Davidkova G, Zhou L W, Morabito M, Zhang S P, Weiss B
Department of Pharmacology, MCP-Hahnemann School of Medicine, Allegheny University of the Health Sciences, Philadelphia, Pennsylvania, USA.
J Pharmacol Exp Ther. 1998 Jun;285(3):1187-96.
Long-term inhibition of D2 dopamine receptors using classic D2 dopamine receptor antagonists such as haloperidol often causes a compensatory up-regulation of the D2 dopamine receptors. We investigated whether the long-term inhibition of D2 dopamine receptors using an eukaryotic expression vector housing a cDNA sequence encoding an antisense RNA directed to the D2 dopamine receptor transcript (D2 antisense vector) would also produce up-regulation of the D2 receptors. Single, bilateral injections of the D2 antisense vector into the corpora striata of mice inhibited the stereotypy induced by acute challenge injections with the D2/D3 dopamine receptor agonist quinpirole but did not inhibit the grooming induced by acute challenge injections with the D1 agonist SKF 38393. Similar treatment with the D2 antisense vector produced a long-term (>1 month) cataleptic response without producing tolerance to challenge injections with haloperidol. By contrast, catalepsy induced by a single injection of haloperidol lasted only approximately 2 days, and tolerance developed to its effects after long-term treatment. Repeated treatment of mice with haloperidol resulted in an inhibition of apomorphine-induced climbing behavior throughout the time of treatment with haloperidol, but the climbing behavior markedly increased to levels significantly higher than that of the control mice immediately after withdrawal from haloperidol treatment. This increased climbing was accompanied by increased levels of D2 dopamine receptors in the striatum. By contrast, single, bilateral intrastriatal injections of the D2 antisense vector significantly inhibited apomorphine-induced climbing for approximately 30 days but failed to increase the climbing behavior or the levels of D2 dopamine receptors in striatum over those of the control values. These results suggest that a single injection of a D2 antisense RNA expression vector into mouse striatum produces specific, long-term inhibition of D2 dopamine receptor behaviors without causing a compensatory increase in the levels or function of D2 dopamine receptors.
使用经典的D2多巴胺受体拮抗剂（如氟哌啶醇）长期抑制D2多巴胺受体会经常导致D2多巴胺受体的代偿性上调。我们研究了使用携带编码针对D2多巴胺受体转录本的反义RNA的cDNA序列的真核表达载体（D2反义载体）长期抑制D2多巴胺受体是否也会导致D2受体上调。将D2反义载体单次双侧注射到小鼠纹状体中，可抑制D2/D3多巴胺受体激动剂喹吡罗急性激发注射所诱导的刻板行为，但不抑制D1激动剂SKF 38393急性激发注射所诱导的梳理行为。用D2反义载体进行类似处理会产生长期（>1个月）的僵住反应，且不会对氟哌啶醇激发注射产生耐受性。相比之下，单次注射氟哌啶醇所诱导的僵住仅持续约2天，长期治疗后会对其作用产生耐受性。用氟哌啶醇反复处理小鼠会在整个氟哌啶醇治疗期间抑制阿扑吗啡诱导的攀爬行为，但在停止氟哌啶醇治疗后，攀爬行为会立即显著增加至明显高于对照小鼠的水平。这种增加的攀爬行为伴随着纹状体中D2多巴胺受体水平的升高。相比之下，单次双侧纹状体内注射D2反义载体可在约30天内显著抑制阿扑吗啡诱导的攀爬行为，但未能使攀爬行为或纹状体中D2多巴胺受体水平超过对照值而增加。这些结果表明，将D2反义RNA表达载体单次注射到小鼠纹状体中可产生对D2多巴胺受体行为的特异性长期抑制，而不会导致D2多巴胺受体水平或功能的代偿性增加。
