Lasting alterations in drug biodistribution in the animal brain regions after repeated administration of methamphetamine or cocaine

在动物中，甲基苯丙胺(MAP)的长期行为敏化已被证实在慢性MAP(反向耐受现象)之后。到目前为止，人们认为MAP引起的纹状体和伏隔核多巴胺(DA)释放的持续增强与大脑对精神病复发的易感性的诱导和表现有关。根据Fischer和Cho(1979)关于MAP诱导的神经末梢DA释放的交换扩散模型，似乎可以提供一个可行的假设，即亚慢性MAP给药可能会在神经末梢的突触前细胞膜产生持久的变化，这反过来可能导致MAP摄取增加(通过DA转运体)，从而增加DA向突触间隙的释放。为了证实这一假设，我们研究了可卡因类似物[^&lt；125&gt；i]RTI 55(可卡因的类似物)在MAP和可卡因致敏大鼠大脑中的生物分布变化。在MAP致敏大鼠，额叶皮质、纹状体、伏隔核、丘脑、杏仁核、海马体、腹侧被盖区、黑质、小脑和脑桥的RTI55放射性显著增加。在可卡因致敏大鼠，[^&lt；125&gt；I]RTI55在同一脑区的放射性下降幅度更大。IMP研究表明，这些变化不是由于新陈代谢或脑血流的变化。多巴胺转运蛋白具有与其他单胺转运蛋白相似的结构。MAP和可卡因可能与5-羟色胺和去甲肾上腺素转运体以及DA转运体结合。因此，亚慢性给予MAP或可卡因可能引起神经末梢突触前细胞膜(包括单胺转运体)的持久改变，尽管MAP和可卡因致敏大鼠这种改变的方向是有争议的。本研究证实了亚慢性MAP和可卡因的假说

In animals, a long-term behavioral sensitization to methamphetamine (MAP) has been confirmed after chronic MAP (reverse tolerance phenomenon). To date, it is suggested that lasting enhancemnt of MAP-induced increase in dopamine (DA) release in the striatum and nucleus accumbens relates to induction and manifestation of the brain vulnerability to psychotic relapses. According to the exchange diffusion model (Fischer and Cho, 1979) regarding the MAP-induced release of DA at nerve terminals, it seems possible to provide a working hypothesis that that subchronic MAP administration may produce an enduring change at the presynaptic cell membrane of the nerve terminal, which may in turn cause an increase in MAP uptake (by DA transporter) with a subsequent increase in DA release to the synaptic cleft. To confirm this hypothesis, we examined the changes in biodistribution of [^<125>I]RTI 55 (an analogue of cocaine) in the MAP-, and cocaine-sensitized rat brain. In MAP-sensitized rat, radioactivity of [^<125>I]RTI 55 increased significantly more in the frontal cortex, striatum, nucleus accumbens, thalamus, amygdala, hippocampus, ventral tegmental area, substantia nigra, cerebellum and pons. In cocaine-sensitized rat, radioactivity of [^<125>I]RTI 55 decreased significantly more in the same brain area. [^<123>I]IMP study showed these changes not due to alterations in metabolism or cerebral blood flow. Dopamine transporter has a structure similar to those of the other monoamine transporters. It seems possible that MAP and cocaine may bind to the 5-HT and noradrenaline transporters as well as DA transporter. Accordingly, it is concluded that subchronic administration of MAP or cocaine may cause a lasting change at the presynaptic cell membrane (including monoamine transporters) of the nerve terminal, though the direction of the changes of MAP- and cocaine-sensitized rats were controversial. This study comfirmed the hypothesis which lsubchronic MAP and cocain