5-HT_(2C)受体的螺旋结构与功能

5-羟色胺(5-HT)是动物中枢神经和外周神经系统中重要的递质〔1〕,在人的中枢神经系统中调节人体的许多活动;在非神经组织中,5-HT也同样起重要作用。迄今为止,在人类的中枢神经系统已经发现了14种5-HT受体亚型,即5-HT1A,5-HT1B,5-HT1D,52HT1E,5-HT1F,5-HT2A,5-HT2B,5-HT2C,5-HT3     

5-HT_(1A)受体激动剂乌拉地尔对吗啡依赖大鼠戒断反应的抑制作用

目的··：观察５－ＨＴ１Ａ受体激动剂乌拉地尔（ｕｒａｐｉｄｉｌ）和８－ＯＨ－ＤＰＡＴ及阿片μ受体激动剂美沙酮（ｍｅｔｈａｄｏｎｅ）对吗啡戒断反应的影响。方法··：采用吗啡依赖大鼠模型侧脑室注射上述药物,并用腹腔注射纳洛酮诱发戒断反应,记录戒断症状。结果··：侧脑室注射乌拉地尔可明显抑制纳洛酮诱发的吗啡躯体戒断反应,并呈量效关系。乌拉地尔抑制吗啡戒断反应的作用与８－ＯＨ－ＤＰＡＴ的作用一致。此效应与美沙酮的作用相比也基本相同。结论··：乌拉地尔通过激活５－ＨＴ１Ａ受体可以抑制吗啡戒断反应。     

河豚毒素对大鼠和小鼠纳洛酮催促吗啡戒断症状的影响

通过建立吗啡 (Mor)依赖大鼠及小鼠模型 ,观察河豚毒素 (TTX ,大鼠 0 .0 0 3～ 0 .1μg·kg- 1·d- 1,im ,5d ;小鼠 0 .0 2～ 0 .2 μg·kg- 1·d- 1,ip ,2d)对纳洛酮 (Nal)催促戒断症状的预防及治疗作用 .结果表明TTX抑制戒断后大鼠体重丢失 ;明显抑制Mor依赖小鼠Nal催促后的跳台反应 ,并促进催促后小鼠体重的恢复 .证实TTX可显著抑制Mor依赖大鼠和小鼠Nal激发的戒断反应 ,其效果与可乐定相近 .在防治戒断症状的有效剂量范围内 ,TTX不影响麻醉大鼠的血压 ,呼吸和心率 ,也不影响尼古丁诱发的神经反射活动 ,对痛觉反应和中枢神经系统无明显抑制作用 .     

海洛因依赖与5-HT_(2A)受体基因-1438A/G多态性的相关研究

目的 :探讨海洛因依赖和 5 -羟色胺 2A (5 -HT2A)受体基因 - 14 38A G多态性的关系。方法 :采用聚合酶链式反应 (polymerasechainreaction ,PCR)技术 ,检测 2 6 5例海洛因依赖者和 195例正常对照的 5 -HT2A 受体基因 -14 38A G多态性。结果 :海洛因依赖者和对照组之间 5 -HT2A受体基因 - 14 38A G多态性的基因型和等位基因频率的差异均无显著性 (χ2 值分别为 3.2 3,P >0 .0 5和 0 .0 0 1,P >0 .0 5 )。结论 :5 -HT2A 受体基因 - 14 38A G多态性和海洛因依赖的易感性无关     

中枢5－羟色胺对大鼠吗啡戒断反应的影响

本实验对吗啡依赖大鼠侧脑室注射５—ＨＴ受体激动剂，可增强其戒断反应强度，并呈量效关系。而注射５—ＨＴ受体阻断剂肉桂硫胺时，则减轻其戒断反应程度，也呈量效关系。同时还发现用５—ＨＴ化学切断剂５，６－双羟色胺破坏大鼠中缝５—ＨＴ神经元后，吗啡戒断反应显著减弱。因此５－ＨＴ受体阻断剂和５—ＨＴ化学切断剂可对开发临床脱毒治疗药物提供有意义的参考。     

5-HT_(2A)受体基因1438A/G多态性与海洛因依赖的关系

目的··:探讨5 -HT2A 受体基因多态性与海洛因依赖易感性的关系。方法··:用聚合酶链式反应 (PCR)技术结合限制性片段长度多态性 (RFLP)分析技术 ,检测了99名海洛因依赖者和80名正常对照者5 -HT2A 受体基因1438A/G多态性的基因型和等位基因频率。结果··:海洛因依赖者5 -HT2A 受体基因1438A/G多态性基因型A1/A2的频率较对照组高。结论··:5 -HT2A 受体基因1438A/G多态性可能与海洛因依赖的易感性有关     

脱瘾扶正康对吗啡依赖大小鼠戒断症状的治疗作用

目的：观察及评价中药制剂脱瘾扶正康对吗啡依赖大小鼠戒断症状的治疗作用。方法：以剂量递增法形成吗啡依赖大小鼠模型,ｉｐ纳洛酮进行催促或自然戒断后,记录成瘾动物的戒断症状及体重变化,所得数据经统计学处理后进行评价。结果：脱瘾扶正康低、中、高三个剂量组均可明显降低成瘾大鼠纳洛酮催促戒断及自然戒断泊总分值,减少成瘾小鼠的跳跃反应次数,对吗啡依赖大、小鼠的体重下降有不同程度的缓解作用。脱瘾扶正康对吗啡依赖大     

5-羟色胺受体基因多态性与海洛因依赖的关系

目的獉獉:探讨5-HT1A受体基因(5-HTR1A)-1019C/G、5-HT1B受体基因(5-HTR1B)-681G/C、5-HT6受体基因(5-HTR6)-267C/T的多态性与海洛因依赖易感性的关系。方法獉獉:用聚合酶链反应-限制性片段长度多态性(PCR-RFLP)技术,检测70例海洛因依赖者(轻度依赖者、重度依赖者)和108例健康对照者的3个基因位点的基因型。结果獉獉:海洛因轻度依赖组和重度依赖组、依赖组和对照组之间3个位点的基因型和等位基因频率均无显著性差异。结论獉獉:没有证据表明5-HTR1A-1019C/G、5-HTR1B-681G/C和5-HTR6-267C/T的多态性与海洛因依赖易感性有关。     

5-HT_(1A)受体激动剂乌拉地尔对吗啡依赖大鼠前列腺组织的病理学影响

目的··:观察5-HT1A 受体激动剂乌拉地尔对吗啡依赖大鼠前列腺的组织学影响。方法··:皮下注射(sc)5d吗啡 ,建立吗啡依赖大鼠模型 ;实验组分别进行侧脑室注射 (icv)乌拉地尔和继续sc吗啡。实验后将前列腺组织作HE染色后在光镜下观察。结果··:吗啡依赖大鼠的前列腺组织有轻度萎缩 ,吗啡依赖大鼠自然戒断后前列腺有明显增生 ,icv乌拉地尔可抑制吗啡戒断大鼠的前列腺组织增生。结论··:乌拉地尔可抑制吗啡戒断大鼠前列腺组织的增生     

芋螺多肽conantokins及其类似物对小鼠吗啡戒断症状的抑制作用

目的:观察及评价NMDA受体抑制剂芋螺多肽conantokins及其类似物对吗啡依赖小鼠催促戒断症状的抑制作用。方法:采用剂量递增法皮下注射吗啡7d,建立吗啡依赖小鼠模型。观察conantokin及类似物con-G(2.5,5,10,15nmol·kg-1,icv),con-G[S16Y]〗(15nmol·kg-1,icv),con-R(1-17)(15,30nmol·kg-1,icv),对照药美金胺(46.3μmol·kg-1,ip)以及艾芬地尔(1.25μmo·lkg-1,icv;25μmol·kg-1,ip)对吗啡依赖小鼠纳洛酮催促戒断的跳跃次数及体重的影响。结果:与吗啡依赖组相比,icv15nmo·lkg-1con-G使吗啡依赖小鼠平均跳跃次数减少89.0%,并呈剂量依赖性(2.5-15nmo·lkg-1);icv15nmol·kg-1con-G[S16Y]〗可完全抑制吗啡依赖小鼠戒断跳跃。con-R(1-17)(15-30nmol·kg-1,icv)使吗啡依赖小鼠平均跳跃次数仅减少40.2%-58.3%。结论:con-G、con-G[S16Y]〗和con-R(1-17)对抑制小鼠的戒断症状非常有效。相对于con-R(1-17),con-G和con-G[S16Y]〗对小鼠的戒断症状的抑制作用更强,这是由于con-G、con-G[S16Y]〗对NMDA受体NR2B亚基的选择性更高。Conantokins及其类似物在抑制吗啡依赖方面很有潜力。     

Modification by muscimol of naloxone-precipitated withdrawal symptoms in morphine-dependent mice

• 1.1. In morphine-dependent mice, muscimol, a GABAA agonist when given i.p. 30 min before naloxone, attenuated the naloxone-precipitated withdrawal symptoms of jumping, “wet dog” shakes and burrowing, but not body weight loss.
• 2.2. Muscimol produced a hypothermic effect which was further aggravated by naloxone.

     

Neuropeptide trefoil factor 3 attenuates naloxone-precipitated withdrawal in morphine-dependent mice

Rationale

The persistence of physical dependence and craving in addicts is considered to contribute to relapse. Increasing evidence indicates that neuropeptide systems are associated with several phases of drug addiction, but little is known about whether the neuropeptide trefoil factor affects withdrawal symptoms.

Objectives

This study aims to investigate the potential effects of the neuropeptide trefoil factor 3 (TFF3) on naloxone-precipitated withdrawal symptoms in morphine-dependent mice.

Results

Mice received increasing doses of morphine over 3 days. On day 4, the mice were injected with TFF3 (1.0 mg/kg, i.p.) 30 min after the last dose of morphine. Thirty minutes after TFF3 treatment, naloxone (1 mg/kg, i.p.) was injected, and body weight, jumping behavior, wet-dog shakes, and locomotor activity were assessed 30 min later. Naloxone caused significant weight loss and increased jumping behavior and wet-dog shakes in morphine-dependent mice. TFF3 (1.0 mg/kg) reversed these behavioral symptoms caused by morphine withdrawal, suggesting that TFF3 might ameliorate physical dependence associated with opiate addiction. Furthermore, TFF3 pretreatment significantly reduced morphine withdrawal-induced increases in plasma corticosterone and adrenocorticotropic hormone levels. The glucocorticoid receptor agonist RU486 blocked the behavioral effects of TFF3 on morphine withdrawal symptoms. Finally, Fos expression in the medial prefrontal cortex which was decreased during morphine withdrawal was increased by TFF3 pretreatment.

Conclusion

These findings indicate that TFF3 might be a potential therapeutic candidate for opiate addiction by regulating glucocorticoid secretion and neuronal activation in the prefrontal cortex.     

Suppression of naloxone-precipitated withdrawal jumps in morphine-dependent mice by stimulation of prostaglandin EP3 receptor.

1. We have shown that intracisternal (i.c.) administration of interleukin-1 beta (IL-1 beta) attenuates naloxone-precipitated withdrawal jumps in morphine-dependent mice, and the effect was partly mediated by the corticotropin-releasing factor. To elucidate further other possible mechanisms involved in the inhibitory effect of IL-1 beta on morphine withdrawal jumping behaviour, in this study, we examined the involvement of the prostaglandin-synthesis pathway, because prostaglandins have been shown to mediate the several central effects of IL-1. Furthermore, we examined the effects of subtype-selective prostaglandin receptor agonists on morphine withdrawal jumping behaviour. 2. Mice were rendered morphine-dependent by subcutaneous implantation of a pellet containing 11.5 +/- 0.3 mg morphine hydrochloride for 48 h. Morphine withdrawal syndromes were precipitated by intraperitoneal (i.p.) injection of naloxone (10 mg kg-1). The degree of physical dependence on morphine was estimated by counting the number of jumps, one of the typical withdrawal signs in mice, for 40 min. 3. The inhibitory effect of IL-1 beta (1 ng/mouse) administered intracisternally 30 min before naloxone (10 mg kg-1, i.p.) was significantly blocked by pretreatment with sodium salicylate (a cyclo-oxygenase inhibitor, 10 ng or 30 ng/mouse) administered intracisternally 15 min before IL-1 beta, while i.c. administration of sodium salicylate alone (3 ng, 10 ng or 30 ng/mouse) followed by i.c. administration of vehicle instead of IL-1 beta did not significantly change the number of jumps precipitated by naloxone. 4. Intracisternal administration of M&B28,767 (an EP3-receptor agonist, 1 fg-30 ng/mouse) and sulprostone (an EP1/EP3-receptor agonist, 10 fg-100 ng/mouse) 30 min before naloxone (10 mg kg,-1 i.p.) attenuated withdrawal jumps with a U-shaped dose-response, reaching a peak at 10 pg/mouse and 100 pg/mouse, respectively. On the other hand, i.c. administration of iloprost (an EP1/IP-receptor agonist, 10 fg-100 ng/mouse), butaprost (an EP2-receptor agonist, 10 fg-100 ng/mouse) or prostaglandin F2 alpha (a FP-receptor agonist, 10 fg-100 ng/mouse) 30 min before naloxone (10 mg kg-1, i.p.) did not significantly change the number of jumps precipitated by naloxone. 5. These results indicate that the prostaglandin-synthesis pathway is, at least in part, involved in the inhibitory effect of IL-1 beta on naloxone-precipitated withdrawal jumps in morphine-dependent mice, and that the prostaglandin synthesized in the brain suppresses the morphine withdrawal jumping behaviour via the EP3-receptor, but not via the EP1-, EP2-, IP- or FP-receptor.     

REM sleep deprivation (REMSD) antagonizes naloxone-precipitated withdrawal in acute morphine-dependent rats

In rats allowed undisturbed sleep (control and stress) the administration of naloxone (10 mg/kg, s.c.) to morphine (7.5 mg/kg, s.c. 90 min prior) pretreated animals precipitated a jumping behaviour. REM sleep deprivation (REMSD 96 h, prior) significantly decreased the frequency of the naloxone-precipitated jumping behaviour compared with control and stressed animals. In second animal model for morphine withdrawal, naloxone (10 mg/kg, s.c.) provoked myoclonic twitch activity (MTA) in rats previously exposed to morphine (7.5 mg/kg, s.c., 90 min prior). The intensity of naloxone-induced MTA in REM sleep deprived rats was significantly lower compared to stressed animals, but it is not different from the control group. It is suggested that REMSD interferes with a neural mechanism involved in the development of acute dependence. Results are discussed in light of a possible functional insufficiency of a mu-opioid system during REMSD.     

Modification of the expression of naloxone-precipitated withdrawal signs in morphine-dependent mice by diabetes: possible involvement of protein kinase C

The involvement of cyclic AMP-dependent protein kinase (PKA) and protein kinase C (PKC) in the modulation of naloxone-precipitated withdrawal jumping in morphine-dependent mice by diabetes was examined. Naloxone-precipitated withdrawal jumps were significantly less in morphine-dependent diabetic mice than in morphine-dependent non-diabetic mice. I.c.v. pretreatment with either calphostin C, a PKC inhibitor, or KT-5720, a PKA inhibitor, attenuated naloxone-precipitated withdrawal jumps in morphine-dependent non-diabetic mice. However, naloxone-precipitated withdrawal jumps in morphine-dependent diabetic mice were not attenuated by i.c.v. pretreatment with either calphostin C or KT5720. Moreover, i.c.v. pretreatment with phorbol-12,13-dibutyrate (PDBu), a PKC activator, attenuated naloxone-precipitated withdrawal jumps in morphine-dependent non-diabetic mice, but not in morphine-dependent diabetic mice. The noradrenaline (NA) turnover in the frontal cortex in morphine-dependent non-diabetic mice, but not in morphine-dependent diabetic mice, was significantly increased 5 min after administration of naloxone. Naloxone-induced enhancement of NA turnover in morphine-dependent non-diabetic mice, but not in morphine-dependent diabetic mice, was blocked by i.c.v. pretreatment with either calphostin C or KT5720 1 hr before naloxone challenge and blocked by PDBu 1 hr before the last injection of morphine. These results suggest that the co-activation of PKC and PKA is needed to elicit naloxone-precipitated withdrawal jumps and enhancement of turnover rate of NA in the frontal cortex in morphine-dependent non-diabetic mice. Furthermore, the attenuation of naloxone-precipitated withdrawal jumps in morphine-dependent diabetic mice may be due, in part, to the desensitization of mu-opioid receptors by the activation of PKC.     

Selective agents for serotonin2C (5-HT2C) receptor

The serotonin2C (5-HT2C) receptor has attracted a lot of attention owing to its role in appetite regulation, depression, obsessive-compulsive disorder (OCD), panic disorders, and substance abuse. This review summarizes non-patent and patent literature up to November 2005 that deals with the synthesis and characterization of selective 5-HT2C receptor agonists and antagonists. Highlights on structure-activity relationships have been included, when possible.     

Effect of some cannabinoids on naloxone-precipitated abstinence in morphine-dependent mice

Mice were rendered morphine-dependent by the subcutaneous implantation of a pellet containing 75 mg of morphine base; 72 h after the implantation, the animals were injected intraperitoneally either with vehicle or with various doses of ₉-tetrahydrocannabinol, ₈-tetrahydrocannabinol, cannabidiol, cannabinol, or 11-hydroxy-₈-tetrahydrocannabinol. Thirty minutes after injection of the cannabinoids, the antagonist, naloxone HCl, was administered to induce the stereotyped withdrawal jumping syndrome. The dose of naloxone needed to induce withdrawal jumping in 50% of the animals (ED₅₀) was determined for each dose of the cannabinoids. All of the cannabinoids inhibited the naloxone-precipitated morphine abstinence as evidenced by an increase in the naloxone ED₅₀. Two additional signs of morphine abstinence, defecation and rearing behavior, were also suppressed by the cannabinoids. The relative effectiveness of the cannabinoids in inhibiting morphine abstinence appeared to be in the following order: ₉-tetrahydrocannabinol > ₈-tetrahydrocannabinol > 11-hydroxy-₈-tetrahydrocannabinol > cannabidiol > cannabinol.These data suggest that cannabinoids may be useful in facilitating narcotic detoxification.     

Effect of NMDA receptor antagonist on naloxone-precipitated withdrawal signs in cholestatic mice

The ability of NMDA antagonist MK-801 to block the expression of opioid-like withdrawal signs was examined in bile duct-ligated mice and the signs were compared with sham operated and unoperated animals. Administration of MK-801 (0/1 mg/kg), 10 min prior to naloxone challenge, significantly reduced the investigated withdrawal signs (jumping, diarrhoea, grooming and climbing) in bile duct-ligated animals. Chronic administration (five consecutive days) of MK-801 (0/1 mg/kg) also decreased all the withdrawal signs in the experimental animals. In an independent series of experiments, the effect of acute and chronic administration of MK-801 on tail-flick latency was investigated in bile duct-ligated animals. Pretreatment with the drug significantly decreased the antinociception induced by bile duct ligation in the mice. The results of this study support evidence for the involvement of the NMDA receptor in yopioidergic-dependent manifestations in a model of obstructive cholestasis. Copyright 2000 John Wiley & Sons, Ltd.     

Modification of naloxone-precipitated withdrawal symptoms in mice by drugs acting on alpha(2)-adrenoceptors

Modification of naloxone-precipitated withdrawal symptoms by drugs acting on alpha-adrenoceptors was investigated in morphine-dependent mice. Clonidine (0.05-1mg/kg) attenuated most withdrawal symptoms, but potentiated withdrawal hypothermia. Jumping was attenuated by doses of clonidine up to 0.3mg/kg, but markedly potentiated by 1mg/kg. Prazosin (0.05mg/kg) neither had effects of its own, nor influenced those of clonidine. Both yohimbine (0.05-5mg/kg) and idazoxan (1-10mg/kg) potentiated naloxone-precipitated withdrawal symptoms. When tested against a low dose of clonidine (0.2mg/kg), idazoxan dose-dependently reduced the suppressive effects of clonidine on jumping, "wet dog" shakes, burrowing and body-weight loss but potentiated the hypothermic response of clonidine. Yohimbine similarly reduced the suppressive effect of clonidine on body-weight loss and potentiated its hypothermic response, but unlike idazoxan, it did not influence the inhibition by clonidine of "wet dog" shakes, and markedly reversed the suppression of jumping and burrowing into potentiation. Yohimbine and idazoxan also differed with respect to their antagonistic profile against a high dose of clonidine (1mg/kg). Yohimbine further aggravated the potentiation of jumping by clonidine, reduced the effect on body-weight loss and reversed the suppression of burrowing by clonidine. On the other hand, idazoxan markedly reduced the potentiation of jumping by clonidine, and reversed its effect on "wet dog" shakes and burrowing. These findings indicate that clonidine has a biphasic effect on jumping, and disclose differences in the antagonistic profiles between yohimbine and idazoxan. The results suggest that in addition to alpha(2)-adrenoceptors, non-adrenergic imidazoline receptors sensitive to clonidine and idazoxan but not to yohimbine may modulate the expression of morphine withdrawal symptoms.