Nestler E J, Tallman J F
Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut 06508.
Mol Pharmacol. 1988 Feb;33(2):127-32.
We have studied a possible role for cyclic AMP-dependent protein kinase in mediating opiate addiction in the central nervous system by focusing on the rat locus coeruleus. This brain region is well suited for these studies because it is relatively homogeneous and because a wealth of electrophysiological and behavioral data indicate that it plays an important role in mediating the chronic effects of opiates in animals, including humans. It was found that chronic, but not acute, in vivo treatment of rats with morphine increased cyclic AMP-dependent protein kinase activity in the locus coeruleus with a time course that closely paralleled the time course by which locus coeruleus neurons become tolerant to and dependent on opiates, based on electrophysiological studies. Concomitant administration of the opiate receptor antagonist naltrexone was found to block the effect of chronic morphine treatment on protein kinase activity, indicating that the effect is mediated via specific activation of opiate receptors. In contrast, chronic morphine treatment did not alter protein kinase activity in several other brain regions studied, including the neostriatum, frontal cortex, and dorsal raphe. We propose that the observed increase in cyclic AMP-dependent protein kinase activity in the locus coeruleus contributes to the biochemical basis of opiate addiction.
我们通过聚焦大鼠蓝斑，研究了环磷酸腺苷（cAMP）依赖性蛋白激酶在介导中枢神经系统阿片类成瘾中的可能作用。这个脑区非常适合这些研究，因为它相对同质，而且大量的电生理和行为数据表明，它在介导阿片类药物对动物（包括人类）的慢性影响中起重要作用。基于电生理研究发现，对大鼠进行慢性而非急性的吗啡体内治疗，会增加蓝斑中环磷酸腺苷依赖性蛋白激酶的活性，其时间进程与蓝斑神经元对阿片类药物产生耐受性和依赖性的时间进程密切平行。同时发现，给予阿片受体拮抗剂纳曲酮可阻断慢性吗啡治疗对蛋白激酶活性的影响，表明该作用是通过阿片受体的特异性激活介导的。相比之下，慢性吗啡治疗并未改变包括新纹状体、额叶皮质和中缝背核在内的其他几个研究脑区的蛋白激酶活性。我们认为，观察到的蓝斑中环磷酸腺苷依赖性蛋白激酶活性增加有助于阿片类成瘾的生化基础。
