Akaoka H, Aston-Jones G
Department of Mental Health Sciences, Hahnemann University, Philadelphia, PA 19102.
Neuroscience. 1993 Jun;54(3):561-5. doi: 10.1016/0306-4522(93)90227-7.
Withdrawal from opiates in dependent subjects produces strongly aversive psychological and autonomic responses which contribute to the chronic ingestion of opiates and the high incidence of relapse after withdrawal. A variety of evidence indicates that hyperactivity of noradrenergic locus coeruleus (LC) neurons is an important brain substrate of opiate withdrawal. In particular, only a few agents have been found to be clinically useful in alleviating these symptoms and treating opiate dependence, all of which potently attenuate the activation of noradrenergic neurons in the LC evoked by opiate withdrawal. However, current pharmacotherapies, especially methadone and clonidine, have serious side effects, including hypotension, sedation and their own withdrawal reactions. Our goal was to find an alternative pharmacological treatment to reduce the magnitude of LC hyperactivity during opiate withdrawal. Previous studies indicated that brain serotonin (5-HT) systems may be involved in opiate withdrawal. Two results from our laboratory led us to study the effect of enhanced serotonergic neurotransmission on withdrawal-induced LC hyperactivity: (i) a substantial part of such LC hyperactivity is mediated by an excitatory amino acid input to the locus coeruleus, and (ii) 5-HT selectively attenuates excitation of LC neurons mediated by excitatory amino acids. Here, we report that agents which increase serotonergic neurotransmission attenuate the hyperactivity of LC neurons induced by naloxone-precipitated withdrawal from chronic morphine exposure in rats. The 5-HT releaser/uptake blocker, d-fenfluramine, as well as the 5-HT reuptake blockers fluoxetine or sertraline, significantly attenuated the withdrawal-induced hyperactivity of LC neurons.(ABSTRACT TRUNCATED AT 250 WORDS)
对阿片类药物产生依赖的个体在停药时会出现强烈的厌恶心理和自主神经反应，这些反应促使他们长期摄入阿片类药物，并导致停药后高复发率。各种证据表明，去甲肾上腺素能蓝斑（LC）神经元的功能亢进是阿片类药物戒断的重要脑内机制。特别是，目前仅发现少数几种药物在缓解这些症状和治疗阿片类药物依赖方面具有临床效用，所有这些药物均能有效减弱阿片类药物戒断引起的LC去甲肾上腺素能神经元的激活。然而，目前的药物治疗，尤其是美沙酮和可乐定，具有严重的副作用，包括低血压、镇静作用以及它们自身的戒断反应。我们的目标是找到一种替代性的药物治疗方法，以减轻阿片类药物戒断期间LC功能亢进的程度。先前的研究表明，脑内血清素（5-HT）系统可能参与阿片类药物戒断过程。我们实验室的两项研究结果促使我们研究增强血清素能神经传递对戒断诱导的LC功能亢进的影响：（i）这种LC功能亢进的很大一部分是由兴奋性氨基酸传入蓝斑介导的，以及（ii）5-HT选择性减弱兴奋性氨基酸介导的LC神经元兴奋。在此，我们报告，增加血清素能神经传递的药物可减弱大鼠因纳洛酮诱发的慢性吗啡戒断所诱导的LC神经元功能亢进。5-HT释放剂/摄取阻滞剂右芬氟拉明以及5-HT摄取阻滞剂氟西汀或舍曲林均能显著减弱戒断诱导的LC神经元功能亢进。（摘要截选至250词）
