Czachura J F, Rasmussen K
Neuroscience Research, Lilly Research Laboratories, Eli Lilly and Co, Indianapolis, IN 46285, USA.
Naunyn Schmiedebergs Arch Pharmacol. 2000 Sep;362(3):266-75. doi: 10.1007/s002100000290.
The gradual recovery of activity of serotonergic neurons following an initial inhibition has been hypothesized to play an important role in the delayed onset of efficacy of selective serotonin reuptake inhibitors. This study explored the clinical relevance of this hypothesis by examining the effects of different doses and routes of administration of fluoxetine on the recovery of activity of serotonergic neurons over the course of a 21-day exposure. Single-unit, extracellular recordings of serotonergic neurons were made in the dorsal raphe nucleus of anesthetized male rats. Acute i.v., s.c. and i.p. administration of fluoxetine inhibited the activity of serotonergic neurons. With chronic administration of fluoxetine, at clinically relevant doses, the activity of serotonergic neurons gradually recovered to baseline levels over the course of 14-21 days. The dose of fluoxetine (5, 10 or 20 mg/kg per day) did not make a significant difference in the time course of the recovery of activity of serotonergic neurons. A significant, non-parallel shift in the dose-response curve of serotonergic neurons to the serotonin-1A (5-HT1A) agonist 8-OH-DPAT occurred over the 21 days of treatment with fluoxetine, indicating a desensitization of the 5-HT1A receptor during this period. The recovery of firing did not correlate with either plasma or cerebrospinal fluid levels of fluoxetine or norfluoxetine. These results indicate that, similar to the effects of dose on the speed of onset of the clinical effects of SSRIs, increasing the dose of fluoxetine does not hasten the recovery of firing of serotonergic neurons during chronic administration. These results support the hypothesis that desensitization of the 5-HT1A receptor and consequent recovery of firing of 5-HT cells in the dorsal raphe nucleus plays a role in the delayed therapeutic onset of fluoxetine.
血清素能神经元在最初受到抑制后逐渐恢复活性，这一现象被认为在选择性血清素再摄取抑制剂疗效延迟起效中发挥重要作用。本研究通过检测氟西汀不同剂量和给药途径在21天暴露过程中对血清素能神经元活性恢复的影响，探讨了这一假说的临床相关性。在麻醉雄性大鼠的中缝背核进行血清素能神经元的单单位细胞外记录。急性静脉注射、皮下注射和腹腔注射氟西汀可抑制血清素能神经元的活性。长期给予临床相关剂量的氟西汀后，血清素能神经元的活性在14 - 21天内逐渐恢复至基线水平。氟西汀的剂量（每天5、10或20 mg/kg）对血清素能神经元活性恢复的时间进程没有显著影响。在氟西汀治疗的21天内，血清素能神经元对5-羟色胺-1A（5-HT1A）激动剂8-羟基二丙胺基四氢萘（8-OH-DPAT）的剂量反应曲线发生了显著的非平行位移，表明在此期间5-HT1A受体脱敏。放电恢复与氟西汀或去甲氟西汀的血浆或脑脊液水平均无相关性。这些结果表明，与剂量对SSRI临床效应起效速度的影响类似，增加氟西汀剂量并不会加速长期给药期间血清素能神经元放电的恢复。这些结果支持了以下假说：5-HT1A受体脱敏以及随后中缝背核5-HT细胞放电的恢复在氟西汀治疗起效延迟中起作用。
