EVIDENCE OF A COMPLETE INDEPENDENCE OF THE NEUROBIOLOGICAL SUBSTRATES FOR THE INDUCTION AND EXPRESSION OF BEHAVIORAL SENSITIZATION TO AMPHETAMINE
EVIDENCE OF A COMPLETE INDEPENDENCE OF THE NEUROBIOLOGICAL SUBSTRATES FOR THE INDUCTION AND EXPRESSION OF BEHAVIORAL SENSITIZATION TO AMPHETAMINE
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DOI：
10.1016/0306-4522(94)00524-9
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发表时间：
1995-03-01
期刊：
影响因子：
3.3
通讯作者：
STINUS, L
中科院分区：
文献类型：
--
作者：
CADOR, M;BJIJOU, Y;STINUS, L
大鼠反复服用苯丙胺会产生行为敏感化，其特征是药物诱导的运动活动逐渐增强，或在药物治疗停止后对药物产生持久的行为过敏。一些作者认为，安非他明在伏核水平上的作用与行为敏化的表达有关，而安非他明在腹侧被盖区多巴胺胞体水平上的作用引起了一些与行为敏化有关的变化。本研究充分验证了这一假设。在两个独立的实验中，测试了在腹侧被盖区或伏隔核重复注射不同剂量的苯丙胺对伏隔核注射苯丙胺后的行为反应的影响。各组大鼠分别在腹侧被盖区(0、1、2.5、5微克/0.5微米)或伏核(0、1、3、10微克/1微克/1微米)重复注射不同剂量的苯丙胺(每隔一天注射一次)。在最后一次脑内注射苯丙胺后两天，每组大鼠在伏隔核内直接注射磷酸盐缓冲液，然后在伏核内注射苯丙胺(1微克/1微克/1微克/侧)，两天后在伏隔核内注射苯丙胺(0.5 mg/kg，sc)，记录每次注射后的运动反应。结果表明，伏隔核内注射安非他明后，大鼠的运动活动呈剂量依赖性增加，且与重复注射相同。在不同的磷酸盐缓冲盐水溶液和苯丙胺刺激下，不同的伏隔内预处理组之间没有观察到差异。相反，腹侧被盖区注射安非他明不会对运动活动产生任何影响。然而，尽管在伏隔核注射磷酸盐缓冲液后，不同处理组之间没有观察到差异，但观察到对伏核攻击剂量的苯丙胺的运动反应的增强，这依赖于腹侧被盖区的苯丙胺预处理剂量。用苯丙胺外周刺激后，也观察到类似的增强作用。最后，在伏隔核内注射激发剂量的可卡因(每侧10微克/1微升)和外围激发剂量的吗啡(2.5毫克/公斤，S.C.)，观察到交叉敏感化。总之，这些结果表明，仅在腹侧被盖区多巴胺细胞体水平上的苯丙胺作用是必要的，并且足以促进为行为敏化服务的变化，这可以稍后被伏核中多巴胺终末水平的苯丙胺作用所揭示。相反，伏隔核水平上的唯一安非他明作用不足以促进这些变化，但却是必要的--允许它们的表达。这些发现证明了神经解剖底物的完全解离，这些底物介导了对苯丙胺行为敏化的诱导和表达。
The repeated administration of amphetamine in rats produces behavioral sensitization which is characterized either by a progressive enhancement of the locomotor activity induced by the drug or by an enduring behavioral hypersensitivity to the drug after the cessation of the treatment. Some authors have suggested that the action of amphetamine at the level of the nucleus accumbens is responsible for the expression of behavioral sensitization, whereas the action of amphetamine at the level of the dopamine cell bodies in the ventral tegmental area induces some changes responsible for the initiation of the phenomenon. The present study fully tested this hypothesis. In two separate experiments, the effects of different doses of amphetamine repeatedly administered in the ventral tegmental area or in the nucleus accumbens were tested on the later behavioral reactivity to the administration of amphetamine in the nucleus accumbens. Independent groups of rats received five repeated administrations (one injection every other day) of different doses of amphetamine either in the ventral tegmental area (0, 1, 2.5, 5 mu g/0.5 mu 1 per side) or in the nucleus accumbens (0, 1, 3, 10 mu g/1 mu 1 per side). Two days following the last intracerebral amphetamine injection, each group received a phosphate buffer solution challenge directly into the nucleus accumbens followed two days later by an amphetamine challenge (1 mu g/1 mu 1 per side) in the nucleus accumbens and two days later by a peripheral challenge with amphetamine (0.5 mg/kg, s.c.), Locomotor responses were recorded following each injection. Results showed that injections of amphetamine into the nucleus accumbens induced a dose-dependent increase in locomotor activity which remained identical with the repetition of the injections. No difference between the different intra-accumbens pretreated groups was observed following the diverse phosphate-buffered saline solution and amphetamine challenges. In contrast, intra-ventral tegmental area administration of amphetamine did not produce any modification of locomotor activity. However, whereas no difference between the differently pretreated groups was observed following phosphate-buffered saline administration into the nucleus accumbens, a potentiation of the locomotor response to a challenge dose of amphetamine into the nucleus accumbens was observed which was dependent on the dose of amphetamine pretreatment into the ventral tegmental area. Similar potentiation was observed following peripheral challenge with amphetamine. Finally, cross-sensitization was observed when a challenge dose of cocaine (10 mu g/1 mu 1 per side) was injected into the nucleus accumbens, as well as when a peripheral challenge dose of morphine (2.5 mg/kg, s.c.) was administered to the ventral tegmental area-pretreated groups.Altogether, these results demonstrate that an amphetamine action solely at the level of the dopamine cell bodies in the ventral tegmental area is necessary and sufficient to promote changes subserving behavioral sensitization, which can be later revealed by an amphetamine action at the level of the dopamine terminals in the nucleus accumbens. On the contrary, the sole amphetamine action at the level of the nucleus accumbens is not sufficient to promote these changes but is necessary-to allow their expression. These findings argue for a complete dissociation for the neuroanatomical substrates which mediate the induction and the expression of the behavioral sensitization to amphetamine.