Modulation of 5-HT4 receptor function in the rat isolated ileum by fluoxetine:: the involvement of endogenous 5-hydroxytryptamine

1 The effect of the selective serotonin reuptake inhibitor fluoxetine was examined on the 5-HT4 receptor-mediated relaxation in the rat isolated ileum. 2 Fluoxetine unsurmountably antagonized the relaxation to exogenous 5-HT with abolition of the response at 10 muM. Fluoxetine (10 muM) 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. 3 Fluoxetine (10 muM) 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 parachlorophenylalanine (300 mg kg(-1)) for 3 and 6 days, which reduced the 5-HT level in the mucosa by 88 and 97.5% respectively. 4 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 Suoxetine to prevent the relaxation to 5-HT in the presence of GR113808 or after the p-CPA treatment supports this hypothesis.