Rasmussen K, Beitner-Johnson D B, Krystal J H, Aghajanian G K, Nestler E J
Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut.
J Neurosci. 1990 Jul;10(7):2308-17. doi: 10.1523/JNEUROSCI.10-07-02308.1990.
We have compared the time course of the behavioral manifestations of opiate withdrawal to the in vivo activity of locus coeruleus (LC) neurons and to increases in the levels of G-proteins, adenylate cyclase, and cAMP-dependent protein kinase known to occur in the LC in opiate-dependent animals. Rats were given morphine by daily subcutaneous implantation of morphine pellets for 5 d. On the sixth day, morphine withdrawal was induced by subcutaneous administration of naltrexone, an opiate receptor antagonist, with additional doses given 6 and 24 hr later, conditions that resulted in sustained, maximal levels of withdrawal over the duration of the experiment. We found a striking parallel between the time courses of the behavioral signs and the increased activity of LC neurons during withdrawal, both of which appeared to follow 2 phases. There was an early, rapid phase, during which withdrawal signs and increased LC activity became most pronounced within 15-30 min after naltrexone administration, and then recovered rapidly by over 50% within 4 hr of withdrawal. Subsequently, there was a slower phase, during which the persisting withdrawal signs and elevated LC activity remained roughly constant from 4 to 24 hr and did not recover completely until after 72 hr of continuous withdrawal. Adenylate cyclase and cAMP-dependent protein kinase activities in isolated LC subcellular fractions, both elevated in dependent animals, recovered to control levels after 6 hr of withdrawal, in parallel with the rapid phase of withdrawal. Levels of G1 and Go, also elevated in dependent animals, remained only slightly elevated at 6 hr and returned to normal by 24 hr. Taken together, these data suggest that increased neuronal activity in the LC is associated temporally with the behavioral morphine withdrawal syndrome and that increased levels of G-proteins and an up-regulated cAMP system may contribute to the early withdrawal activation of these neurons.
我们已将阿片类药物戒断的行为表现的时间进程与蓝斑（LC）神经元的体内活性以及已知在阿片类药物依赖动物的LC中发生的G蛋白、腺苷酸环化酶和cAMP依赖性蛋白激酶水平的升高进行了比较。通过每天皮下植入吗啡丸剂给大鼠注射吗啡，持续5天。在第6天，通过皮下注射阿片受体拮抗剂纳曲酮诱导吗啡戒断，并在6小时和24小时后给予额外剂量，这些条件导致在实验持续时间内出现持续的、最大程度的戒断。我们发现行为体征的时间进程与戒断期间LC神经元活性增加之间存在惊人的平行关系，两者似乎都遵循两个阶段。有一个早期的快速阶段，在此期间，戒断体征和LC活性增加在纳曲酮给药后15 - 30分钟内最为明显，然后在戒断4小时内迅速恢复超过50%。随后，有一个较慢的阶段，在此期间，持续的戒断体征和升高的LC活性在4至24小时内大致保持恒定，直到连续戒断72小时后才完全恢复。分离的LC亚细胞组分中的腺苷酸环化酶和cAMP依赖性蛋白激酶活性，在依赖动物中均升高，在戒断6小时后恢复到对照水平，与戒断的快速阶段平行。G1和Go的水平，在依赖动物中也升高，在6小时时仅略有升高，并在24小时时恢复正常。综上所述，这些数据表明LC中神经元活性增加在时间上与行为性吗啡戒断综合征相关，并且G蛋白水平的升高和cAMP系统的上调可能有助于这些神经元的早期戒断激活。
