Wolf M E, Dahlin S L, Hu X T, Xue C J, White K
Department of Neuroscience, Finch University of Health Sciences/The Chicago Medical School, IL 60064-3095, USA.
Neuroscience. 1995 Nov;69(2):417-39. doi: 10.1016/0306-4522(95)00248-h.
Behavioral sensitization to amphetamine involves the mesoaccumbens dopamine system and is accompanied by cellular changes in this system. Excitatory amino acid antagonists, when co-administered with amphetamine, prevent both behavioral sensitization and associated changes in the mesoaccumbens dopamine system. This suggests that excitatory amino acid-dependent events are critical to the initiation of sensitization. This study sought to identify excitatory amino acid projections required for sensitization, focusing on projections to the nucleus accumbens or ventral tegmental area. The major excitatory projections to the nucleus accumbens originate in the prefrontal cortex, amygdala and hippocampus. The prefrontal cortex and amygdala also send excitatory projections to the ventral tegmental area. Ibotenic acid lesions of the prefrontal cortex or amygdala and electrolytic lesions of the fornix were performed in rats. After one week of recovery, rats were treated with water or 2.5 mg/kg amphetamine for six days and challenged with amphetamine on day 8. Activity was tested in photobeam cages on days 1 and 8. On day 1, control and sham-lesioned rats exhibited stereotyped behaviors followed by a period of post-stereotypy locomotion. On day 8, sensitization was evident as an enhancement of both stereotypy and post-stereotypy locomotion. Co-administration of N-methyl-D-aspartate antagonists [MK-801 (dizocilpine maleate) or CGS 19755] with amphetamine prevented the development of sensitization of both stereotypy and post-stereotypy locomotion. Neither antagonist, however, prevented the expression of sensitization. None of the lesions completely mimicked these effects of N-methyl-D-aspartate antagonists. Lesions of hippocampal projections traveling in the fornix produced a general disinhibition of locomotor activity, but did not prevent sensitization of either stereotypy or post-stereotypy locomotion. Lesions of the prefrontal cortex failed to prevent sensitization of stereotypy was obtained following repeated amphetamine administration. However, like prefrontal cortical lesions, amygdala lesions prevented sensitization of post-stereotypy locomotion. When interpreted in the light of previous studies demonstrating the importance of the ventral tegmental area in the initiation of sensitization, the present results suggest a likely role for neuronal circuits involving the prefrontal cortex, amygdala and ventral tegmental area in the development of sensitization of post-stereotypy locomotion following repeated amphetamine administration. Such circuits may initiate sensitization through a mechanism involving excitatory amino acid regulation of the activity of mesoaccumbens dopamine neurons. Parallel circuits, involving other brain regions, may similarly contribute to sensitization of stereotyped behaviors.
对苯丙胺的行为敏化涉及中脑伏隔核多巴胺系统，并伴有该系统的细胞变化。兴奋性氨基酸拮抗剂与苯丙胺共同给药时，可预防行为敏化以及中脑伏隔核多巴胺系统的相关变化。这表明兴奋性氨基酸依赖性事件对于敏化的起始至关重要。本研究旨在确定敏化所需的兴奋性氨基酸投射，重点关注投向伏隔核或腹侧被盖区的投射。投向伏隔核的主要兴奋性投射起源于前额叶皮质、杏仁核和海马体。前额叶皮质和杏仁核也向腹侧被盖区发送兴奋性投射。对大鼠进行前额叶皮质或杏仁核的鹅膏蕈氨酸损伤以及穹窿的电解损伤。恢复一周后，大鼠连续六天接受水或2.5mg/kg苯丙胺治疗，并在第8天用苯丙胺进行激发试验。在第1天和第8天在光电束笼中测试活动情况。在第1天，对照和假损伤大鼠表现出刻板行为，随后是一段刻板后运动期。在第8天，敏化表现为刻板行为和刻板后运动的增强。N-甲基-D-天冬氨酸拮抗剂[MK-801（马来酸氯氮平）或CGS 19755]与苯丙胺共同给药可预防刻板行为和刻板后运动敏化的发展。然而，两种拮抗剂均不能阻止敏化的表达。没有一种损伤能完全模拟N-甲基-D-天冬氨酸拮抗剂的这些作用。沿穹窿走行的海马投射损伤导致运动活动普遍去抑制，但不能阻止刻板行为或刻板后运动的敏化。前额叶皮质损伤不能阻止重复给予苯丙胺后刻板行为的敏化。然而，与前额叶皮质损伤一样，杏仁核损伤可阻止刻板后运动的敏化。根据先前证明腹侧被盖区在敏化起始中重要性的研究来解释，目前的结果表明，在重复给予苯丙胺后，涉及前额叶皮质、杏仁核和腹侧被盖区的神经回路可能在刻板后运动敏化的发展中发挥作用。这样的神经回路可能通过一种涉及兴奋性氨基酸调节中脑伏隔核多巴胺神经元活性的机制来启动敏化。涉及其他脑区的平行神经回路可能同样有助于刻板行为的敏化。
