Wolf M E
Department of Neuroscience, Finch University of Health Sciences/The Chicago Medical School, North Chicago, Il 60064-3095, USA.
Prog Neurobiol. 1998 Apr;54(6):679-720. doi: 10.1016/s0301-0082(97)00090-7.
Behavioral sensitization refers to the progressive augmentation of behavioral responses to psychomotor stimulants that develops during their repeated administration and persists even after long periods of withdrawal. It provides an animal model for the intensification of drug craving believed to underlie addiction in humans. Mechanistic similarities between sensitization and other forms of neuronal plasticity were first suggested on the basis of the ability of N-methyl-D-aspartate (NMDA) receptor antagonists to prevent the development of sensitization [Karler, R., Calder, L. D., Chaudhry, I. A. and Turkanis, S. A. (1989) Blockade of "reverse tolerance" to cocaine and amphetamine by MK-801. Life Sci., 45, 599-606]. This article will review the large number of subsequent studies addressing: (1) the roles of NMDA, alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) and metabotropic glutamate receptors in the development and expression of behavioral sensitization, (2) excitatory amino acids (EAAs) and the role of conditioning in sensitization, (3) controversies regarding EAA involvement in behavioral sensitization based on studies with MK-801, (4) the effects of acute and repeated stimulant administration on EAA neurochemistry and EAA receptor expression, and (5) the neuroanatomy of EAA involvement in sensitization. To summarize, NMDA, AMPA metabotropic glutamate receptors all participate in the development of sensitization, while maintenance of the sensitized state involves alterations in neurochemical measures of EAA transmission as well as in the expression and sensitivity of AMPA and NMDA receptors. While behavioral sensitization likely involves complex neuronal circuits, with EAAs participating at several points within this circuitry, EAA projections originating in prefrontal cortex may play a particularly important role in the development of sensitization, perhaps via their regulatory effects on midbrain dopamine neurons. The review concludes by critically evaluating various hypotheses to account for EAA involvement in the development of behavioral sensitization, and considering the question of whether EAA receptors are involved in mediating the rewarding effects of psychomotor stimulants and sensitization of such rewarding effects.
行为敏化是指在反复给予精神运动兴奋剂期间，对其行为反应逐渐增强，且即使在长时间戒断后仍持续存在。它为人类成瘾背后被认为的药物渴望增强提供了一种动物模型。基于N-甲基-D-天冬氨酸（NMDA）受体拮抗剂预防敏化发展的能力，敏化与其他形式的神经元可塑性之间的机制相似性首次被提出[卡勒，R.，考尔德，L. D.，乔德里，I. A.和图尔卡尼斯，S. A.（1989年）MK-801对可卡因和苯丙胺“反向耐受”的阻断。生命科学，45，599 - 606]。本文将综述大量后续研究，这些研究涉及：（1）NMDA、α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）和代谢型谷氨酸受体在行为敏化的发展和表达中的作用，（2）兴奋性氨基酸（EAA）以及条件作用在敏化中的作用，（3）基于MK-801研究关于EAA参与行为敏化的争议，（4）急性和反复给予兴奋剂对EAA神经化学和EAA受体表达的影响，以及（5）EAA参与敏化的神经解剖学。总之，NMDA、AMPA和代谢型谷氨酸受体都参与敏化的发展，而敏化状态的维持涉及EAA传递的神经化学指标的改变以及AMPA和NMDA受体的表达和敏感性的改变。虽然行为敏化可能涉及复杂的神经回路，EAA在该回路中的多个点参与其中，但起源于前额叶皮质的EAA投射可能在敏化的发展中发挥特别重要的作用，也许是通过它们对中脑多巴胺神经元的调节作用。综述通过批判性地评估各种假说来解释EAA参与行为敏化的发展，并考虑EAA受体是否参与介导精神运动兴奋剂的奖赏效应以及这种奖赏效应的敏化问题来得出结论。
