Hammer R P, Cooke E S
Laboratory of Cellular and Molecular Neuropharmacology, University of Hawaii School of Medicine, Honolulu 96822.
J Neurosci. 1994 Jul;14(7):4289-98. doi: 10.1523/JNEUROSCI.14-07-04289.1994.
Acute administration of cocaine is known to enhance extracellular dopamine levels in the striatum and to activate immediate-early gene expression in striatal neurons. Regional cerebral metabolic rate for glucose (rCMRglc) reportedly increases in extrapyramidal and mesolimbic brain regions in response to acute cocaine treatment. However, chronic administration attenuates the cocaine-induced enhancement of regional dopamine response and the induction of immediate-early gene expression in these regions. Chronic treatment also produces tolerance to cocaine's reinforcing effects. Thus, differential responses to cocaine occur with increasing length of treatment. Therefore, we examined the time course of effects of repeated daily cocaine treatment on rCMRglc in rat brain. Acute administration of 10 mg/kg cocaine slightly increased rCMRglc in mesolimbic and extrapyramidal regions. However, no significant effects were observed until more than 7 d of treatment, whereupon rCMRglc was reduced compared to saline treatment in the infralimbic portion of the medial prefrontal cortex, nucleus accumbens, olfactory tubercle, habenula, amygdala, and a few other brain regions. In contrast, after 13 d of 10 mg/kg cocaine treatment, challenge with 30 mg/kg cocaine increased rCMRglc in the striatum, globus pallidus, entopeduncular nucleus, subthalamus, substantia nigra pars reticulata, and a few other regions without affecting limbic or mesolimbic regions. Thus, repeated daily treatment with a low dose of cocaine gradually decreased metabolic activity particularly in mesolimbic regions. Subsequent treatment with a higher dose produced metabolic activation mostly in extrapyramidal regions. This effect of chronic treatment could represent tolerance to the initial metabolic response, which can be replicated thereafter but only by increasing the drug dose. These results suggest that tolerance to the metabolic effects of cocaine in selective mesolimbic circuits may contribute to the development of behavioral dependence with repeated exposure.
已知急性给予可卡因可提高纹状体中的细胞外多巴胺水平，并激活纹状体神经元中的即刻早期基因表达。据报道，急性可卡因治疗会使锥体外系和中脑边缘脑区的局部脑葡萄糖代谢率（rCMRglc）升高。然而，长期给药会减弱可卡因诱导的这些区域多巴胺反应增强以及即刻早期基因表达的诱导。长期治疗还会产生对可卡因强化作用的耐受性。因此，随着治疗时间延长，对可卡因会出现不同反应。所以，我们研究了每日重复给予可卡因对大鼠脑rCMRglc影响的时间进程。急性给予10mg/kg可卡因会使中脑边缘和锥体外系区域的rCMRglc略有升高。然而，直到治疗超过7天才有显著影响，此时与生理盐水治疗相比，内侧前额叶皮质的下缘部分、伏隔核、嗅结节、缰核、杏仁核以及其他一些脑区的rCMRglc降低。相反，在10mg/kg可卡因治疗13天后，用30mg/kg可卡因激发会使纹状体、苍白球、内苍白球核、下丘脑、黑质网状部以及其他一些区域的rCMRglc升高，而不影响边缘或中脑边缘区域。因此，每日重复给予低剂量可卡因会逐渐降低代谢活性，尤其是在中脑边缘区域。随后给予更高剂量治疗则主要在锥体外系区域产生代谢激活。长期治疗的这种效应可能代表对初始代谢反应的耐受性，此后可以复制，但只能通过增加药物剂量来实现。这些结果表明，对可卡因在选择性中脑边缘回路中代谢作用的耐受性可能有助于反复接触后行为依赖性的发展。
