Watanabe Arata, Hasegawa Shu, Nishi Kyoko, Nguyen Khnah Q, Diksic Mirko
Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Que., H3A 2B4, Canada.
Brain Res Bull. 2006 Mar 31;69(2):101-8. doi: 10.1016/j.brainresbull.2005.11.008. Epub 2005 Dec 9.
The effects of chronic buspirone treatments, administered by minipump at doses of 10 and 20 mg/(kg day) for 14 days, on brain 5-HT synthesis in olfactory bulbectomized (OBX) rats were evaluated. The alpha-[14C]methyl-L-tryptophan autoradiographic method was used. We compared the synthesis in the buspirone treated OBX rats (administered either 10 mg/(kg day) (OBX-10) or 20 mg/(kg day) (OBX-20)) to that of the saline treated OBX rats (OBX-SAL), and the sham operated rats (SHX) treated with saline. In addition, OBX-10 rats were compared to SHX rats treated with 10 mg/(kg day) (SHX-10) of buspirone. All treatments were carried out for 14 days. Adult Sprague-Dawley rats were used. Two weeks following the OBX or SHX procedures, the rats were assigned to the OBX-10, OBX-20, OBX-SAL, SHX-10, or SHX-SAL groups, respectively. The 5-HT synthesis rates R (pmol/(g/min)) were calculated from the trapping constant of alpha-[14C]MTrp (K*; ml/(g min)) and the plasma concentration of the plasma non-protein-bound tryptophan (Cp; pmol/ml) using the lumped constant (LC) measured previously in the rat brain. There was no significant difference in the plasma free or total tryptophan among these groups. The overall synthesis in the OBX-10 group was not statistically different from the OBX-SAL group, but it was different from the OBX-20 and SHX-SAL groups. The OBX-20 rats had an overall significant reduction in 5-HT synthesis, when compared to the OBX-SAL group, but did not differ from the SHX-SAL group, which did not differ from the SHX-10 group. These results suggest that 10 mg/(kg day) of buspirone for 14 days in the OBX rats did not produce a significant alteration in 5-HT synthesis, but 20 mg/(kg day) for 14 days resulted in an overall significant reduction in brain 5-HT synthesis. The latter treatment brought the synthesis to the level found in the sham operated rats, i.e., a normal level. These results suggest that normalization (reduction to the level found in the SHX-SAL rats) of 5-HT synthesis in the OBX requires a greater dose of buspirone (20 mg/(kg day)) than that needed to produce a desensitization of the 5-HT1A receptors in the sham operated rats (10 mg/(kg day)). This probably indicates that 5-HT1A receptors have different functionality in the OBX rats than that found in the intact or sham operated rats. Furthermore, our results support the hypothesis that 5-HT1A receptors mediate the antidepressant-like effect of 5-HT1A agonists, as the chronic 5-HT1A agonist treatment in the depression model known to be sensitive to antidepressants resulted in the normalization of 5-HT synthesis.
评估了通过微型泵以10和20毫克/（千克·天）的剂量持续给药14天的慢性丁螺环酮治疗对嗅球切除（OBX）大鼠脑5-羟色胺（5-HT）合成的影响。采用α-[14C]甲基-L-色氨酸放射自显影法。我们将接受丁螺环酮治疗的OBX大鼠（分别给予10毫克/（千克·天）（OBX-10）或20毫克/（千克·天）（OBX-20））的合成与接受生理盐水治疗的OBX大鼠（OBX-SAL）以及接受生理盐水治疗的假手术大鼠（SHX）的合成进行了比较。此外，将OBX-10大鼠与接受10毫克/（千克·天）（SHX-10）丁螺环酮治疗的SHX大鼠进行了比较。所有治疗均持续14天。使用的是成年Sprague-Dawley大鼠。在OBX或SHX手术两周后，将大鼠分别分配到OBX-10、OBX-20、OBX-SAL、SHX-10或SHX-SAL组。5-HT合成速率R（皮摩尔/（克·分钟））是根据α-[14C]MTrp的捕获常数（K*；毫升/（克·分钟））以及血浆中非蛋白结合色氨酸的血浆浓度（Cp；皮摩尔/毫升），利用先前在大鼠脑中测得的集总常数（LC）计算得出的。这些组之间血浆游离或总色氨酸没有显著差异。OBX-10组的总体合成与OBX-SAL组在统计学上没有差异，但与OBX-20组和SHX-SAL组不同。与OBX-SAL组相比，OBX-20大鼠的5-HT合成总体上显著降低，但与SHX-SAL组没有差异，而SHX-SAL组与SHX-10组也没有差异。这些结果表明，在OBX大鼠中，14天给予10毫克/（千克·天）的丁螺环酮不会对5-HT合成产生显著改变，但14天给予20毫克/（千克·天）会导致脑5-HT合成总体上显著降低。后一种治疗使合成达到假手术大鼠中发现的水平，即正常水平。这些结果表明，OBX中5-HT合成的正常化（降低到SHX-SAL大鼠中发现的水平）需要比使假手术大鼠中5-HT1A受体脱敏所需剂量（10毫克/（千克·天））更大的丁螺环酮剂量（20毫克/（千克·天））。这可能表明5-HT1A受体在OBX大鼠中的功能与完整或假手术大鼠中的不同。此外，我们的结果支持5-HT1A受体介导5-HT1A激动剂的抗抑郁样作用这一假设，因为在已知对抗抑郁药敏感的抑郁模型中，慢性5-HT1A激动剂治疗导致了5-HT合成的正常化。
