Westerink B H, Enrico P, Feimann J, De Vries J B
Department of Medicinal Chemistry, University Center for Pharmacy, University of Groningen, Groningen, The Netherlands.
J Pharmacol Exp Ther. 1998 Apr;285(1):143-54.
Receptor-specific compounds were applied by retrograde microdialysis to the ventral tegmental area (VTA) of the rat brain. The effects of intrategmental infusions on extracellular dopamine in the ipsilateral prefrontal cortex (PFC) were recorded with a second microdialysis probe. Intrategmental infusion of tetradotoxin (1 microM), muscimol (20 microM) or baclofen (50 microM) decreased extracellular dopamine in the PFC. Infusion of N-methyl-D-aspartate (NMDA) (300 microM; 1 mM, 15 min) or kainate (50 microM, 15 min) increased extracellular dopamine in the PFC. The effects of the excitatory amino acids were suppressed by co-infusion with (+/-)-3(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (300 microM), with (+/-)-2-amin-5-phosphonopentanoic acid (500 microM), with dizocilpine maleate (500 microM) (partly) or with 6-cyano-7-nitroquinoxaline-2,3-dione (500 microM) (partly). Intrategmental infusion of carbachol (50 microM) increased extracellular dopamine in the PFC. These results provide evidence for the localization of GABAA, GABAB, NMDA, non-NMDA and cholinergic receptors on mesocortical neurons in the VTA. Intrategmental infusion of AP-5, (+/-)-2-amino-5-phosphonopentanoic acid (500 microM), of (+/-)-3(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (300 microM), of (+)-3-amino-1-hydroxy-2-pyrrolidone (1 mM) and of 6-cyano-7-nitroquinoxaline-2,3-dione (500 microM) decreased extracellular dopamine in the PFC. Infusion of mecamylamine, of atropine, and of 3-[(3, 4)-dichlorophenyl)methyl]propyl phosphonic acid into the VTA did not modify extracellular dopamine in the PFC. Infusion of bicuculline (50 microM) and that of (-)-sulpiride (50 microM) were followed by an increase in extracellular dopamine in the PFC. These data suggest that mesocortical dopamine neurons, at the level of the VTA, are tonicly excitated by glutamatergic neurons by acting on NMDA and non-NMDA receptors and are tonicly inhibited by GABA and dopamine by acting on GABAA and D2 receptors, respectively. No tonic stimulation by cholinergic neurons was detected. The effects on mesocortical neurons and earlier published data on mesolimbic and nigrostriatal dopamine neurons are compared and discussed.
通过逆向微透析将受体特异性化合物应用于大鼠脑腹侧被盖区（VTA）。用第二个微透析探针记录VTA内注入药物对同侧前额叶皮质（PFC）细胞外多巴胺的影响。向VTA内注入河豚毒素（1微摩尔）、蝇蕈醇（20微摩尔）或巴氯芬（50微摩尔）可降低PFC中的细胞外多巴胺水平。注入N-甲基-D-天冬氨酸（NMDA）（300微摩尔；1毫摩尔，15分钟）或 kainate（50微摩尔，15分钟）可增加PFC中的细胞外多巴胺水平。兴奋性氨基酸的作用可通过与（±）-3-（2-羧基哌嗪-4-基）-丙基-1-膦酸（300微摩尔）、与（±）-2-氨基-5-膦酸戊酸（500微摩尔）、与马来酸氯氮平（500微摩尔）（部分）或与6-氰基-7-硝基喹喔啉-2,3-二酮（500微摩尔）（部分）共同注入而受到抑制。向VTA内注入卡巴胆碱（50微摩尔）可增加PFC中的细胞外多巴胺水平。这些结果为VTA中中皮质神经元上GABAA、GABAB、NMDA、非NMDA和胆碱能受体的定位提供了证据。向VTA内注入AP-5、（±）-2-氨基-5-膦酸戊酸（500微摩尔）、（±）-3-（2-羧基哌嗪-4-基）-丙基-1-膦酸（300微摩尔）、（+）-3-氨基-1-羟基-2-吡咯烷酮（1毫摩尔）和6-氰基-7-硝基喹喔啉-2,3-二酮（500微摩尔）可降低PFC中的细胞外多巴胺水平。向VTA内注入美加明、阿托品和3-[[（3,4）-二氯苯基]甲基]丙基（二乙氧基甲基）膦酸不会改变PFC中的细胞外多巴胺水平。注入荷包牡丹碱（50微摩尔）和（-）-舒必利（50微摩尔）后，PFC中的细胞外多巴胺水平会升高。这些数据表明，在VTA水平，中皮质多巴胺神经元受到谷氨酸能神经元通过作用于NMDA和非NMDA受体的紧张性兴奋，以及分别通过作用于GABAA和D2受体的GABA和多巴胺的紧张性抑制。未检测到胆碱能神经元的紧张性刺激。对中皮质神经元的影响与先前发表的关于中脑边缘和黑质纹状体多巴胺神经元的数据进行了比较和讨论。
