Wolf M E, White F J, Nassar R, Brooderson R J, Khansa M R
Department of Psychiatry, Wayne State University School of Medicine, Detroit, Michigan.
J Pharmacol Exp Ther. 1993 Jan;264(1):249-55.
Various changes in the function of dopamine neurons have been proposed to underly the development of behavioral sensitization to the locomotor stimulant effects of d-amphetamine. The present study examined the relative importance of two such mechanisms after both short (3-4 days off) and longer (10-14 days off) withdrawals from repeated amphetamine or saline injection (1 mg/kg/day, days 1-5 and 8-12). First, single-unit recording was used to examine the sensitivity of impulse-regulating somatodendritic autoreceptors located on mesoaccumbens dopamine neurons in the rat ventral tegmental area. Second, in vivo microdialysis was used to examine the ability of amphetamine challenge to increase extracellular dopamine levels in the rat nucleus accumbens. Amphetamine-treated rats exhibited robust behavioral sensitization at both time points as compared to saline-treated rats. At 3 to 4 days off, autoreceptor subsensitivity was observed in the ventral tegmental area of amphetamine-treated rats, but there was no significant change in the ability of amphetamine to increase extracellular dopamine levels in nucleus accumbens. However, after 10 to 14 days off, autoreceptor subsensitivity was no longer observed, but amphetamine challenge resulted in a significantly greater increase in extracellular dopamine levels in amphetamine-treated as compared to saline-treated rats. These findings suggest that autoreceptor subsensitivity is a transient effect which may be related to the development of sensitization, whereas enhancement of amphetamine-stimulated dopamine release does not accompany early stages of behavioral sensitization, but may be involved in the persistence of the phenomenon after longer withdrawal periods.
多巴胺神经元功能的各种变化被认为是对d-苯丙胺运动刺激作用产生行为敏化的基础。本研究考察了在从重复注射苯丙胺或生理盐水（1毫克/千克/天，第1 - 5天和第8 - 12天）短期（停药3 - 4天）和长期（停药10 - 14天）撤药后，两种此类机制的相对重要性。首先，使用单细胞记录来检测位于大鼠腹侧被盖区中脑伏隔核多巴胺神经元上的冲动调节树突体自身受体的敏感性。其次，使用体内微透析来检测苯丙胺激发增加大鼠伏隔核细胞外多巴胺水平的能力。与生理盐水处理的大鼠相比，苯丙胺处理的大鼠在两个时间点均表现出强烈的行为敏化。在停药3至4天时，在苯丙胺处理的大鼠腹侧被盖区观察到自身受体敏感性降低，但苯丙胺增加伏隔核细胞外多巴胺水平的能力没有显著变化。然而，在停药10至14天后，不再观察到自身受体敏感性降低，但与生理盐水处理的大鼠相比，苯丙胺激发导致苯丙胺处理的大鼠细胞外多巴胺水平显著增加。这些发现表明，自身受体敏感性降低是一种短暂效应，可能与敏化的发展有关，而苯丙胺刺激的多巴胺释放增强并不伴随行为敏化的早期阶段，但可能参与了较长撤药期后该现象的持续存在。
