Landry Michelle, Frasier Mark, Chen Zhuo, Van De Kar Louis D, Zhang Yahong, Garcia Francisca, Battaglia George
Department of Pharmacology and Experimental Therapeutics, Center for Serotonin Disorders Research, Loyola University Chicago, Stritch School of Medicine, Maywood, IL 60153, USA.
Synapse. 2005 Nov;58(2):102-9. doi: 10.1002/syn.20187.
Various childhood mood disorders are being treated with serotonin selective reuptake inhibitors (SSRIs) such as fluoxetine (Prozac(R)), yet limited data are available on their effects on serotonergic systems prior to maturation. This study investigated the effects of chronic fluoxetine treatment on 5-HT2A serotonin receptor-mediated neuroendocrine responses in young male rats. Prepubescent male rats were treated with saline or fluoxetine (10 mg/kg/day, i.p.) for 14 days, a treatment regimen producing maximal changes in postsynaptic 5-HT2A function in adults. Eighteen hours post-treatment, the rats received saline or increasing doses (0.5, 2.0, or 5.0 mg/kg, i.p.) of the 5-HT2 receptor agonist (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane HCl ((+/-)-DOI). Trunk blood was obtained to determine changes in oxytocin, ACTH, corticosterone, and renin responses. Fluoxetine produced a small ( approximately 6%) but significant reduction in body weight gain, but no changes were observed in basal hormone levels. In both saline- and fluoxetine-treated rats, (+/-)-DOI increased plasma oxytocin levels in a dose-dependent manner. However, the magnitude of the oxytocin responses to all doses of (+/-)-DOI were markedly attenuated ( approximately 50%) in the fluoxetine-treated rats, indicating a functional reduction in the E(max) of 5-HT(2A) receptor-mediated oxytocin responses. In contrast, fluoxetine did not alter the (+/-)-DOI-induced increases in plasma ACTH, corticosterone, or renin. These data provide the first demonstration of selective neuroadaptive responses in 55-HT2A serotonin receptor function due to prepubescent treatment with fluoxetine. These data may be clinically relevant with respect to the use of selective serotonin reuptake inhibitors in children and adolescents.
多种儿童期情绪障碍正在使用5-羟色胺选择性再摄取抑制剂（SSRI）进行治疗，如氟西汀（百忧解®），然而，关于它们在成熟前对5-羟色胺能系统影响的数据有限。本研究调查了慢性氟西汀治疗对年轻雄性大鼠中5-HT2A 5-羟色胺受体介导的神经内分泌反应的影响。青春期前雄性大鼠用生理盐水或氟西汀（10毫克/千克/天，腹腔注射）治疗14天，该治疗方案可使成年大鼠突触后5-HT2A功能产生最大变化。治疗后18小时，大鼠接受生理盐水或递增剂量（0.5、2.0或5.0毫克/千克，腹腔注射）的5-HT2受体激动剂（±）-1-（2,5-二甲氧基-4-碘苯基）-2-氨基丙烷盐酸盐（（±）-DOI）。采集躯干血以确定催产素、促肾上腺皮质激素、皮质酮和肾素反应的变化。氟西汀使体重增加略有（约6%）但显著减少，但基础激素水平未观察到变化。在生理盐水和氟西汀治疗的大鼠中，（±）-DOI均以剂量依赖性方式增加血浆催产素水平。然而，氟西汀治疗的大鼠中，对所有剂量（±）-DOI的催产素反应幅度均明显减弱（约50%），表明5-HT2A受体介导的催产素反应的E(max)功能降低。相比之下，氟西汀并未改变（±）-DOI诱导的血浆促肾上腺皮质激素、皮质酮或肾素的增加。这些数据首次证明青春期前用氟西汀治疗会导致5-HT2A 5-羟色胺受体功能出现选择性神经适应性反应。这些数据对于儿童和青少年使用选择性5-羟色胺再摄取抑制剂可能具有临床相关性。
