Alteration of central serotonin modifies onset and severity of adjuvant-induced arthritis in the rat.
OBJECTIVE
Previous studies have determined that depletion of serotonin reduces the severity of hind-paw inflammation in adjuvant-induced arthritis (AA) in the rat. We wished to (i) test the hypothesis that this effect may be mediated, at least in part, through a central mechanism and (ii) to investigate further the pro-inflammatory role of serotonin we determined whether increasing serotonin using a selective serotonin reuptake inhibitor (SSRI), to increase serotonin availability at the active site of release, would increase inflammation.


METHODS
(i) Serotonin was depleted in the brain of rats with the selective neurotoxin 5'7'-dihydroxytryptamine. (ii) Rats were treated with an SSRI on days 10, 11 and 12 following adjuvant injection. Hind-paw inflammation was determined with plethysmometry as an index of severity of inflammation, and brain, pituitaries and blood were collected for assessment of changes in the hypothalamo -pituitary adrenal (HPA) axis.


RESULTS
(i) Serotonin depletion significantly reduced hind-paw inflammation. (ii) SSRI-treated animals developed hind-paw inflammation sooner, and the severity was increased compared to vehicle-treated AA rats. The changes in the HPA axis associated with inflammation were partly reversed by this treatment.


CONCLUSIONS
These data suggest a pro-inflammatory role for central serotonin in this disease model and indicate that treatment with SSRIs may exacerbate the development of inflammation.
Harbuz
M S
MS
Department of Hospital Medicine, University of Bristol, Bristol Royal Infirmary.
Marti
O
O
Lightman
S L
SL
Jessop
D S
DS
D015116:5,7-Dihydroxytryptamine / Q000633:toxicity; D000818:Animals; D001169:Arthritis, Experimental / Q000378:metabolism* / Q000503:physiopathology; D001921:Brain / Q000378:metabolism*; D003345:Corticosterone / Q000097:blood; D003346:Corticotropin-Releasing Hormone / Q000235:genetics / Q000378:metabolism; D004487:Edema / Q000188:drug therapy; D006614:Hindlimb / Q000187:drug effects / Q000473:pathology; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects / Q000378:metabolism; D008297:Male; D010913:Pituitary-Adrenal System / Q000187:drug effects / Q000378:metabolism; D011333:Pro-Opiomelanocortin / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D012701:Serotonin / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000494:pharmacology; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology
D015116:5,7-Dihydroxytryptamine; D003345:Corticosterone; D003346:Corticotropin-Releasing Hormone; D006897:Hydroxyindoleacetic Acid; D011333:Pro-Opiomelanocortin; D012333:RNA, Messenger; D012701:Serotonin; D012702:Serotonin Antagonists; D017367:Selective Serotonin Reuptake Inhibitors