Modulation of 5-HT4 receptor function in the rat isolated ileum by fluoxetine: the involvement of endogenous 5-hydroxytryptamine.
The effect of the selective serotonin reuptake inhibitor fluoxetine was examined on the 5-HT4 receptor-mediated relaxation in the rat isolated ileum. Fluoxetine unsurmountably antagonized the relaxation to exogenous 5-HT with abolition of the response at 10 microM. Fluoxetine (10 microM) also caused a gradual loss of the resting tension. These effects of fluoxetine were prevented by a prior addition of the 5-HT4 receptor selective antagonist GR113808 (100 nM), which itself caused a contraction of the tissues when administered alone. Fluoxetine (10 microM) also failed to prevent the relaxation due to exogenous 5-HT and the 5-HT4 receptor agonist 5-methoxytryptamine in tissues taken from the rats treated with para-chlorophenylalanine (300 mg kg-1) for 3 and 6 days, which reduced the 5-HT level in the mucosa by 88 and 97.5% respectively. The contraction of the tissues with GR113808 indicates the presence of an endogenous 5-HT tone at the 5-HT4 receptor in the rat ileum. It is hypothesized that in the presence of fluoxetine, the concentration of endogenous 5-HT at the receptor was increased sufficiently to reduce or abolish the relaxation to 5-HT added exogenously. The inability of fluoxetine to prevent the relaxation to 5-HT in the presence of GR113808 or after the p-CPA treatment supports this hypothesis.
Tuladhar
B R
BR
Bradford School of Pharmacy, University of Bradford, Bradford BD7 1DP, UK. b.r.tuladhar@bradford.ac.uk
Costall
B
B
Naylor
R J
RJ
D000818:Animals; D002851:Chromatography, High Pressure Liquid; D005260:Female; D010134:Fenclonine / Q000494:pharmacology; D005473:Fluoxetine / Q000494:pharmacology*; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D007082:Ileum / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism; D009126:Muscle Relaxation / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D051381:Rats; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000502:physiology; D044422:Receptors, Serotonin, 5-HT4; D012701:Serotonin / Q000502:physiology*; D012702:Serotonin Antagonists / Q000494:pharmacology; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology
D010134:Fenclonine; D005473:Fluoxetine; D006897:Hydroxyindoleacetic Acid; D007211:Indoles; D011985:Receptors, Serotonin; D044422:Receptors, Serotonin, 5-HT4; D012701:Serotonin; D012702:Serotonin Antagonists; D017367:Selective Serotonin Reuptake Inhibitors; D013449:Sulfonamides; C082871:GR 113808