University of Ottawa Institute of Mental Health Research, Ottawa, ON, Canada.
J Psychopharmacol. 2010 Aug;24(8):1223-35. doi: 10.1177/0269881109348178. Epub 2009 Nov 25.
Nomifensine potently inhibits the reuptake of norepinephrine and dopamine in vitro. It is one of few antidepressants with marked potency to block dopamine reuptake that has ever been used clinically. Acute and sustained administration of nomifensine was investigated on the firing of monoaminergic neurons to understand its mechanism of action. In vivo extracellular recordings of locus coeruleus, ventral tegmental area and dorsal raphe nucleus neurons were obtained from male Sprague-Dawley rats. The intravenous injection of nomifensine in the locus coeruleus and ventral tegmental area yielded ED(50) values of 40 +/- 1 and 450 +/- 41 microg/kg, respectively, suggesting that nomifensine directly acted upon dopamine and norepinephrine neurons, since these values are proportional to its affinities for norepinephrine and dopamine transporters. There was no effect on 5-HT neurons. Nomifensine (5 mg/kg/day, subcutaneous, using minipumps) potently and significantly inhibited dopamine neuronal firing in the ventral tegmental area after 2 days, with recovery to normal after the 14-day treatment due to D(2) autoreceptor desensitization. Norepinephrine neuronal firing in the locus coeruleus was significantly decreased after 2 and 14 days. A significant increase in dorsal raphe nucleus 5-HT neuronal firing was seen after a two-day regimen, and remained elevated after 14 days. Desensitization of the 5-HT(1A) receptor on 5-HT neurons of the dorsal raphe nucleus occurred after two days of nomifensine administration. Nomifensine likely treated depression by acting on dopamine, norepinephrine and 5-HT neurons, highlighting the importance of the functional connectivity between these three monoaminergic systems.
去甲咪嗪在体外能强有力地抑制去甲肾上腺素和多巴胺的再摄取。它是少数几种具有显著阻断多巴胺再摄取作用的抗抑郁药之一，曾被临床应用。本文急性和持续给予去甲咪嗪以观察单胺能神经元的放电，来了解其作用机制。雄性 Sprague-Dawley 大鼠脑内蓝斑核、腹侧被盖区和中缝背核神经元进行在体细胞外记录。静脉注射去甲咪嗪于蓝斑核和腹侧被盖区的 ED（50）值分别为 40±1 和 450±41μg/kg，提示去甲咪嗪直接作用于多巴胺和去甲肾上腺素神经元，因为这些值与它对去甲肾上腺素和多巴胺转运体的亲和力成比例。对 5-HT 神经元无影响。去甲咪嗪（5mg/kg/天，皮下，用微量泵）在 2 天后能强有力地和显著地抑制腹侧被盖区多巴胺神经元的放电，14 天治疗后由于 D2 自身受体脱敏而恢复正常。蓝斑核的去甲肾上腺素神经元放电在 2 天和 14 天后显著减少。两天方案后中缝背核 5-HT 神经元的放电显著增加，14 天后仍保持升高。2 天的去甲咪嗪给药后，中缝背核 5-HT 神经元的 5-HT1A 受体脱敏发生。去甲咪嗪可能通过作用于多巴胺、去甲肾上腺素和 5-HT 神经元来治疗抑郁症，强调了这三个单胺能系统之间功能连接的重要性。
