Wang S, Zhang Q J, Liu J, Wu Z H, Wang T, Gui Z H, Chen L, Wang Y
Department of Physiology and Pathophysiology, School of Medicine, Xi'an Jiaotong University, Xi'an 710061, Shaanxi, China.
Neuroscience. 2009 Mar 17;159(2):850-61. doi: 10.1016/j.neuroscience.2008.12.051. Epub 2009 Jan 3.
Several studies have shown that the 5-hydroxytryptamine (serotonin, 5-HT) system is severely affected after degeneration of nigrostriatal dopaminergic neurons. In the present study, we examined the changes in the firing rate and firing pattern of the dorsal and median raphe nuclei (DRN and MRN) 5-HT neurons, and the effect of the selective 5-HT(1A) receptor agonist (R)-(+)-8-hydroxy-2-(dipropylamino)tetralin hydrobromide (8-OH-DPAT) and antagonist (N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-2-pyridylcyclohexane carboxamide maleate salt (WAY-100635) on the neuronal firing in rats with 6-hydroxydopamine (6-OHDA) lesions of the substantia nigra pars compacta by using extracellular recording. The unilateral lesion of the nigrostriatal pathway significantly increased the mean firing rate of DRN and MRN 5-HT neurons compared with normal rats, and the firing pattern of these neurons also changed significantly towards a more bursty one. The lower dose of 8-OH-DPAT, 4 microg/kg (cumulative doses, i.v.), completely inhibited the firing activity of all DRN and MRN 5-HT neurons examined in normal and sham rats. In contrast to normal and sham rats, only the higher doses of 8-OH-DPAT, 128 and 64 microg/kg, completely inhibited the firing rate of DRN and MRN 5-HT neurons in 6-OHDA-lesioned rats, respectively. Furthermore, the local application of 8-OH-DPAT, 1.5 microg, in the DRN completely inhibited the firing rate of 5-HT neurons in normal and sham rats, while having no effect on firing rate in the lesioned rats. Altogether, these results indicate that lesion of the nigrostriatal pathway leads to hyperactivity of DRN and MRN 5-HT neurons, suggesting the implication of the DRN and MRN in the pathophysiology of Parkinson's disease, and the decreased response of these 5-HT neurons to 5-HT(1A) receptor stimulation, reflecting 5-HT(1A) receptor dysfunction in 6-OHDA-lesioned rats.
多项研究表明，黑质纹状体多巴胺能神经元变性后，5-羟色胺（血清素，5-HT）系统受到严重影响。在本研究中，我们通过细胞外记录，检测了背侧和中缝核（DRN和MRN）5-HT神经元的放电频率和放电模式的变化，以及选择性5-HT(1A)受体激动剂（R）-（+）-8-羟基-2-（二丙基氨基）四氢萘溴化物（8-OH-DPAT）和拮抗剂（N-（2-（4-（2-甲氧基苯基）-1-哌嗪基）乙基）-N-2-吡啶基环己烷羧酰胺马来酸盐（WAY-100635）对黑质致密部6-羟基多巴胺（6-OHDA）损伤大鼠神经元放电的影响。与正常大鼠相比，黑质纹状体通路的单侧损伤显著提高了DRN和MRN 5-HT神经元的平均放电频率，并且这些神经元的放电模式也显著改变，变得更加爆发式。较低剂量的8-OH-DPAT，4μg/kg（静脉注射累积剂量），完全抑制了正常和假手术大鼠中所有检测的DRN和MRN 5-HT神经元的放电活动。与正常和假手术大鼠不同，只有较高剂量的8-OH-DPAT，128和64μg/kg，分别完全抑制了6-OHDA损伤大鼠中DRN和MRN 5-HT神经元的放电频率。此外，在DRN局部应用1.5μg的8-OH-DPAT，完全抑制了正常和假手术大鼠中5-HT神经元的放电频率，而对损伤大鼠的放电频率没有影响。总之，这些结果表明，黑质纹状体通路损伤导致DRN和MRN 5-HT神经元活动亢进，提示DRN和MRN参与帕金森病的病理生理学过程，并且这些5-HT神经元对5-HT(1A)受体刺激的反应降低，反映了6-OHDA损伤大鼠中5-HT(1A)受体功能障碍。
