Hu X T, White F J
Department of Neuroscience, Finch University of Health Sciences, Chicago Medical School, Illinois 60064-3095.
Synapse. 1994 May;17(1):43-61. doi: 10.1002/syn.890170106.
Many effects resulting from D2 dopamine (DA) receptor stimulation are manifest only when D1 DA receptors are stimulated by endogenous DA. When D1 receptor stimulation is enhanced by administration of selective D1 receptor agonists, the functional effects of selective D2 agonists are markedly increased. These qualitative and quantitative forms of D1/D2 DA receptor synergism are abolished by chronic DA depletion when both D1 and D2 DA receptors are supersensitive. Using both electrophysiological and behavioral methods, the present study examined the effects of selective D1 and D2 receptor supersensitivity, induced by repeated administration of selective D1 or D2 receptor antagonists, on the synergistic relationships between D1 and D2 receptors. Daily administration of the selective D2 antagonist eticlopride (0.5 mg/kg, s.c.) for 3 weeks produced a selective supersensitivity of both dorsal (caudate-putamen) and ventral (nucleus accumbens) striatal neurons to the inhibitory effects of the D2 agonist quinpirole (applied by microiontophoresis). This treatment also abolished the normal ability of the D1 agonist SKF 38393 to potentiate quinpirole-induced inhibition, and relieved D2 receptors from the necessity of D1 receptor stimulation by endogenous DA (enabling), as indicated by significant electrophysiological and behavioral (stereotypy) effects of quinpirole in eticlopride-pretreated, but not saline-pretreated, rats that were also acutely depleted of DA. Daily administration of the selective D1 receptor antagonist SCH 23390 (0.5 mg/kg, s.c.) caused supersensitivity of striatal neurons to the inhibitory effects of SKF 38393 and also abolished both the ability of SKF 38393 to potentiate quinpirole-induced inhibition and the necessity of D1 receptor stimulation for such inhibition. However, both quinpirole-induced inhibition of striatal cells and stereotyped responses were also somewhat enhanced in SCH 23390-pretreated rats. When such D1-sensitized rats were acutely depleted of DA, the behavioral effects of quinpirole were intermediate between saline-pretreated rats with acute DA depletion and SCH 23390-pretreated rats without acute DA depletion. Based upon these and related results, it is argued that the enhanced effects of quinpirole in D1-sensitized rats are due to a heterologous sensitization of D2 receptors rather than to enhanced enabling resulting from supersensitive D1 receptors. It is suggested that supersensitivity of either D1 or D2 receptors can lead to an uncoupling of normal qualitative and quantitative D1/D2 synergisms and that the heterologous regulation of D2 receptor sensitivity by D1 receptors may be related to uncoupling of functional D1/D2 synergisms.
许多由D2多巴胺（DA）受体刺激产生的效应只有在内源性DA刺激D1 DA受体时才会显现。当通过给予选择性D1受体激动剂增强D1受体刺激时，选择性D2激动剂的功能效应会显著增加。当D1和D2 DA受体都超敏时，慢性DA耗竭会消除D1/D2 DA受体协同作用的这些定性和定量形式。本研究使用电生理和行为学方法，研究了由反复给予选择性D1或D2受体拮抗剂诱导的选择性D1和D2受体超敏对D1和D2受体之间协同关系的影响。每天皮下注射选择性D2拮抗剂依替必利（0.5 mg/kg）3周，可使背侧（尾状核-壳核）和腹侧（伏隔核）纹状体神经元对D2激动剂喹吡罗的抑制作用产生选择性超敏（通过微离子透入法施加）。这种处理还消除了D1激动剂SKF 38393增强喹吡罗诱导的抑制作用的正常能力，并使D2受体不再需要内源性DA刺激D1受体（即“启用”），这在喹吡罗对依替必利预处理但未用生理盐水预处理且也急性耗竭DA的大鼠中产生的显著电生理和行为（刻板行为）效应中得到体现。每天皮下注射选择性D1受体拮抗剂SCH 23390（0.5 mg/kg）会使纹状体神经元对SKF 38393的抑制作用产生超敏，同时也消除了SKF 38393增强喹吡罗诱导的抑制作用的能力以及这种抑制作用对D1受体刺激的必要性。然而，在SCH 23390预处理的大鼠中，喹吡罗诱导的纹状体细胞抑制和刻板反应也有所增强。当这种D1致敏的大鼠急性耗竭DA时，喹吡罗的行为效应介于急性耗竭DA的生理盐水预处理大鼠和未急性耗竭DA的SCH 23390预处理大鼠之间。基于这些及相关结果，有人认为喹吡罗在D1致敏大鼠中增强的效应是由于D2受体的异源致敏，而非超敏的D1受体导致的增强的“启用”作用。有人提出，D1或D2受体的超敏都可能导致正常的定性和定量D1/D2协同作用解偶联，并且D1受体对D2受体敏感性的异源调节可能与功能性D1/D2协同作用的解偶联有关。
