Pharmacological Blockade of 5-HT7 Receptors as a Putative Fast Acting Antidepressant Strategy

Abstract

Current antidepressants still display unsatisfactory efficacy and a delayed onset of therapeutic action. Here we show that the pharmacological blockade of serotonin 7 (5-HT 7 ) receptors produced a faster antidepressant-like response than the commonly prescribed antidepressant fluoxetine. In the rat, the selective 5-HT 7 receptor antagonist SB-269970 counteracted the anxiogenic-like effect of fluoxetine in the open field and exerted an antidepressant-like effect in the forced swim test. In vivo, 5-HT 7 receptors negatively regulate the firing activity of dorsal raphe 5-HT neurons and become desensitized after long-term administration of fluoxetine. In contrast with fluoxetine, a 1-week treatment with SB-269970 did not alter 5-HT firing activity but desensitized cell body 5-HT autoreceptors, enhanced the hippocampal cell proliferation, and counteracted the depressive-like behavior in olfactory bulbectomized rats. Finally, unlike fluoxetine, early-life administration of SB-269970, did not induce anxious/depressive-like behaviors in adulthood. Together, these findings indicate that the 5-HT 7 receptor antagonists may represent a new class of antidepressants with faster therapeutic action.

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

“…It has been shown that the blockade of 5-HT 7 receptors increases 5-HT raphe-hippocampus transmission [11]. Enhancement of 5-HT transmission in such projection areas as the dorsal hippocampus after 1 week of SB 269970 administration has also been reported by other researchers [42]. On the other hand, some authors have found that the 5-HT 7 receptor antagonist SB 269970 significantly inhibits 5-HT efflux [51]; however, other investigators have shown that inhibition of 5-HT release is likely to be mediated by 5-HT 7 receptor agonists [22].…”

“…To achieve a similar effect for standard antidepressants, at least 21-day treatment is necessary. Thus, the pharmacological blockade of 5-HT 7 receptors produces a considerably faster antidepressant-like response than do most antidepressant drugs [42]. Such a phenomenon may occur as a result of either an increased 5-HT 7 receptor activation or activation of other 5-HT receptors by an elevated extracellular 5-HT level due to the enhanced activity of serotonergic neurons.…”

“…It has recently been shown that the blockade of the 5-HT 7 receptor synergistically potentiates the effect of clinically used antidepressants in an animal model of depression [70]. Moreover, it has been demonstrated that the antagonist of the 5-HT 7 receptor per se can exert antidepressive action [42]. The above data suggest that the blockade of the 5-HT 7 receptor may play a role in the antidepressive action, and that some antidepressants can exert their therapeutic effect via blockade of the 5-HT 7 receptor or via a decrease in 5-HT 7 receptor reactivity.…”

“…The swift action of SB 269970 on the reactivity of the 5-HT 7 receptor is in line with the results obtained by other authors. Mnie-Filali and coworkers [42] found a reduced 5-HT 1A and/or 5-HT 7 receptor responsiveness in the dorsal raphe nucleus (DRN) after one week of 5-HT 7 receptor blockade. To achieve a similar effect for standard antidepressants, at least 21-day treatment is necessary.…”

“…Moreover, blockade of the 5-HT 7 receptor may produce a faster antidepressant effect than do contemporary antidepressant drugs [42].…”