Acute and repeated treatment with the 5-HT(7) receptor antagonist SB 269970 induces functional desensitization of 5-HT(7) receptors in rat hippocampus.
Journal Title: Pharmacological Reports - Year 2012, Vol 64, Issue 2
Abstract
Background: SB 269970, a 5-HT(7) receptor antagonist may produce a faster antidepressant-like effect in animal models, than do antidepressant drugs, e.g., imipramine. The present work was aimed at examining the effect of single and repeated (14 days) administration of SB 269970 on the 5-HT(7) receptor in the hippocampus. Methods: The reactivity of 5-HT(7) receptors was determined using 5-carboxamidotryptamine (5-CT), which increased the bursting frequency of spontaneous epileptiform activity in hippocampal slices. Additionally, the effects of SB 269970 administration on the affinity and density of 5-HT(7) receptors were investigated using [(3)H]-SB 269970 and the influence of SB 269970 and imipramine on mRNA expression levels of Gα(s) and Gα(12) mRNA were studied using RT-qPCR. Results: Acute and repeated treatment with SB 269970 led to attenuation of the excitatory effects of activation of 5-HT(7) receptors. Neither single nor repeated administration of SB 269970 changed the mean affinity of 5-HT(7) receptors for [(3)H]-SB 269970. Repeated, but not single, administration of SB 269970 decreased the maximum density of [(3)H]-SB 269970 binding sites. While administration of imipramine did not change the expression of mRNAs for Gα(s) and Gα(12) proteins after both single and repeated administration of SB 269970, a reduction in Gα(s) and Gα(12) mRNA expression levels was evident. Conclusions: These findings indicate that even single administration of SB269970 induces functional desensitization of the 5-HT(7) receptor system, which precedes changes in the receptor density. This mechanism may be responsible for the rapid antidepressant-like effect of the 5-HT(7) antagonist in animal models.
Authors and Affiliations
Krzysztof Tokarski, Agnieszka Zelek-Molik, Beata Duszyńska, Grzegorz Satała, Bartosz Bobula, Magdalena Kusek, Piotr Chmielarz, Irena Nalepa
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