Fujitsuka Naoki, Asakawa Akihiro, Hayashi Mizuki, Sameshima Marie, Amitani Haruka, Kojima Shinya, Fujimiya Mineko, Inui Akio
Department of Psychosomatic Internal Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.
Biol Psychiatry. 2009 May 1;65(9):748-59. doi: 10.1016/j.biopsych.2008.10.031. Epub 2008 Dec 5.
Selective serotonin reuptake inhibitors (SSRIs) are widely used to treat anxiety and depressive disorders. These agents may cause upper gastrointestinal (GI) symptoms that lead to their discontinuation. We examined whether SSRIs modify physiologic GI motor activities in freely moving rats.
The SSRIs fenfluramine, fluvoxamine, paroxetine, and fluoxetine were administered to 24-hour food-deprived rats, and then GI motility was measured in conscious, freely moving rats using a strain gauge force transducer method. Plasma acyl ghrelin levels were determined by enzyme immunoassay.
Plasma acyl ghrelin levels were analyzed in conjunction with fasted motor activities. Acyl ghrelin was increased in association with the occurrence of Phase III-like contractions of the migrating motor complex in the antrum and duodenum. SSRIs decreased acyl ghrelin and changed Phase III-like contractions to fed-like motor activities. Both effects were blocked by 5-HT2c, but not 5-HT1b, receptor antagonist. Neither melanocortin 4 nor the 3/4 receptor antagonists blocked this motor effect, although they restored the anorexia induced by SSRIs. The improving effect on GI motility by 5-HT2c receptor (5-HT2cR) antagonist disappeared after treatment with a growth-hormone secretagogue receptor antagonist, whereas ghrelin or ghrelin-releasing drug such as TJ-43 changed SSRI-induced fed-like motor activities to fasted activities.
SSRIs have inhibitory effects on acyl ghrelin and GI motor activities through 5-HT2cR. Our study identifies the importance and divergence of central 5-HT2cR pathways that regulate GI motor activities through ghrelin and feeding/energy metabolism via melanocortin 4 receptor signaling.
选择性5-羟色胺再摄取抑制剂（SSRIs）被广泛用于治疗焦虑症和抑郁症。这些药物可能会引起上消化道（GI）症状，导致停药。我们研究了SSRIs是否会改变自由活动大鼠的生理性胃肠运动。
给禁食24小时的大鼠服用SSRI氟苯丙胺、氟伏沙明、帕罗西汀和氟西汀，然后使用应变片式力传感器方法在清醒、自由活动的大鼠中测量胃肠动力。通过酶免疫测定法测定血浆酰基胃饥饿素水平。
结合禁食时的运动活动分析血浆酰基胃饥饿素水平。酰基胃饥饿素随着胃窦和十二指肠移行运动复合波III期样收缩的出现而增加。SSRIs降低了酰基胃饥饿素水平，并将III期样收缩转变为进食样运动活动。这两种作用均被5-HT2c受体拮抗剂阻断，但未被5-HT1b受体拮抗剂阻断。促黑素细胞激素4受体拮抗剂和促黑素细胞激素3/4受体拮抗剂均未阻断这种运动效应，尽管它们恢复了SSRIs诱导的厌食症。在用生长激素促分泌素受体拮抗剂治疗后，5-HT2c受体（5-HT2cR）拮抗剂对胃肠动力的改善作用消失，而胃饥饿素或胃饥饿素释放药物（如TJ-43）将SSRI诱导的进食样运动活动转变为禁食活动。
SSRIs通过5-HT2cR对酰基胃饥饿素和胃肠运动活动具有抑制作用。我们的研究确定了中枢5-HT2cR通路的重要性和差异，该通路通过胃饥饿素调节胃肠运动活动，并通过促黑素细胞激素4受体信号传导调节进食/能量代谢。
