Qin Z H, Zhou L W, Zhang S P, Wang Y, Weiss B
Department of Pharmacology, Medical College of Pennsylvania, Philadelphia, USA.
Mol Pharmacol. 1995 Oct;48(4):730-7.
In vivo administration of an antisense oligonucleotide targeted toward the D2 dopamine (DA) receptor mRNA (D2 AS) markedly inhibited D2 receptor-mediated behaviors but produced only a relatively small reduction in the levels of D2 DA receptors in mouse striatum. This apparent dissociation between DA receptor-mediated behaviors and the levels of D2 DA receptors was addressed by inhibiting the total number of D2 DA receptors by intraperitoneal administration of the selective, irreversibly acting D2 DA receptor antagonist fluphenazine-N-mustard (FNM) and then determining the effects of D2 AS, administered intracerebroventricularly, on the rate of synthesis of D2 DA receptors and on the recovery of D2 receptor-mediated behaviors. FNM inactivated approximately 90% of D2 DA receptors within 4 hr of treatment, after which the receptors returned to normal levels by approximately 8 days. D2 AS treatment significantly inhibited the rate of recovery of D2 DA receptors in striatum of FNM-treated mice. FNM treatment also produced a number of behavioral alterations, including catalepsy, and the inhibition of stereotypic behavior induced by the D2/D3 DA receptor agonist quinpirole. Both of these behaviors returned to normal within 8 days after FNM treatment. D2 AS treatment delayed the restoration of these FNM-induced behaviors. Thus, it reduced the rate of disappearance of the cataleptic behavior induced by FNM and significantly delayed the restoration of the stereotypic behavior induced by quinpirole. The changes induced by D2 AS on D2 receptor-mediated behaviors were reversed on cessation of D2 AS treatment. A random oligomer given in the same amount and for the same length of time as that of the D2 AS had no significant effects on either D2 DA receptor synthesis or DA receptor-mediated behaviors. These studies demonstrate that in vivo administration of D2 AS decreased the rate of recovery of D2 DA receptors and inhibited the recovery of D2 DA receptor-mediated behaviors after irreversible receptor inactivation and suggest that D2 AS treatment inhibits the synthesis of a functional pool of D2 DA receptors.
向D2多巴胺（DA）受体mRNA（D2反义寡核苷酸，D2 AS）靶向给药反义寡核苷酸可显著抑制D2受体介导的行为，但仅使小鼠纹状体中D2 DA受体水平相对小幅降低。通过腹腔注射选择性、不可逆作用的D2 DA受体拮抗剂氟奋乃静 - N - 芥子气（FNM）抑制D2 DA受体总数，然后确定脑室内给药的D2 AS对D2 DA受体合成速率以及D2受体介导行为恢复的影响，解决了DA受体介导行为与D2 DA受体水平之间这种明显的分离现象。FNM在治疗后4小时内使约90%的D2 DA受体失活，之后受体在约8天内恢复到正常水平。D2 AS治疗显著抑制了FNM处理小鼠纹状体中D2 DA受体的恢复速率。FNM治疗还产生了一些行为改变，包括僵住症以及对D2 / D3 DA受体激动剂喹吡罗诱导的刻板行为的抑制。这两种行为在FNM治疗后8天内恢复正常。D2 AS治疗延迟了这些FNM诱导行为的恢复。因此，它降低了FNM诱导的僵住症行为的消失速率，并显著延迟了喹吡罗诱导的刻板行为的恢复。D2 AS停止治疗后，其对D2受体介导行为的诱导变化得以逆转。给予与D2 AS相同量和相同时间长度的随机寡聚物对D2 DA受体合成或DA受体介导行为均无显著影响。这些研究表明，体内给予D2 AS可降低D2 DA受体的恢复速率，并在不可逆受体失活后抑制D2 DA受体介导行为的恢复，提示D2 AS治疗可抑制功能性D2 DA受体池的合成。
