Cooper B R, Wang C M, Cox R F, Norton R, Shea V, Ferris R M
Division of Pharmacology Burroughs Wellcome Co., Research Triangle Park, North Carolina 27709.
Neuropsychopharmacology. 1994 Oct;11(2):133-41. doi: 10.1038/npp.1994.43.
Bupropion (BW 323U66) has been considered a dopaminergic antidepressant based on its ability to inhibit the uptake of dopamine (DA) somewhat more selectively than it inhibits uptake of norepinephrine (NE) or serotonin (5-HT). This report describes new evidence that bupropion selectively inhibits firing rates of NE cells in the locus coeruleus (LC) at doses significantly lower than those that inhibit activity of midbrain DA cells or dorsal raphe 5-HT cells. The IC50 dose (13 mg/kg i.p.) for inhibition of LC firing produced plasma concentrations that were not significantly different from those generated by the ED50 in the Porsolt test (10 mg/kg i.p.). The fourfold higher dose needed to inhibit DA cell firing (IC50 = 42 mg/kg i.p.) was similar to the dose associated with locomotor stimulation in freely moving rats. Bupropion did not change the firing rates of 5-HT cells in the dorsal raphe nucleus at any dose. In both in vitro and in vivo tests, the metabolite 306U73 (hydroxybupropion), a weak inhibitor of NE uptake, was approximately equipotent to bupropion with regard to inhibition of LC cells. Another metabolite, 494U73, had no effect on LC firing rates over a wide range of doses. Because of species variation in metabolism, 306U73 was not detected in plasma of rats after i.v. doses of bupropion that inhibited LC firing. Only trace amounts of 306U73 were detected after bupropion dosing for the Porsolt test. Pretreatment with reserpine markedly depleted catecholamines and reduced (by 30-fold) the potency of bupropion to inhibit LC firing.(ABSTRACT TRUNCATED AT 250 WORDS)
安非他酮（BW 323U66）被认为是一种多巴胺能抗抑郁药，因为它抑制多巴胺（DA）摄取的能力比抑制去甲肾上腺素（NE）或5-羟色胺（5-HT）摄取的能力更具选择性。本报告描述了新的证据，即安非他酮在显著低于抑制中脑DA细胞或中缝背核5-HT细胞活性的剂量下，能选择性抑制蓝斑（LC）中NE细胞的放电频率。抑制LC放电的半数抑制浓度（IC50）剂量（腹腔注射13mg/kg）产生的血浆浓度与波索尔特试验（腹腔注射10mg/kg）中半数有效剂量（ED50）产生的血浆浓度无显著差异。抑制DA细胞放电所需的四倍高剂量（IC50 = 腹腔注射42mg/kg）与自由活动大鼠的运动刺激相关剂量相似。安非他酮在任何剂量下都不会改变中缝背核中5-HT细胞的放电频率。在体外和体内试验中，代谢物306U73（羟基安非他酮）是一种较弱的NE摄取抑制剂，在抑制LC细胞方面与安非他酮的效力大致相当。另一种代谢物494U73在很宽的剂量范围内对LC放电频率没有影响。由于代谢的种属差异，静脉注射抑制LC放电的安非他酮剂量后，在大鼠血浆中未检测到306U73。在波索尔特试验中给予安非他酮后，仅检测到痕量的306U73。利血平预处理可显著消耗儿茶酚胺，并使安非他酮抑制LC放电的效力降低（30倍）。（摘要截短于250字）
