Selective serotonin reuptake inhibitors modify physiological gastrointestinal motor activities via 5-HT2c receptor and acyl ghrelin.
BACKGROUND
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Fujitsuka
Naoki
N
Department of Psychosomatic Internal Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.
Asakawa
Akihiro
A
Hayashi
Mizuki
M
Sameshima
Marie
M
Amitani
Haruka
H
Kojima
Shinya
S
Fujimiya
Mineko
M
Inui
Akio
A
D000818:Animals; D004365:Drugs, Chinese Herbal / Q000494:pharmacology; D004435:Eating / Q000187:drug effects; D005277:Fenfluramine / Q000494:pharmacology; D005473:Fluoxetine / Q000494:pharmacology; D016666:Fluvoxamine / Q000494:pharmacology; D005769:Gastrointestinal Motility / Q000187:drug effects* / Q000502:physiology; D054439:Ghrelin / Q000097:blood / Q000494:pharmacology / Q000502:physiology*; D013006:Growth Hormone / Q000097:blood; D007276:Injections, Intraventricular; D008297:Male; D009842:Oligopeptides / Q000494:pharmacology; D017374:Paroxetine / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D044405:Receptor, Serotonin, 5-HT2C / Q000502:physiology*; D054440:Receptors, Ghrelin / Q000037:antagonists & inhibitors; D058826:Serotonin 5-HT2 Receptor Agonists; D058830:Serotonin 5-HT2 Receptor Antagonists; D012702:Serotonin Antagonists / Q000494:pharmacology; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*
D004365:Drugs, Chinese Herbal; D005277:Fenfluramine; D005473:Fluoxetine; D016666:Fluvoxamine; D054439:Ghrelin; D013006:Growth Hormone; D009842:Oligopeptides; D017374:Paroxetine; D010879:Piperazines; D044405:Receptor, Serotonin, 5-HT2C; D054440:Receptors, Ghrelin; D058826:Serotonin 5-HT2 Receptor Agonists; D058830:Serotonin 5-HT2 Receptor Antagonists; D012702:Serotonin Antagonists; D017367:Selective Serotonin Reuptake Inhibitors; C520836:GHRP-6, Lys(3)-; C084136:liu-jun-zi-tang; C015068:1-(3-chlorophenyl)piperazine