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

Abstract

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 Ga s and Ga 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 Ga s and Ga 12 proteins after both single and repeated administration of SB 269970, a reduction in Ga s and Ga 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 antidepressantlike effect of the 5-HT 7 antagonist in animal models.

5-HT7 receptors as modulators of neuronal excitability, synaptic transmission and plasticity: physiological role and possible implications in autism spectrum disorders

“…Desensitization of 5-HT 7 receptors was also observed after antagonist treatment (Tokarski et al, 2012b). Thus, systemic treatments of animals should be carefully designed to minimize 5-HT 7 receptor desensitization; in this respect, a preferential use of agonists with a short half-life, such as LP-211 and related compounds (Hedlund et al, 2010) might be considered preferentially.…”

Emotional and risk seeking behavior after prepuberal subchronic or adult acute stimulation of 5-HT7-Rs in naples high excitability rats

“…Different strategies have allowed to investigate the properties of this receptor population related to modulation of anxiety levels. Studies on this issue have been carried out on transgenic mice lacking the 5-HT7-R (Guscott et al, 2005;Hedlund and Sutcliffe, 2007) or by administration of selective 5-HT7-R antagonists (e.g., SB-269970, SB-258719, and SB-656104) (Forbes et al, 2002;Hagan et al, 2000;Thomas et al, 1998;Tokarski et al, 2012).…”

Stress- and antidepressant treatment-induced modifications of 5-HT7 receptor functions in the rat brain

“…The data demonstrated that both single and repeated SB 269970 administration lowered the level of mRNA of those G proteins (Gas and Ga12) which couple to the 5-HT 7 receptor in the hippocampus [103]. Repeated treatment with SB 269970 also decreased the density of 5-HT 7 receptors [98]. These effects differed markedly from the effects of the antidepressant imipramine, which altered neither the level of the mRNAs nor the density of 5-HT 7 receptors when administered once or repeatedly for 14 days.…”

“…-free incubation conditions [98]. The mechanisms underlying the observed attenuation of the excitatory effect of the 5-HT 7 receptor activation by SB 269970 may potentially be related to either the decreased receptor density or the modification in the capacity of the receptor to activate G protein, changes in G protein expression or phosphorylation, or modifications at the level of effectors.…”