Acute and repeated treatment with the 5-HT7 receptor antagonist SB 269970 induces functional desensitization of 5-HT7 receptors in rat hippocampus

作者：Tokarski Krzysztof^*; Zelek Molik Agnieszka; Duszynska Beata; Satala Grzegorz; Bobula Bartosz; Kusek Magdalena; Chmielarz Piotr; Nalepa Irena; Hess Grzegorz

来源：Pharmacological Reports, 2012, 64(2): 256-265.

DOI：10.1016/S1734-1140(12)70763-6

• 5-carboxamidotryptamine
• adaptive changes
• epileptiform activity
• hippocampal slice
• imipramine
• SB 269970

Background: SB 269970, a 5-HT7 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-HT7 receptor in the hippocampus. %26lt;br%26gt;Methods: The reactivity of 5-HT7 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-HT7 receptors were investigated using [H-3]-SB 269970 and the influence of SB 269970 and imipramine on mRNA expression levels of G alpha(s) and G alpha(12) mRNA were studied using RT-qPCR. %26lt;br%26gt;Results: Acute and repeated treatment with SB 269970 led to attenuation of the excitatory effects of activation of 5-HT7 receptors. Neither single nor repeated administration of SB 269970 changed the mean affinity of 5-HT7 receptors for [H-3]-SB 269970. Repeated, but not single, administration of SB 269970 decreased the maximum density of [H-3]-SB 269970 binding sites. While administration of imipramine did not change the expression of mRNAs for G alpha(s) and G alpha(12) proteins after both single and repeated administration of SB 269970, a reduction in G alpha(s) and G alpha(12) mRNA expression levels was evident. %26lt;br%26gt;Conclusions: These findings indicate that even single administration of SB269970 induces functional desensitization of the 5-HT7 receptor system, which precedes changes in the receptor density. This mechanism may be responsible for the rapid antidepressant-like effect of the 5-HT7 antagonist in animal models.

• 出版日期2012-4