Fatigue of cholestasis and the serotoninergic neurotransmitter system in the rat.
Fatigue associated with cholestasis may impair health-related quality of life. The pathogenesis of this symptom is largely unknown, but it has been suggested that central serotoninergic neurotransmission may be implicated and that serotonin 1A receptor agonists may yield improvement. The aim of this study was to study the central serotoninergic system, specifically the serotonin (5-HT)(1A) receptor-mediated pathway of serotoninergic neurotransmission, in a bile duct resection rat model of cholestasis. Fatigue was assessed in the forced swim test in sham and bile duct-resected rats. The serotonin behavioral syndrome, which includes hyperlocomotion, was assessed in both groups of rats after escalating doses of the 5-HT(1A) receptor agonist 8-hydroxy(di-n-propylamine)tetralin (8-OH DPAT). 5-HT(1A) and 5-HT(2) receptor densities were explored in four brain regions using a receptor-binding assay. Extracellular 5-HT and 5-hydroxyindoleacetic acid were measured via in vivo brain dialysis. Bile duct-resected rats spent more time floating in the forced swim test, and 8-OH DPAT decreased floating time in cholestatic rats (P < .01). Dose-response curves created with 8-OH DPAT for the serotonin behavioral syndrome were similar in bile duct-resected and sham-operated rats. 5-HT(1A) and 5-HT(2) receptor densities in most brain regions and extracellular serotonin levels were similar in both groups of rats. In conclusion, 5-HT(1A) receptor agonist-induced amelioration of fatigue in cholestatic rats may be nonspecific and not linked to reversal of the pathophysiology of fatigue associated with cholestasis; however, these data do not exclude a potential role of the central serotoninergic system in the evolution of fatigue.
Celik
Turgay
T
Department of Medical Pharmacology, Gülhane Military Academy, Ankara, Turkey.
Gören
M Zafer
MZ
Cinar
Kubilay
K
Gürdal
Hakan
H
Onder
F Oğuz
FO
Tan
Akif
A
Terzioğlu
Berna
B
Bozdayi
A Mithat
AM
Bozkaya
Hakan
H
Uzunalimoğlu
Ozden
O
Yurdaydin
Cihan
C
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal; D001921:Brain / Q000378:metabolism*; D002779:Cholestasis / Q000150:complications* / Q000378:metabolism* / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D005221:Fatigue / Q000209:etiology*; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D006948:Hyperkinesis / Q000139:chemically induced / Q000503:physiopathology; D008297:Male; D017551:Microdialysis; D018377:Neurotransmitter Agents / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism*; D012701:Serotonin / Q000378:metabolism*; D058825:Serotonin 5-HT1 Receptor Agonists; D017366:Serotonin Receptor Agonists / Q000008:administration & dosage / Q000494:pharmacology; D013550:Swimming; D013577:Syndrome
D018377:Neurotransmitter Agents; D058825:Serotonin 5-HT1 Receptor Agonists; D017366:Serotonin Receptor Agonists; D044282:Receptor, Serotonin, 5-HT1A; D012701:Serotonin; D006897:Hydroxyindoleacetic Acid; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin