Hu X T, Wachtel S R, Galloway M P, White F J
Neuropsychopharmacology Laboratory, Wayne State University School of Medicine, Lafayette Clinic, Detroit, Michigan 48207.
J Neurosci. 1990 Jul;10(7):2318-29. doi: 10.1523/JNEUROSCI.10-07-02318.1990.
Extracellular single unit recording and microiontophoretic techniques were used to determine the sensitivities and interactions of D1 and D2 dopamine (DA) receptors in the caudate putamen (CPu) of rats that were denervated of DA by intraventricular injections of the catecholamine neurotoxin 6-hydroxydopamine (6-OHDA). Seven to 10 d after the 6-OHDA injection, DA levels in the ipsilateral CPu were reduced to 11.8% of control. Current-response curves revealed that the inhibitory responses of CPu neurons to microiontophoretic administration of both the selective D1 receptor agonist SKF-38393 and the selective D2 receptor agonist quinpirole were significantly increased in 6-OHDA-pretreated rats, suggesting up-regulation of both receptor subtypes. Although our previous studies have established that D1 receptor activation is normally required for (enables) the inhibitory effects of selective D2 agonists in the CPu, this requirement was no longer evident in 6-OHDA-denervated rats. Whereas acute DA depletion [produced by the tyrosine hydroxylase inhibitor alpha-methyl-p-tyrosine (AMPT)] attenuated the inhibitory effects of quinpirole on CPu neurons, long-term DA denervation (produced by 6-OHDA) enhanced the inhibitory effects of the D2 agonist. The enhanced effects of quinpirole in 6-OHDA-lesioned rats were not due to residual DA stimulating supersensitive D1 receptors (i.e., enabling) since further DA depletion (99.7%), produced by acute administration of AMPT in 6-OHDA-lesioned rats, failed to diminish the inhibitory efficacy of quinpirole. In addition to relieving D2 receptors from the need for D1 receptor-mediated enabling, 6-OHDA lesions also abolished the normal synergistic relationship between the receptor subtypes since low (subinhibitory) currents of SKF-38393 (4 nA) failed to potentiate the inhibitory effects of quinpirole on CPu neurons in lesioned rats. Similar findings (i.e., supersensitivity and loss of synergistic effects) were obtained from rats that had received repeated pretreatment with reserpine (2.5 mg/kg) for 4 d, indicating that these effects of 6-OHDA lesions were due to the depletion of synaptic DA rather than to the structural loss of DA terminals. Therefore, both the quantitative (potentiation) and the qualitative (enabling) synergistic effects between D1 and D2 receptors in the rat CPu were abolished when these receptors were functionally supersensitive. The present study provides electrophysiological support for previous behavioral studies indicating that the requirement of D1 receptor stimulation for D2 receptor-mediated functional effects (enabling) is not maintained in rats chronically depleted of DA by either 6-OHDA lesions or repeated reserpine.
采用细胞外单单位记录和微离子透入技术，来测定经脑室内注射儿茶酚胺神经毒素6-羟基多巴胺（6-OHDA）使多巴胺（DA）去神经支配的大鼠尾壳核（CPu）中D1和D2多巴胺（DA）受体的敏感性及相互作用。在注射6-OHDA后7至10天，同侧CPu中的DA水平降至对照值的11.8%。电流-反应曲线显示，在经6-OHDA预处理的大鼠中，CPu神经元对微离子透入给予选择性D1受体激动剂SKF-38393和选择性D2受体激动剂喹吡罗的抑制反应均显著增强，提示两种受体亚型均上调。尽管我们之前的研究已证实，在CPu中选择性D2激动剂的抑制作用通常需要D1受体激活，但在经6-OHDA去神经支配的大鼠中这一需求不再明显。酪氨酸羟化酶抑制剂α-甲基-对-酪氨酸（AMPT）引起的急性DA耗竭减弱了喹吡罗对CPu神经元的抑制作用，而长期DA去神经支配（由6-OHDA引起）增强了D2激动剂的抑制作用。喹吡罗在6-OHDA损伤大鼠中的增强作用并非由于残留DA刺激超敏D1受体（即促成作用），因为在6-OHDA损伤大鼠中急性给予AMPT导致的进一步DA耗竭（99.7%）未能减弱喹吡罗的抑制效力。除了使D2受体不再需要D1受体介导的促成作用外，6-OHDA损伤还消除了受体亚型之间正常的协同关系，因为低（亚抑制性）电流的SKF-38393（4 nA）未能增强喹吡罗对损伤大鼠CPu神经元的抑制作用。从接受利血平（2.5 mg/kg）重复预处理4天的大鼠中也获得了类似的结果（即超敏性和协同效应丧失），表明6-OHDA损伤的这些效应是由于突触DA耗竭而非DA终末的结构丧失。因此，当大鼠CPu中的D1和D2受体功能超敏时，它们之间的定量（增强）和定性（促成）协同效应均被消除。本研究为之前的行为学研究提供了电生理支持，表明在经6-OHDA损伤或重复给予利血平使DA长期耗竭的大鼠中，D1受体刺激对D2受体介导的功能效应（促成作用）的需求不再存在。
