D'Souza D N, Zhang Y, Garcia F, Battaglia G, Van de Kar L D
Dept. of Pharmacology, Loyola Univ. of Chicago, School of Medicine, 2160 South First Ave., Maywood, IL 60153, USA.
Am J Physiol Regul Integr Comp Physiol. 2004 Feb;286(2):R390-7. doi: 10.1152/ajpregu.00335.2003. Epub 2003 Nov 6.
Tryptophan depleting protocols are commonly used to study the role of serotonin in mood disorders. The present study examined the impact of a tryptophan-deficient diet and fluoxetine on the serotonergic regulation of neuroendocrine function and body weight. We hypothesized that the regulation of postsynaptic 5-HT1A receptors is dependent on the levels of 5-HT in the synapse. Rats on a control or a tryptophan-deficient diet received daily injections of saline or fluoxetine (5 or 10 mg.kg-1.day-1 ip) from day 7 to day 21. The tryptophan-deficient diet produced a 41% reduction in the level of 5-HT but no change in the density of [3H]paroxetine-labeled 5-HT transporters. Treatment with fluoxetine inhibited the gain in weight in rats maintained on the control diet. The tryptophan-deficient diet produced a significant loss in body weight that was not significantly altered by treatment with fluoxetine. Treatment with fluoxetine produced a dose-dependent desensitization of hormone responses to injection of the 5-HT1A receptor agonist (+/-)8-hydroxy-2-(di-n-propylamino)tetralin ((+/-)8-OH-DPAT). The tryptophan-deficient diet produced an increase in the basal levels of corticosterone but did not alter the basal levels of ACTH or oxytocin. Also, this diet inhibited the magnitude of 8-OH-DPAT-induced increase in plasma levels of ACTH and oxytocin but did not impair the ability of fluoxetine to desensitize the 5-HT1A receptor-mediated increase in plasma hormones. These data suggest that a reserve of 5-HT enables fluoxetine to desensitize postsynaptic 5-HT1A receptors in the hypothalamus. In conclusion, the profound physiological changes induced by tryptophan depletion may complicate the interpretation of studies using this experimental approach.
色氨酸耗竭方案常用于研究血清素在情绪障碍中的作用。本研究考察了色氨酸缺乏饮食和氟西汀对神经内分泌功能和体重的血清素能调节的影响。我们假设突触后5-HT1A受体的调节取决于突触中5-HT的水平。从第7天到第21天，给予对照饮食或色氨酸缺乏饮食的大鼠每日腹腔注射生理盐水或氟西汀（5或10mg·kg-1·天-1）。色氨酸缺乏饮食使5-HT水平降低了41%，但[3H]帕罗西汀标记的5-HT转运体密度没有变化。氟西汀治疗抑制了维持对照饮食大鼠的体重增加。色氨酸缺乏饮食导致体重显著下降，氟西汀治疗对此没有显著改变。氟西汀治疗使激素对5-HT1A受体激动剂（±）8-羟基-2-（二正丙基氨基）四氢萘（（±）8-OH-DPAT）注射的反应产生剂量依赖性脱敏。色氨酸缺乏饮食使皮质酮的基础水平升高，但未改变促肾上腺皮质激素（ACTH）或催产素的基础水平。此外，这种饮食抑制了8-OH-DPAT诱导的ACTH和催产素血浆水平升高的幅度，但没有损害氟西汀使5-HT1A受体介导的血浆激素增加脱敏的能力。这些数据表明，5-HT储备使氟西汀能够使下丘脑突触后5-HT1A受体脱敏。总之，色氨酸耗竭引起的深刻生理变化可能会使使用这种实验方法的研究的解释复杂化。
