Lasting alterations of dopamine uptake sites in animal brain after repeated administration of cocaine.

在动物实验中，在亚慢性给药这些中枢兴奋剂后，证实了对可卡因或释放胺的长期行为致敏（LTBS）（反向耐受现象）。在致敏动物体内注入这些刺激物后，纹状体和伏隔核的多巴胺（DA）释放显著增加，这与LTBS的诱导和表现以及大脑对精神病复发的易感性有关。由于可卡因作用于多巴胺转运体（DAT）， DAT可能在可卡因诱导的LTBS中起重要作用。可卡因类似物RTI 55是DAT最有效的配体之一。为了确定亚慢性可卡因给药是否会产生持久的DAT改变，我们通过离体放射自显影检查了可卡因致敏大鼠大脑中[^<125>I] RTI 55的区域积累，以及可卡因致敏大鼠纹状体中[^<125>I] RTI 55与DAT的体外结合。雄性Sprague Dawley大鼠每天注射可卡因（20 mg/kg, i.p.） 21天。最后一次注射后7天，处于稳定状态的大鼠接受腹腔注射[^<125>I] RTI 55进行放射自显像分析或斩首进行放射性标记受体试验。在可卡因致敏的动物中，包括额叶皮质、纹状体和伏隔核在内的大脑区域的放射性积累明显减少。但[^<125>I] RTI 55结合纹状体DAT的低亲和位点和高亲和位点均未发生变化。这些结果表明，很难用纹状体数据的变化来解释可卡因诱导的LTBS。

In animals, a long-term behavioral sensitization (LTBS) to cocaine or releasing amines (reverse tolerance phenomenon) has been confirmed after subchronic administration of these central stimulants. A challenge injection of these stimulants to sensitized animals induces a significantly greater increase in dopamine (DA) release in the striatum and nucleus accumbens, which relates to induction and manifestation of the LTBS and the brain vulnerability to psychotic relapse. Since cocaine acts at a dopamine transporter (DAT), DAT may play an essential role for the cocaine-induced LTBS.The cocaine analogue RTI 55 is one of the most potent ligand for DAT.To determine if subchronic administration of cocaine produces long-lasting alterations in DAT,we examined the regional accumulation of [^<125>I] RTI 55 in the cocaine sensitized rat brain by ex vivo autoradiography and in vitro binding of [^<125>I] RTI 55 to DAT in the striatum of cocaine sensitized rats. Male Sprague Dawley rats received a daily injection of cocaine (20 mg/kg, i.p.) for 21 days. Seven days after the last injection, rats in the steady state received i.p.injection of [^<125>I] RTI 55 for the autoradiographical analysis or were decapitated for the radio-labeled receptor assay. In the cocaine sensitized animals, the accumulation of radioactivity decreased significantly more in the brain regions including frontal cortex, striatum and nucleus accumbens. But [^<125>I] RTI 55 binding to the striatal DAT did not change in neither low or high affinity sites. These results suggest that it is difficult to explain the cocaineinduced LTBS by a change in striatal DAT.