Rabin B C, Guo T Z, Gregg K, Maze M
Department of Anesthesia, Stanford University School of Medicine, CA 94305, USA.
Eur J Pharmacol. 1996 Jun 13;306(1-3):51-9. doi: 10.1016/0014-2999(96)00194-x.
The role of serotonergic pathways in the hypnotic response to dexmedetomidine was examined in neurochemical and behavioral studies. Following acute administration of dexmedetomidine, loss of righting reflex and changes in serotonin (5-hydroxytryptamine, 5-HT) and norepinephrine turnover in different brain regions (locus coeruleus and hippocampus) were assessed. In separate experiments, the effect of dexmedetomidine on 5-HT turnover was measured in rats rendered tolerant to the hypnotic effects of dexmedetomidine. These neurochemical data were complemented by a study of dexmedetomidine-induced hypnotic response in the presence of a 5-HT2 receptor agonist and antagonist, 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) and ritanserin, respectively. Dexmedetomidine (1-500 micrograms.kg-1) dose dependently reduced 5-HT and norepinephrine turnover in both the locus coeruleus and hippocampus. The decrease in 5-HT turnover more closely correlated with the dose-response curve for loss of righting reflex, a behavioral measure of hypnosis, than did the norepinephrine turnover. In previous studies with chronic administration of dexmedetomidine (3 micrograms.kg-1.h-1 for 7 days), the norepinephrine turnover effect of acute dexmedetomidine (30 micrograms.kg-1) persisted while the hypnotic effect was blunted. Following the same regimen, the drug's ability to diminish 5-HT turnover was also blunted. This biochemical evidence for the role of 5-HT in sleep was supported by the behavioral evidence that dexmedetomidine (100 micrograms.kg-1 i.p. or 7 micrograms.0.2 microliter-1 locus coeruleus)-induced hypnosis was dose dependently blocked by DOI (0.08-0.32 mg.kg-1 i.p.). The selectivity of this effect was demonstrated by the finding that ritanserin (0.16 mg.kg-1 i.p.) pretreatment blocked the effects of DOI (0.16 mg.kg-1 i.p.) on dexmedetomidine (100 micrograms.kg-1 i.p. or 7 micrograms.0.2 microliter-1 locus coeruleus)-induced loss of righting reflex. In conclusion, these findings suggest that the hypnotic effect of the alpha 2-adrenoceptor agonist, dexmedetomidine, is not mediated solely by changes in noradrenergic neurtransmission, but instead is strongly associated with a decrease in serotonergic neurotransmission and correspondingly diminished by stimulation of 5-HT2 receptors.
在神经化学和行为学研究中，对血清素能通路在右美托咪定催眠反应中的作用进行了研究。急性给予右美托咪定后，评估了翻正反射消失以及不同脑区（蓝斑和海马体）中血清素（5-羟色胺，5-HT）和去甲肾上腺素周转率的变化。在单独的实验中，测量了右美托咪定对已对其催眠作用产生耐受性的大鼠5-HT周转率的影响。这些神经化学数据通过在分别存在5-HT2受体激动剂和拮抗剂1-(2,5-二甲氧基-4-碘苯基)-2-氨基丙烷（DOI）和利坦色林的情况下对右美托咪定诱导的催眠反应的研究得到补充。右美托咪定（1 - 500微克·千克-1）剂量依赖性地降低了蓝斑和海马体中5-HT和去甲肾上腺素的周转率。与去甲肾上腺素周转率相比，5-HT周转率的降低与翻正反射消失的剂量反应曲线（催眠的一种行为指标）的相关性更强。在先前慢性给予右美托咪定（3微克·千克-1·小时-1，持续7天）的研究中，急性给予右美托咪定（30微克·千克-1）时去甲肾上腺素周转率的影响持续存在，而催眠作用减弱。遵循相同方案后，该药物降低5-HT周转率的能力也减弱。5-HT在睡眠中作用的这一生化证据得到了行为学证据的支持，即右美托咪定（100微克·千克-1腹腔注射或7微克·0.2微升-1蓝斑）诱导的催眠被DOI（0.08 - 0.32毫克·千克-1腹腔注射）剂量依赖性地阻断。利坦色林（0.16毫克·千克-1腹腔注射）预处理可阻断DOI（0.16毫克·千克-1腹腔注射）对右美托咪定（100微克·千克-1腹腔注射或7微克·0.2微升-1蓝斑）诱导的翻正反射消失的影响，这一发现证明了这种作用的选择性。总之，这些发现表明，α2肾上腺素能受体激动剂右美托咪定的催眠作用并非仅由去甲肾上腺素能神经传递的变化介导，而是与血清素能神经传递的减少密切相关，并且相应地会因5-HT2受体的刺激而减弱。
