Selective blockade of dopamine D3 versus D2 receptors enhances frontocortical cholinergic transmission and social memory in rats:: a parallel neurochemical and behavioural analysis
Selective blockade of dopamine D3 versus D2 receptors enhances frontocortical cholinergic transmission and social memory in rats:: a parallel neurochemical and behavioural analysis
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DOI：
10.1111/j.1471-4159.2006.04262.x
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发表时间：
2007-02-01
影响因子：
4.7
通讯作者：
Gobert, Alain
中科院分区：
文献类型：
--
作者：
Millan, Mark J.;Di Cara, Benjamin;Gobert, Alain
虽然多巴胺能机制调节胆碱能传递和认知功能，但特定受体亚型的意义仍不确定。在这里，我们研究了多巴胺D-3与D-2受体的作用。与他克林（0.16-2.5 mg/kg，s.c.）类似，选择性D3受体拮抗剂S33084（0.01-0.63）和SB 277，011（0.63-40.0）引起自由移动大鼠额叶皮质中乙酰胆碱（ACh）透析水平的剂量依赖性、显著和持续的升高，但不引起海马中乙酰胆碱（ACh）透析水平的升高。这些拮抗剂的作用被（+）S14297（1.25）立体特异性地模拟，而它的非活性异构体（-）S17777则无效。优先使用的D-2受体拮抗剂L741，626（10.0）不能改变ACh水平。S33084（0.01-0.63）和SB 277，011（0.16-2.5）也通过剂量依赖性减弱东莨菪碱（1.25）对社会记忆（成年大鼠识别幼年同种）的有害影响来模拟他克林（0.04-0.63）。此外，（+）S14297（1.25）与（-）S17777立体特异性阻断东莨菪碱的作用。使用120分钟的会话间隔（自发性识别丧失），S33084（0.04-0.63），SB 277，011（0.16-10.0）和（+）S14297（0.63-10.0）在增强社交记忆方面也类似于他克林（0.16-2.5）。相反，L741，626（0.16-10.0）显示出遗忘特性。总之，选择性阻断D-3受体有利于额叶皮质胆碱能传递，提高大鼠的社会记忆。这些数据支持D-3受体作为治疗认知功能受损的疾病的靶标的相关性。
Though dopaminergic mechanisms modulate cholinergic transmission and cognitive function, the significance of specific receptor subtypes remains uncertain. Here, we examined the roles of dopamine D-3 versus D-2 receptors. By analogy with tacrine (0.16-2.5 mg/kg, s.c.), the selective D3 receptor antagonists, S33084 (0.01-0.63) and SB277,011 (0.63-40.0), elicited dose-dependent, pronounced and sustained elevations in dialysis levels of acetylcholine (ACh) in the frontal cortex, but not the hippocampus, of freely-moving rats. The actions of these antagonists were stereospecifically mimicked by (+)S14297 (1.25), whereas its inactive distomer, (-)S17777, was ineffective. The preferential D-2 receptor antagonist, L741,626 (10.0), failed to modify levels of ACh. S33084 (0.01-0.63) and SB277,011 (0.16-2.5) also mimicked tacrine (0.04-0.63) by dose-dependently attenuating the deleterious influence of scopolamine (1.25) upon social memory (recognition by an adult rat of a juvenile conspecific). Further, (+)S14297 (1.25) versus (-)S17777 stereospecifically blocked the action of scopolamine. Using an intersession interval of 120 min (spontaneous loss of recognition), S33084 (0.04-0.63), SB277,011 (0.16-10.0) and (+) S14297 (0.63-10.0) likewise mimicked tacrine (0.16-2.5) in enhancing social memory. In contrast, L741,626 (0.16-10.0) displayed amnesic properties. In conclusion, selective blockade of D-3 receptors facilitates frontocortical cholinergic transmission and improves social memory in rats. These data support the pertinence of D-3 receptors as a target for treatment of disorders in which cognitive function is compromised.