SB 242 084, a selective serotonin2C receptor antagonist, increases dopaminergic transmission in the mesolimbic system
SB 242 084, a selective serotonin2C receptor antagonist, increases dopaminergic transmission in the mesolimbic system
复制标题
DOI：
10.1016/s0028-3908(99)00047-7
复制
发表时间：
1999-08-01
影响因子：
4.7
通讯作者：
Esposito, E
中科院分区：
文献类型：
--
作者：
Di Matteo, V;Di Giovanni, G;Esposito, E
电生理技术和在体微透析被用来研究SE 242 084，一种有效的和选择性的5-HT 2C，受体拮抗剂在黑质纹状体和中脑边缘多巴胺能功能的控制的效果。因此，在给予SE 242 084和RO 60-0175后，对麻醉大鼠黑质、致密部（SNc）和腹侧被盖区（VTA）中神经化学鉴定的多巴胺（DA）神经元进行细胞外单单位记录，并监测纹状体和中脑基底DA释放。给予SE 242 084（160-640 μ g/kg，i. v.）引起腹侧被盖区DA神经元基础放电率的剂量依赖性增加，在640 μ g/kg后达到最大值（27.8 +/-6%，高于基线）。此外，爆发活动显着增强SE 242 084在VTA。另一方面，SE 242 084（160-640 μ g/kg，i. v.）对黑质腹侧核DA能神经元的基础放电频率和爆发活动无明显影响。注射5-HT 2c受体激动剂RO 60-0175（80-320% μ g/kg，i. v.）剂量依赖性地减少腹侧被盖区DA神经元的基础放电，但在SNc没有。RO 60-0175在320 μ g/kg剂量下在VTA中发挥最大抑制作用（53.9 +/-15.1%，低于基线）。腹膜内给予10 mg/kg SE 242 084后，丘脑核中的基础DA释放（34.8 +/-9%，高于基线）和二羟基苯乙酸（DOPAC）流出（19.7 +/-7%，高于基线）显著增强。腹膜内注射5 mg/kg SE 242 084显著增加延髓核中的DA释放（16.4 +/-6%，高于基线），但不影响DOPAC流出。在纹状体中，SE 242 084（5和10 mg/kg，腹腔注射）仅略微增加DA释放超过基线（分别为3.5 +/- 3和11.2 +/-6%），而不影响该区域的DOPAC流出。然而，SE 242 084在纹状体中的作用通过以下事实变得更加明显：在对照组大鼠中注射用于溶解药物的载体，显著降低基础DA输出19.6 +/-7%。通过RO 60-0175（lmg/kg，i. p.）在注射后60分钟，显著降低丘脑核中的DA释放26.1 +/-4%（低于基线）。另一方面，RO 60-0175（lmg/kg，i. p.）纹状体DA释放无明显变化。然而，通过RO 60-0175（lmg/kg，i. p.）纹状体和脑桥核都有两者合计，这些数据表明，中央5-HT系统施加紧张性和阶段性抑制控制中脑边缘DA神经元的活动和5-HT 2C受体亚型参与这种效果。此外，这些发现可能为5-HT 2C受体拮抗剂用于治疗与中枢DA神经元功能减退相关的神经精神疾病开辟新的可能性。(C)1999 Elsevier Science Ltd.保留所有权利。
Electrophysiological techniques and in vivo microdialysis were used to investigate the effect of SE 242 084, a potent and selective 5-HT2C, receptor antagonist in the control of nigro-striatal and mesolimbic dopaminergic function. Thus, extracellular single unit recordings were performed from neurochemically-identified dopamine (DA) neurons in the substantia nigra, pars compacts (SNc) and the ventral tegmental area (VTA), as well as monitoring of striatal and accumbal basal DA release in anesthetized rats following the administration of SE 242 084 and RO 60-0175. Administration of SE 242 084 (160-640 mu g/kg, i.v.) caused a dose-dependent increase in the basal firing rate of VTA DA neurons, reaching its maximum (27.8 +/- 6%, above baseline) after 640 mu g/kg. Moreover, bursting activity was significantly enhanced by SE 242 084 in the VTA. On the other hand, SE 242 084 (160-640 mu g/kg, i.v.) did not cause any significant change in the basal firing rate and bursting activity of DA neurons in the SNc. Injection of the 5-HT2c, receptor agonist RO 60-0175 (80-320% mu g/kg, i.v.) dose-dependently decreased the basal firing of DA neurons in the VTA but not in the SNc. RO 60-0175 exerted its maximal inhibitory effect (53.9 +/- 15.1%, below baseline) in the VTA at the dose of 320 mu g/kg. Basal DA release (34.8 +/- 9%, above baseline) and dihydroxyphenylacetic acid (DOPAC) efflux (19.7 +/- 7%, above baseline) were significantly enhanced in the nucleus accumbens following the intraperitoneal administration of 10 mg/kg SE 242 084. Intraperitoneal injection of 5 mg/kg SE 242 084 significantly increased DA release (16.4 +/- 6%, above baseline) in the nucleus accumbens, but did not affect DOPAC efflux. In the striatum, SE 242 084 (5 and 10 mg/kg, i.p.) only slightly increased DA release above baseline (3.5 +/- 3 and 11.2 +/- 6%, respectively), without affecting DOPAC efflux in this area. However, the effect of SE 242 084 in the striatum was rendered more evident by the fact that injection of the vehicle used to dissolve the drug in a group of control rats, significantly reduced basal DA output by 19.6 +/- 7%. Stimulation of 5-HT2C receptors by RO 60-0175 (1 mg/kg, i.p.) significantly decreased DA release in the nucleus accumbens by 26.1 +/- 4% (below baseline) 60 min after injection. On the other hand, RO 60-0175 (1 mg/kg, i.p.) did not cause any significant change of DA release in the striatum. However, DOPAC efflux was reduced by RO 60-0175 (1 mg/kg, i.p.) both in the striatum and the nucleus accumbens. Taken together, these data indicate that the central 5-HT system exerts a tonic and phasic inhibitory control on mesolimbic DA neuron activity and that 5-HT2C receptor subtypes are involved in this effect. Moreover, these findings might open new possibilities for the employment of 5-HT2C, receptor antagonists in the treatment of neuropsychiatric disorders related to a hypofunction of central DA neurons. (C) 1999 Elsevier Science Ltd. All rights reserved.