DOI both increased activity, with DOI exhibiting differential effects with regard to sex. Finally, the 5-HT₃ agonist SR 57227 produced significant locomotor increases only in female mice at the lowest dose. The results of these experiments define locomotor profiles of several 5-HT agonists in male and female C57BL/6J mice, providing a foundation for further explorations of 5-HT receptor effects on activity.