Segal D S, Kuczenski R
Department of Psychiatry, School of Medicine, University of California at San Diego, La Jolla, California, USA.
J Pharmacol Exp Ther. 1999 Oct;291(1):19-30.
Our previous studies indicate that exposure of rats to an escalating-dose, multibinge pattern of amphetamine or methamphetamine administration results in a unique emergent behavioral profile and concomitant regionally specific dopamine response patterns in the nucleus accumbens and caudate-putamen. In the present study, we explored the generality of these effects by using an escalating-dose, multibinge treatment with methylphenidate (MP), a stimulant that, unlike the amphetamines, produces no increase in serotonin transmission. Furthermore, MP exerts many of its effects through dopamine uptake blockade, in contrast to the amphetamines that primarily release dopamine. The results showed that MP administered according to an escalating-dose, multibinge regimen produced the expression of the emergent behavioral profile. This pattern of behavior was also evident in these animals in response to 2.5 mg/kg acute amphetamine after the last MP binge exposure. Consistent with previous evidence, neither acute nor multibinge MP treatment produced a significant serotonin response. In contrast, a regionally specific dopamine response alteration was observed during the course of this treatment. Caudate-putamen dopamine exhibited a pattern of increasing response during an acute MP binge but pronounced tolerance developed to this effect after multiple binges. By contrast, the nucleus accumbens dopamine response did not significantly change during the acute binge and exhibited a slight incremental pattern to the injections of the final binge. These findings, along with the effects of other stimulants, are discussed in terms of a possible role for serotonin and for the differential changes in the caudate-putamen and nucleus accumbens dopamine responses in the emergent behavioral profile. The similarity between the effects of MP and the amphetamines provides further support for the multibinge-induced behavioral profile as a possible animal model for stimulant-induced psychosis.
我们之前的研究表明，给大鼠使用剂量递增、多次 binge 模式的苯丙胺或甲基苯丙胺，会导致独特的新出现行为特征以及伏隔核和尾状核 - 壳核中伴随的区域特异性多巴胺反应模式。在本研究中，我们通过使用剂量递增、多次 binge 方式给予哌甲酯（MP）来探究这些效应的普遍性，MP 是一种兴奋剂，与苯丙胺不同，它不会增加 5-羟色胺传递。此外，与主要释放多巴胺的苯丙胺相反，MP 通过阻断多巴胺摄取发挥其许多作用。结果显示，按照剂量递增、多次 binge 方案给予的 MP 产生了新出现行为特征的表达。在最后一次 MP binge 暴露后，这些动物对 2.5mg/kg 急性苯丙胺的反应中，这种行为模式也很明显。与先前的证据一致，急性或多次 binge 的 MP 治疗均未产生显著的 5-羟色胺反应。相比之下，在该治疗过程中观察到了区域特异性多巴胺反应改变。尾状核 - 壳核多巴胺在急性 MP binge 期间呈现出反应增加的模式，但多次 binge 后对这种效应产生了明显的耐受性。相比之下，伏隔核多巴胺反应在急性 binge 期间没有显著变化，并且对最后一次 binge 的注射呈现出轻微的递增模式。这些发现以及其他兴奋剂的作用，从 5-羟色胺的可能作用以及尾状核 - 壳核和伏隔核多巴胺反应在新出现行为特征中的差异变化方面进行了讨论。MP 和苯丙胺效应之间的相似性为多次 binge 诱导的行为特征作为兴奋剂诱导精神病的一种可能动物模型提供了进一步支持。
