5-羟色胺1A受体激动剂8-OH-DPAT对癫痫合并抑郁大鼠的干预作用及其机制研究

目的 探讨5-羟色胺1A(5-HT1A)受体激动剂8-OH-DPAT对癫痫合并抑郁大鼠的干预作用及其机制.方法 成年级SD大鼠160只,随机选取8只为正常对照组,其余大鼠采用匹罗卡品诱导慢性癫痫大鼠模型.25 d后通过体质量与摄食量测量及旷场试验筛选出癫痫合并抑郁模型大鼠32只,随机分为模型组、卡马西平(CBZ)组、CBZ+ 8-OH-DPAT低剂量组(8-OH-DPAT低剂量组)及CBZ+ 8-OH-DPAT高剂量组(8-OH-DPAT高剂量组);分别给予CBZ 100 mg/kg、CBZ +8-OH-DPAT 0.1mg/(kg·d)、CBZ+ 8-OH-DPAT 1 mg/(kg·d).连续治疗7d后,进行癫痫发作的Racine分级、体质量、摄食量测量及旷场试验;采用荧光实时定量聚合酶链反应测定大鼠海马齿状回神经生长因子(NGF) mRNA表达,免疫组化染色观察苔藓纤维出芽(M FS).结果 治疗后,与正常对照组比较,模型组、CBZ组、8-OH-DPAT低、高剂量组的体质量与摄食量明显下降,海马NGF mRNA表达与Timm评分明显增高(均P＜0.05).与模型组比较,CBZ组、8-OH-DPAT低、高剂量组的体质量、摄食量及旷场试验评分明显提高,Racine分级、海马NGF mRNA表达与Timm评分明显下降(均P＜0.05);其中8-OH-DPAT高剂量组上述改变更明显(均P＜0.05).结论 高剂量的5-HT1A受体激动剂8-OH-DPAT能抑制癫痫合并抑郁大鼠海马齿状回的MFS和神经生长因子的表达,促进海马神经重塑.这可能是5-HT1A受体激动剂抗癫痫、抗抑郁的分子机制之一.     

改善精神分裂症认知障碍与5-羟色胺1A受体的关系研究进展

综述精神分裂症认知障碍与5-羟色胺1A受体间的关系。     

5-羟色胺1A受体激动剂8-OH-DPAT改善帕金森病运动并发症的实验研究

目的 探讨5-羟色胺1A(5-HT1A)受体激动剂8-OH-DPAT对左旋多巴诱发的运动并发症的细胞学与行为学效应.方法 通过6-羟基多巴胺立体定向注射至大鼠前脑内侧前脑束建立帕金森病(Parkinson disease,PD)动物模型.对模型成功的PD大鼠进行两套实验:第1套实验中3组PD大鼠接受每日2次左旋多巴甲酯(50 mg/kg加12.5 mg/kg苄丝肼)腹腔注射,持续22 d.在第23天左旋多巴注射前,3组PD大鼠先分别接受8-OH-DPAT、8-OH-DPAT+5-羟色胺1A(5-HT1A)受体阻断剂WAY-100635(0.1 mg/kg)及溶剂对照注射;第2套实验中2组PD大鼠每日2次分别接受左旋多巴/苄丝肼+8-OH-DPAT与左旋多巴/苄丝肼+溶剂,持续22 d.评估旋转时间、关期发生频率情况;采用蛋白印迹法检测纹状体区谷氨酸受体1(GluR1)亚细胞分布及GluR1的845位丝氨酸(GluR1Ser845)磷酸化的表达情况.结果 8-OH-DPAT逆转了左旋多巴所诱导的PD大鼠旋转时间的缩短,延长约27.8%±6.1%;并使关期发生频率减少约7.2%±1.7%.5-HT1A受体阻断剂WAY-100635与8-OH-DPAT联合应用则消除了8-OH-DPAT的效应,提示所观察到的8-OH-DPAT的效应是通过5-HT1A受体起作用的.此外,8-OH-DPAT能调节与运动并发症密切相关的GluR1的亚细胞分布,且使GluR1Ser845的磷酸化水平降低约22.1%±3.5%.结论 激动5-HT1A受体的药物可能是治疗及预防PD运动并发症有益的疗法.     

5-羟色胺转运体基因LPR及5-羟色胺1A受体C(-1019)G基因多态性的联合作用与重性抑郁症的关联研究

目的探讨5-羟色胺转运体基因LPR(5-HTT LPR)多态性和5-羟色胺1A受体(5-HT_(1A)R)C(-1019)G基因多态性的联合作用与重性抑郁症的关系。方法采用病例对照研究,以2005年10月-2007年5月在山西医科大学第一医院就诊的197例重性抑郁症患者为患者组,选取同期该院体检中心与患者组性别、年龄匹配的健康对照者197例为对照组。应用聚合酶链反应技术(PCR)、SDS-聚丙烯酰胺凝胶电泳(SDS-PAGE)及DNA直接测序法对两组的5-HTT LPR及5-HT_(1A)R C(-1019)G基因多态性进行检测。应用UNPHASED软件进行统计分析。结果患者组与对照组的5-HTT LPR和5-HT_(1A)R C(-1019)G多态性位点基因型及等位基因分布频率差异均无统计学意义(P均0.05)。多态性联合作用分析显示,患者组G-S等位基因组合频率高于对照组,差异有统计学意义(21.4%vs.12.4%,P=0.022)。结论在中国汉族人群中,5-HTT LPR和5-HT_(1A)R C(-1019)G的联合作用与重性抑郁症存在关联,G-S等位基因组合可能会增加重性抑郁症发病的危险性。     

5-羟色胺及其受体与癫痫关系的研究进展

研究表明,神经递质的异常与癫痫发作有着密切的联系。5-羟色胺作为中枢和外周神经系统中的抑制性神经递质,对癫痫的发作有一定的抑制作用。而激动5-HT1A和5-HT2C受体、拮抗5-HT3和5-HT7受体同样可抑制癫痫的发作。由此可知,5-羟色胺与其受体一同对癫痫的发作起着调节的作用。这些作用的机制得到了广泛的研究,并且已经得到了大量试验结果的支持。     

5-羟色胺受体的研究现状

５羟色胺（５ＨＴ）既是一种神经递质，又是一种血管活性物质，在中枢神经系统和周围组织中起着多种生理作用。有研究表明，５ＨＴ在中枢神经系统中的分布十分广泛，参与了各种精神活动的调节［１］，如与焦虑症、强迫症、孤独症、情感性精神障碍、精神分裂症以及酒...     

5-羟色胺2A受体基因多态性与精神疾病

五羟色胺2A受体基因是人类精神疾病研究的重要候选基因之一,本文对其基因多态性与精神疾病的研究作了简要的文献综述。     

5-羟色胺2A受体基因多态性与精神分裂症的相关性研究

目的探讨５－羟色胺２Ａ受体基因多态性与精神分裂症的相关性。方法采用Ａｍｐ－ＲＦＬＰ方法对精神分裂症患者和各对照组的５－羟色胺２Ａ受体（简称５－ＨＴ２ＡＲ）基因的相关性进行了研究。结果精神分裂症患者５－ＨＴ２ＡＲ基因Ａ２Ａ２纯合子基因型频率及等位基因Ａ２频率均高于对照组（χ２＝８．９９，８３８Ｐ均＜０．０１），对发生精神分裂症的５－ＨＴ２ＡＲ基因Ａ２Ａ２纯合子相对危险度是２３６。结论本实验结果提示５－ＨＴ２ＡＲ基因的变异与精神分裂症有密切相关性。     

色氨酸羟化酶1与5-羟色胺2A受体基因对抑郁症患者额叶情绪加工的影响

目的:分析色氨酸羟化酶1 (TPH1)基因A218C多态性、5-羟色胺(5-HT)2A受体基因(HTR2A) T102C多态性对抑郁症患者额叶情绪识别功能异常的影响. 方法:28例抑郁症患者(患者组)及34名性别、年龄、受教育年限相匹配的健康对照(对照组)均进行情绪识别任务态下功能磁共振扫描,并以聚合酶链式反应-限制...     

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.     

Chronic administration of the 5-HT1A receptor agonist 8-OH-DPAT differentially desensitizes 5-HT1A autoreceptors of the dorsal and median raphe nuclei

The present study investigated alterations of the regulation of serotonin (5-hydroxytryptamine; 5-HT) release by 5-HT_1A autoreceptors following single and repeated treatment with the 5-HT_1A receptor agonist 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT). Rats were pretreated with 8-OH-DPAT (1.0 mg/kg, s.c.) for 1, 7, or 14 days. The ability of an acute challenge administration of 8-OH-DPAT (1.0 mg/kg, i.p.) to decrease 5-HT release in the ventral striatum and the ventral hippocampus of rats maintained under chloral hydrate anesthesia was examined 24 h after the last pretreatment injection using in vivo microdialysis. The decrease of 5-HT release in the striatum produced by the challenge dose of the 5-HT_1A receptor agonist was diminished following 7 and 14 days of pretreatment, but not after 1 day of pretreatment, with 8-OH-DPAT. In contrast, decreases of 5-HT release in the hippocampus by the 8-OH-DPAT challenge were not altered after 1 or 7 days of pretreatment, and only a trend for attenuation appeared after pretreatment for 14 days. The results of the present study indicate that desensitization of 5-HT_1A autoreceptors regulating 5-HT release in different brain regions by repeated treatment with 8-OH-DPAT occurs at different rates. Synapse 25:107–116, 1997. © 1997 Wiley-Liss, Inc.     

The 5-HT1A receptor agonist, 8-OH-DPAT, attenuates stress-induced anorexia in conjunction with the suppression of hypothalamic serotonin release in rats

The effect of the selective 5-HT_1A receptor agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) on stress-induced anorexia and serotonin (5-HT) release in the rat hypothalamus was studied with brain microdialysis. Subcutaneous injection of 8-OH-DPAT (1 mg/kg) significantly attenuated the immobilization-induced anorexia for 3 h, but had no effect during the following 9 h. Injection of 8-OH-DPAT itself had no effect on basal release of 5-HT, while it significantly blocked the immobilization-induced 5-HT release in the lateral hypothalamus. The results suggest that 8-OH-DPAT attenuated the stress-induced anorexia through the activation of 5-HT_1A autoreceptors in dorsal raphe nucleus.     

5-HT1A受体激动剂减轻GluR1Ser831磷酸化和改善帕金森病异动症的研究

目的:探讨5-HT1A受体激动剂8-OH-DPAT对左旋多巴诱发的异动症细胞学与行为学效应。方法:6-羟基多巴胺立体定向注射至大鼠前脑内侧束建立帕金森病(PD)动物模型。对模型成功的PD大鼠进行两套实验:第1套实验中3组PD大鼠接受每日2次左旋多巴(50mg穔g-1加苄丝肼12.5mg穔g-1)腹腔注射,持续22d。在第23天左旋多巴注射前,3组PD大鼠先分别接受8-OH-DPAT、8-OH-DPAT 5-HT1A受体阻断剂WAY-1006350.1mg穔g-1及溶剂;第2套实验中2组PD大鼠每日2次分别接受左旋多巴/苄丝肼 8-OH-DPAT与左旋多巴/苄丝肼 溶剂,持续22d。评估剂峰旋转次数;采用蛋白印迹法检测纹状体区谷氨酸受体亚型GluR1亚细胞分布及GluR1Ser831磷酸化的表达情况。结果:8-OH-DPAT减轻了PD大鼠的剂峰旋转次数。5-HT1A受体阻断剂WAY-100635与8-OH-DPAT联合应用则消除了8-OH-DPAT的效应。此外,8-OH-DPAT能调节与异动症相关的GluR1的亚细胞分布且明显降低GluR1Ser831的磷酸化水平。结论:8-OH-DPAT是通过5-HT1A受体起作用的,激动5-HT1A受体的药物可能对于PD异动症治疗及预防有益。     

Suppression of conditioned avoidance by 8-OH-DPAT in the rat

Summary Rats were trained to perform an aversely motivated discriminative task in a shuttle-box. The conditioned avoidance response was selectively suppressed by 8-OH-DPAT in a dose-dependent manner (25–100 g·kg^–1). There were no statistically significant deficits in discriminative performance. The present results suggest antipsychotic-like properties of 8-OH-DPAT.     

Progesterone attenuates the effect of the 5-HT1A receptor agonist, 8-OH-DPAT,and of mild restraint on lordosis behavior

Ovariectomized, hormone-primed rats were used to test the hypothesis that progesterone treatment attenuated the effects of the 5-HT(1A) receptor agonist, (+/-)-8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), on female rat lordosis behavior. Based upon prior evidence that prepriming with estradiol benzoate (EB) reduced the ability of 8-OH-DPAT to inhibit lordosis behavior, rats were preprimed with 10 microg EB 7 days before a second priming with 10 microg EB followed 48 h later with 500 microg progesterone or vehicle. Independent of the presence of progesterone, prepriming with EB attenuated the lordosis-inhibiting effects of systemic treatment with 8-OH-DPAT. However, progesterone also reduced the effects of 8-OH-DPAT and this effect was also seen in females primed only once with EB. In contrast, progesterone was relatively ineffective in attenuating the effects of bilateral infusion with 8-OH-DPAT into the ventromedial nucleus of the hypothalamus (VMN). The failure of progesterone to substantially reduce the effects of VMN infusion with 8-OH-DPAT contrasts with prior studies in which estrogen's protective action against the drug did include the VMN. Thus, while both estrogen and progesterone reduce the lordosis-inhibiting effect of 8-OH-DPAT, the mechanisms responsible for the effects of the two gonadal hormones may be different. Priming with progesterone also prevented the effects of 5 min of restraint. When rats were hormonally primed with EB and oil, rats showed a transient, but significant, decline in lordosis behavior 5 and 10 min after restraint. Rats primed with EB and progesterone were unaffected by the restraint. These results are discussed in terms of their implications for the role of progesterone in altering the 5-HT(1A) receptor modulation of lordosis behavior.     

5-HT1A agonists and dopamine: the effects of 8-OH-DPAT and buspirone on brain-stimulation reward

Summary Two specific 5-HT_1A agonists, 8-OH-DPAT (0–300 g/kg), and buspirone (0–3.0 mg/kg), were tested on variable-interval, threshold-current self-stimulation of rat lateral hypothalamus. Buspirone produced a prolonged monotonic depression of responding, whereas the effects of 8-OH-DPAT were biphasic: 3.0 g/kg produced a sustained enhancement of responding while higher doses (100–300 g/kg) produced a relatively short-lasting depression. This biphasic pattern parallels previously reported effects of 8-OH-DPAT on food intake and on various other behaviours. Threshold-current self-stimulation is highly sensitive to alterations in dopaminergic transmission but relatively insensitive to changes in 5-HT. Thus the facilitatory effect of low-dose 8-OH-DPAT seems most plausibly interpreted in terms of enhanced dopaminergic transmission. This could be brought about by 5HT_1A autoreceptor-mediated inhibition of 5-HT release and consequent disinhibition of dopaminergic transmission. Depression of self-stimulation by higher doses of 8-OH-DPAT may reflect the activity of 8-OH-DPAT at postsynaptic 5-HT receptors, with consequent inhibition of DA transmission. Suppression of responding after buspirone at all doses tested may reflect the action of this compound as a partial agonist at postsynaptic 5-HT receptors, and/or its effects on other systems.     

Citalopram and 8-OH-DPAT attenuate nicotine-induced excitation of central noradrenaline neurons

Summary Previous electrophysiological studies have demonstrated that nicotine, intravenously administered, excites noradrenergic neurons in the locus coeruleus (LC) indirectly by releasing excitatory amino acids (EAA). In the present study the excitatory action of nicotine was inhibited by treatment with the selective 5-HT re-uptake inhibitor citalopram or the 5-HT_1A receptor agonist 8-OH-DPAT. It is proposed that the antagonism between nicotine and citalopram or 8-OH-DPAT reflects an interaction between endogenous EAA, e.g. glutamate, and 5-HT. The results may, on a cellular basis, explain the attributed effectiveness of drugs that facilitate serotonergic neurotransmission in promoting smoking cessation.     

8-hydroxy-dipropylaminotetralin promotes neural plasticity in epileptic rats with depression

Rats with chronic pilocarpine-induced temporal lobe epilepsy complicated with depression were studied. Anti-5-bromodeoxyuridine immunofluorescence staining and Timms staining showed that neurogenesis within the hippocampal dentate gyrus and mossy fiber sprouting were increased in model rats. Neurogenesis within the hippocampal dentate gyrus was further enhanced, while mossy fiber sprouting was decreased in model rats administered carbamazepine alone or in combination with the 5-hydroxytryptamine 1A receptor agonist, 8-hydroxy-dipropylaminotetralin (0.1 and 1 mg/kg). Among the groups, the effect was the most significant in rats receiving carbamazepine in conjunction with 1 mg/kg 8-hydroxy-dipropylaminotetralin. Thus, high dose 8-hydroxy-dipropylaminotetralin can improve neural plasticity in epileptic rats with depression.