Culver K E, Rosenfeld J M, Szechtman H
Department of Psychiatry and Behavioral Neurosciences, McMaster University, Hamilton, L8N 3Z5, Ontario, Canada.
Neuropharmacology. 2002 Sep;43(3):385-93. doi: 10.1016/s0028-3908(02)00128-4.
Previous studies have shown that the monoamine oxidase inhibitor (MAOI) clorgyline, blocks locomotor sensitization to the D(2)/D(3) dopamine agonist quinpirole and sensitizes self-directed mouthing behavior in rats by a mechanism independent of MAO inhibition. However, clorgyline is also an inhibitor of striatal dopamine uptake, and this mechanism could account for the effect of clorgyline on quinpirole sensitization. To investigate this possibility, the effects of clorgyline and pargyline were examined. Of these two MAOIs, only clorgyline inhibits dopamine uptake in the striatum. Rats received subcutaneous injections of clorgyline (1 mg/kg), pargyline (10 mg/kg) or vehicle 90 min prior to each injection of quinpirole (0.5 mg/kg, s.c., x8, twice weekly) or saline. Clorgyline and pargyline blocked the development of quinpirole-induced locomotor sensitization and sensitized self-directed mouthing behaviors in quinpirole rats. Thus, it is unlikely that clorgyline blocks locomotor sensitization to quinpirole via an inhibition of striatal dopamine uptake. Both MAOIs increased dopamine metabolism in the striatum, showed opposite effects in the prefrontal cortex, and eliminated the correlation between prefrontal dopamine and striatal DOPAC content found in quinpirole sensitized rats. We suggest that clorgyline and pargyline may affect the behavioral and neurochemical response to quinpirole via a previously reported MAOI-displaceable quinpirole binding site, a site which we hypothesize serves as a 'switch' to select what motor output becomes sensitized to repeated injections of quinpirole.
先前的研究表明，单胺氧化酶抑制剂（MAOI）氯吉兰可阻断对D(2)/D(3)多巴胺激动剂喹吡罗的运动敏化作用，并通过一种独立于MAO抑制的机制使大鼠的自我指向性口部行为敏感化。然而，氯吉兰也是纹状体多巴胺摄取的抑制剂，这种机制可能解释氯吉兰对喹吡罗敏化的作用。为了研究这种可能性，研究了氯吉兰和帕吉林的作用。在这两种MAOI中，只有氯吉兰抑制纹状体中的多巴胺摄取。在每次注射喹吡罗（0.5mg/kg，皮下注射，共8次，每周两次）或生理盐水前90分钟，给大鼠皮下注射氯吉兰（1mg/kg）、帕吉林（10mg/kg）或赋形剂。氯吉兰和帕吉林阻断了喹吡罗诱导的运动敏化的发展，并使喹吡罗处理的大鼠的自我指向性口部行为敏感化。因此，氯吉兰不太可能通过抑制纹状体多巴胺摄取来阻断对喹吡罗的运动敏化。两种MAOI均增加了纹状体中的多巴胺代谢，在前额叶皮质显示出相反的作用，并消除了喹吡罗敏化大鼠中前额叶多巴胺与纹状体DOPAC含量之间的相关性。我们认为，氯吉兰和帕吉林可能通过先前报道的MAOI可置换的喹吡罗结合位点影响对喹吡罗的行为和神经化学反应，我们假设该位点作为一个“开关”，来选择哪种运动输出对重复注射喹吡罗变得敏感。
