Blackburn Thomas P, Minabe Yoshio, Middlemiss Derek N, Shirayama Yukihiko, Hashimoto Kenji, Ashby Charles R
GlaxoSmithKline, New Frontiers Science Park, Harlow, Essex, CM19 5AW, UK.
Synapse. 2002 Dec 1;46(3):129-39. doi: 10.1002/syn.10116.
In this study, we examined the effect of the acute and chronic administration of the selective 5-HT2C receptor antagonist SB-243213 (SB) on the activity of spontaneously active dopamine (DA) cells in the substantia nigra pars compacta (SNC) and ventral tegmental area (VTA) in anesthetized, albino, male Sprague-Dawley rats. This was accomplished using the technique of in vivo extracellular single cell recording. The acute i.v. administration of SB-243213 (0.025-3.2 mg/kg) did not significantly alter the basal firing rate or pattern of either spontaneously active SNC or VTA DA neurons compared to vehicle-treated controls. The acute i.p. administration of either 1 or 10 mg/kg of SB-243213 did not significantly alter the number of spontaneously active DA cells in the SNC or VTA compared to vehicle-treated controls, whereas the 3 mg/kg dose only significantly decreased the number of spontaneously active VTA DA neurons. Overall, the 1 mg/kg dose of SB-243213 did not significantly alter the firing pattern of either SNC or VTA DA neurons compared to vehicle-treated controls. In contrast, the 3 mg/kg dose significantly altered the firing pattern of SNC DA neurons, whereas the 10 mg/kg dose altered the firing pattern of DA neurons in both the SNC and VTA. The repeated i.p. administration (21 days) of 1, 3, and 10 mg/kg of SB-243213 or 20 mg/kg of clozapine produced a significant decrease in the number of spontaneously active DA cells in the VTA compared to vehicle-treated controls. The decrease in the number of spontaneously active VTA DA cells was not reversed by the i.v. administration of (+)-apomorphine (50 microg/kg). The repeated administration of either 1 or 3 mg/kg of SB-243213 had minimal effects on the firing pattern of either SNC or VTA DA neurons. In contrast, the firing pattern of VTA DA neurons was significantly altered by 10 mg/kg dose of SB-243213. Overall, our results indicate that antagonism of the 5-HT2C receptor alters the activity of midbrain DA neurons in anesthetized rats and suggest that SB-243213 has an atypical antipsychotic profile following chronic administration.
在本研究中，我们检测了选择性5 - HT2C受体拮抗剂SB - 243213（SB）急性和慢性给药对麻醉的白化雄性Sprague - Dawley大鼠黑质致密部（SNC）和腹侧被盖区（VTA）中自发活动的多巴胺（DA）细胞活性的影响。这是通过体内细胞外单细胞记录技术完成的。与给予赋形剂的对照组相比，急性静脉注射SB - 243213（0.025 - 3.2 mg/kg）并未显著改变自发活动的SNC或VTA DA神经元的基础放电率或放电模式。与给予赋形剂的对照组相比，急性腹腔注射1或10 mg/kg的SB - 243213并未显著改变SNC或VTA中自发活动的DA细胞数量，而3 mg/kg剂量仅显著减少了自发活动的VTA DA神经元数量。总体而言，与给予赋形剂的对照组相比，1 mg/kg剂量的SB - 243213并未显著改变SNC或VTA DA神经元的放电模式。相比之下，3 mg/kg剂量显著改变了SNC DA神经元的放电模式，而10 mg/kg剂量改变了SNC和VTA中DA神经元的放电模式。与给予赋形剂的对照组相比，重复腹腔注射（21天）1、3和10 mg/kg的SB - 243213或20 mg/kg的氯氮平使VTA中自发活动的DA细胞数量显著减少。静脉注射（+） - 阿扑吗啡（50μg/kg）并未逆转自发活动的VTA DA细胞数量的减少。重复给予1或3 mg/kg的SB - 243213对SNC或VTA DA神经元的放电模式影响极小。相比之下，10 mg/kg剂量的SB - 243213显著改变了VTA DA神经元的放电模式。总体而言，我们的结果表明，5 - HT2C受体拮抗作用改变了麻醉大鼠中脑DA神经元的活性，并提示SB - 243213在慢性给药后具有非典型抗精神病药物的特征。
