D-amphetamine-induced behavioral sensitization: Implication of a glutamatergic medial prefrontal cortex-ventral tegmental area innervation
D-amphetamine-induced behavioral sensitization: Implication of a glutamatergic medial prefrontal cortex-ventral tegmental area innervation
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DOI：
10.1016/s0306-4522(99)00361-9
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发表时间：
1999-01-01
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
苯丙胺的行为敏感化表现为重复注射时药物的行为激活效应逐渐增强，以及对后来的环境或药物挑战的长期超敏反应。到目前为止，中隔伏隔区多巴胺系统被认为是该过程的主要候选者，这一过程的诱导和表达分别依赖于苯丙胺在腹侧被盖区和伏隔核的作用。这一过程的发展被认为是躯体树突状细胞释放的多巴胺和多巴胺能D-1受体之间相互作用的结果，这些受体位于腹侧被盖区的不同输入，包括部分来自中皮质边缘区的谷氨酸传入，如内侧前额叶皮质和杏仁核。设计了三组实验来测试这些成分在苯丙胺行为敏化中的作用。首先，研究了腹侧被盖区谷氨酸能传递对苯丙胺致敏的干预作用。本实验观察了静脉注射甲基-D-天冬氨酸拮抗剂3-(R-2-羧基哌嗪-4-基)-丙基-1-磷酸对苯丙胺在腹侧被盖区重复给药引起的行为敏化的影响。结果发现，在腹侧被盖区用3-(R-2-carboxypiperazin-4-yl)-propyl-1-phosphonic酸和苯丙胺联合阻断N-甲基-D-天冬氨酸受体，可剂量依赖性地阻止致敏的诱导。在第二步中，测试了将谷氨酸能输入发送到腹侧被盖区的结构在行为敏化过程中的作用。我们评估了损毁内侧前额叶皮质和杏仁核的鹅掌酸对外周或腹侧被盖区注射苯丙胺所引起的行为敏感化的影响。我们发现损毁内侧前额叶皮质的鹅掌酸阻断了腹侧被盖区和安非他明外周处理所引起的行为敏感化。相反，杏仁核的鹅膏酸损毁对外周或中枢诱导的行为敏化没有影响。这些实验证实：(I)多巴胺能神经元所在的腹侧被盖区是行为敏化诱导的关键部位，(Ii)这一过程涉及腹侧被盖区的谷氨酸能传递，以及(Iii)内侧前额叶皮质受到严重影响，仅仅是因为其谷氨酸能直接输入到被盖区腹侧神经元。此外，这些结果强化了这样的观点，即对苯丙胺的行为敏化不仅涉及中脑伏隔区的多巴胺能神经元，还涉及中皮质边缘系统的其他结构，如内侧前额叶皮质，更具体地说，它的谷氨酸能成分。(C)1999年IBRO。爱思唯尔科学有限公司出版。
Behavioral sensitization to amphetamine is expressed as a progressive enhancement of the behavioral activating effects of the drug when repeated injections are performed as well as a long-lasting hypersensitivity to later environmental or pharmacological challenges. The mesoaccumbens dopamine system has been proposed to be the major candidate so far responsible for the induction and expression of this process, which are dependent on the action of amphetamine in the ventral tegmental area and nucleus accumbens, respectively. The development of this process has been proposed to be the result of an interaction between somatodendritically released dopamine and dopaminergic D-1 receptors localized on different inputs to the ventral tegmental area, including glutamate afferents arising in part from mesocorticolimbic areas such as the medial prefrontal cortex and the amygdala, Three groups of experiments were designed to test the role of each of these components in the behavioral sensitization to amphetamine. First, the intervention of the glutamatergic transmission of the ventral tegmental area in the induction of sensitization to amphetamine was tested. The effects of an iv-methyl-D-aspartate antagonist, 3-(R-2-carboxypiperazin-4-yl) -propyl-1-phosphonic acid, on the behavioral sensitization induced by amphetamine administered repeatedly in the ventral tegmental area was tested. It was found that the blockade of N-methyl-D-aspartate receptors with 3-(R-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid coadministered with amphetamine in the ventral tegmental area dose-dependently prevented the induction of sensitization. In a second step, the role of the structures which send glutamatergic inputs to the ventral tegmental area in the process of behavioral sensitization was tested. We evaluated the effects of ibotenic acid lesion of the medial prefrontal cortex and the amygdala on behavioral sensitization induced by peripheral or intra-ventral tegmental area administration of amphetamine. We found that ibotenic acid lesion of the medial prefrontal cortex blocked the behavioral sensitization induced by both intra-ventral tegmental area and peripheral treatment with amphetamine. In contrast, ibotenic acid lesion of the amygdala produced no effect on behavioral sensitization induced peripherally or centrally. These experiments confirmed (i) that the ventral tegmental area, where dopaminergic cell bodies are located, is a critical site for the induction of behavioral sensitization, (ii) that this process implicates the glutamatergic transmission in the ventral tegmental area, and (iii) that the medial prefrontal cortex is crucially implicated merely because of its direct glutamatergic inputs on to ventral tegmental area neurons.Together, these results reinforce the view that the behavioral sensitization to amphetamine implicates not only the mesoaccumbens dopaminergic neurons, but also other structures of the mesocorticolimbic system, such as the medial prefrontal cortex and more specifically its glutamatergic component. (C) 1999 IBRO. Published by Elsevier Science Ltd.