El Mansari Mostafa, Ghanbari Ramez, Janssen Shannon, Blier Pierre
University of Ottawa Institute of Mental Health Research, Room 7407, 1145 Carling Avenue, Ottawa, Ontario, Canada K1Z 7K4.
Neuropharmacology. 2008 Dec;55(7):1191-8. doi: 10.1016/j.neuropharm.2008.07.028. Epub 2008 Jul 30.
Bupropion is widely used in the treatment of depression. There are, however, limited data on its long-term effects on monoaminergic neurons and therefore the mechanism of its delayed onset of action is at present not well understood. The present study was conducted to examine the effects of prolonged bupropion administration on the firing activity of dorsal raphe nucleus (DRN), locus coeruleus (LC), and ventral tegmental area (VTA) neurons. Spontaneously firing neurons were recorded extracellularly in rats anesthetized with chloral hydrate. Bupropion (30 mg/kg/day) was administered using subcutaneously implanted minipumps. In the DRN, the firing rate of serotonin (5-HT) neurons was significantly increased after 2, 7 and 14 days of administration. The suppressant effect of LSD was significantly diminished after the two-day regimen, indicating a desensitization of 5-HT1A autoreceptors. In the LC, the firing rate of norepinephrine (NE) neurons was significantly attenuated after a 2-day regimen, but recovered progressively over 14 days of administration. The suppressant effect of clonidine on NE neuronal firing was significantly attenuated in rats treated with bupropion for 14 days, indicating a desensitization of alpha2-adrenoceptors. In the VTA, neither 2 nor 14 days of bupropion administration altered the firing and burst activity of dopamine neurons. These results indicate that bupropion, unlike 5-HT reuptake inhibitors, promptly increased 5-HT neuronal activity, due to early desensitization of the 5-HT1A autoreceptor. The gradual recovery of neuronal firing of NE neurons, due to the desensitization of alpha2-adrenoceptors, in the presence of the sustained increase in 5-HT neuronal firing, may explain in part the delayed onset of action of bupropion in major depression.
安非他酮广泛用于治疗抑郁症。然而，关于其对单胺能神经元长期影响的数据有限，因此其延迟起效的机制目前尚不清楚。本研究旨在探讨长期给予安非他酮对中缝背核（DRN）、蓝斑核（LC）和腹侧被盖区（VTA）神经元放电活动的影响。在用水合氯醛麻醉的大鼠中，细胞外记录自发放电神经元。使用皮下植入的微型泵给予安非他酮（30mg/kg/天）。在DRN中，给药2、7和14天后，5-羟色胺（5-HT）能神经元的放电频率显著增加。两天给药方案后，LSD的抑制作用显著减弱，表明5-HT1A自身受体脱敏。在LC中，去甲肾上腺素（NE）能神经元的放电频率在2天给药方案后显著减弱，但在给药14天期间逐渐恢复。可乐定对NE神经元放电的抑制作用在用安非他酮治疗14天的大鼠中显著减弱，表明α2-肾上腺素能受体脱敏。在VTA中，给予安非他酮2天和14天均未改变多巴胺能神经元的放电和爆发活动。这些结果表明，与5-HT再摄取抑制剂不同，安非他酮由于5-HT1A自身受体的早期脱敏而迅速增加5-HT神经元活性。在5-HT神经元放电持续增加的情况下，由于α2-肾上腺素能受体脱敏，NE神经元放电逐渐恢复，这可能部分解释了安非他酮在重度抑郁症中延迟起效的原因。
