Serotonin (5-HT) receptors are expressed in the gastrointestinal tract and play an important role in gastrointestinal activity regulation. 5-HT binding to receptors depends on 5-HT availability, which is, in part, modulated by the 5-HT transporter (SERT) expressed in enterocytes. This work concerns the expression of 5-HT1A and 5-HT7 receptors (5-HTR1A and 5-HTR7) in the human enterocyte-like Caco-2 cell line and their role in SERT activity modulation. The results demonstrate the mRNA and protein expression of 5-HTR1A and 5-HTR7 in these cells. In addition, both receptors are shown to modulate SERT activity; 5-HTR1A activation increased 5-HT uptake and 5-HTR7 activation inhibited it. In both cases, SERT modulation might involve a cAMP/PKA pathway. Effects on SERT disappeared after long-term activation of 5-HTR1A and 5-HTR7, indicating their desensitization. However, in both cases, the desensitization did not show itself to be mediated by a reduction of the amount of receptors in the membrane.
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Using extracellular recording we studied changes in the reactivity of rat hippocampal slices to an agonist of the 5-HT7 receptor, 5-carboxamidotryptamine (5-CT; 0.025-1 µM), induced by an earlier treatment of animals with corticosterone. Spontaneous bursting activity was recorded in ex vivo slices incubated in the presence of 2-[4-(2-methoxyphenyl)-1piperazinyl]ethyl]-N-2-pyridinylcyclohexanecarboxamide (WAY 100635; 2 µM), an antagonist of the 5-HT1A receptor, in the medium devoid of Mg2+ ions. Saturation binding assays were performed using [3H]-(2R)-1-[(3-hydroxyphenyl)sulfonyl]-2-[2-(4-methyl-1-piperidinyl)ethyl]pyrrolidine hydrochloride (SB 269970), a specific antagonist of the 5-HT7 receptor. Repetitive, but not single, corticosterone administration lasting 7 and 21 days, resulted in an enhancement of the effect related to the 5-HT7 receptor activation without changes in its binding properties. In a separate set of experiments rats were treated with corticosterone for 3 weeks and additionally with imipramine, beginning on the eighth day of corticosterone administration. In the corticosterone plus imipramine group the excitatory effect of 5-CT was weaker than in the corticosterone group, indicating that corticosterone-induced functional modifications in the reactivity of the 5-HT7 receptor were reversed and further weakened by imipramine treatment. This effect was accompanied by a reduction in the density of [3H]-SB 269970 binding sites. Thus, imipramine treatment counteracts the corticosterone-induced increase in the reactivity of the hippocampal circuitry to the activation of the 5-HT7 receptor.
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