Damjanoska K J, Van de Kar L D, Kindel G H, Zhang Y, D'Souza D N, Garcia F, Battaglia G, Muma N A
Department of Pharmacology, Loyola University Chicago, Stritch School of Medicine, Maywood, IL 60153, USA.
J Pharmacol Exp Ther. 2003 Aug;306(2):563-71. doi: 10.1124/jpet.103.050534. Epub 2003 Apr 29.
Differential adaptive changes in serotonin2A [5-hydroxytryptamine (5-HT)2A] receptor signaling during treatment may be one mechanism involved in the latency of therapeutic improvement with antidepressants, such as fluoxetine. We examined the effects of fluoxetine (2, 3, 7, 21, or 42 days) on hypothalamic 5-HT2A receptor signaling. The hormone responses to an injection of the 5-HT2A receptor agonist (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-amino-propane HCl (DOI) were used as an index of hypothalamic 5-HT2A receptor function. Treatment with fluoxetine for 21 or 42 days produced diminished adrenocorticotropic hormone (ACTH) and oxytocin (but not corticosterone) responses to DOI injections (2.5 mg/kg i.p.; 15 min postinjection). Regulators of G protein signaling 4 and Galphaq protein levels in the hypothalamic paraventricular nucleus were not altered during fluoxetine treatment. Because previous studies indicate that treatment with fluoxetine for 21 days resulted in increased hormone responses to DOI when measured at 30 min after injection, we examined the effect of fluoxetine (21 days) on DOI-induced increase hormone levels at 15, 30, and 60 min after DOI injection. Fluoxetine decreased the oxytocin response at 15 but not at 30 min post-DOI injection, and potentiated the ACTH and corticosterone responses at 30 min post-DOI injection. For comparison, we examined the effect of fluoxetine on 5-HT2A receptor-mediated increase in phospholipase C (PLC) activity in the frontal cortex. 5-HT-stimulated, but not guanosine 5'-O-(3-thio)triphosphate-stimulated PLC activity was increased after 21 days of fluoxetine-treatment. Overall, these results indicate that chronic fluoxetine treatment can potentiate 5-HT2A receptor signaling in frontal cortex but differentially alters 5-HT2A receptor signaling in oxytocin-containing neurons and corticotropin-releasing factor-containing neurons in the paraventricular nucleus.
在治疗过程中，血清素2A [5-羟色胺（5-HT）2A] 受体信号的差异性适应性变化可能是抗抑郁药（如氟西汀）治疗改善延迟所涉及的一种机制。我们研究了氟西汀（2、3、7、21或42天）对下丘脑5-HT2A受体信号的影响。对注射5-HT2A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）的激素反应被用作下丘脑5-HT2A受体功能的指标。用氟西汀治疗21或42天会使对DOI注射（2.5mg/kg腹腔注射；注射后15分钟）的促肾上腺皮质激素（ACTH）和催产素（但不包括皮质酮）反应减弱。在氟西汀治疗期间，下丘脑室旁核中G蛋白信号调节因子4和Gαq蛋白水平未发生改变。因为先前的研究表明，在注射后30分钟测量时，用氟西汀治疗21天会导致对DOI的激素反应增加，所以我们研究了氟西汀（21天）对DOI注射后15、30和60分钟时DOI诱导的激素水平升高的影响。氟西汀在DOI注射后15分钟时降低了催产素反应，但在30分钟时未降低，并在DOI注射后30分钟时增强了ACTH和皮质酮反应。为了进行比较，我们研究了氟西汀对额叶皮质中5-HT2A受体介导的磷脂酶C（PLC）活性增加的影响。氟西汀治疗21天后，5-HT刺激而非鸟苷5'-O-（3-硫代）三磷酸刺激的PLC活性增加。总体而言，这些结果表明，慢性氟西汀治疗可增强额叶皮质中的5-HT2A受体信号，但差异性地改变室旁核中含催产素神经元和含促肾上腺皮质激素释放因子神经元中的5-HT2A受体信号。
