The 5-HT7 receptor as a mediator and modulator of antidepressant-like behavior

Abstract

The 5-HT 7 receptor has been suggested as a target for treating depression since inactivation or blockade of the receptor has an antidepressant-like behavioral effect. The present study investigated possible interactions between various classes of drugs with antidepressant properties and blockade or inactivation of the 5-HT 7 receptor. Immobility despair in the tail suspension test and the forced swim test was evaluated in mice lacking the 5-HT 7 receptor (5-HT 7 −/− ) and in wild-type controls (5-HT 7 +/+ ) following acute drug treatments. Citalopram, a selective serotonin reuptake inhibitor and widely used antidepressant, dose-dependently reduced immobility in the tail suspension test in both 5-HT 7 +/+ and 5-HT 7 −/− mice. Combining doses of citalopram and the 5-HT 7 receptor antagonist SB-269970 that by themselves did not affect behavior, reduced immobility in 5-HT 7 +/+ mice in both the tail suspension test and the forced swim test. No effect was seen in 5-HT 7 −/− mice. Desipramine and reboxetine, two norepinephrine reuptake inhibitors, dose-dependently reduced immobility in the tail suspension test in 5-HT 7 +/+ mice, but had no effect in 5-HT 7 −/− mice. A synergistic effect between desipramine and SB-269970 was found in both behavioral tests in 5-HT 7 +/+ mice. Reboxetine combined with SB-269970 had effect only in the forced swim test. GBR 12909, a dopamine reuptake inhibitor, dose-dependently reduced tail suspension test immobility in both genotypes. There was no interaction between GBR 12909 and SB-269970. Aripiprazole, an antipsychotic, reduced immobility in both tests in 5-HT 7 +/+ mice, but not in 5-HT 7 −/− mice. The results show that the 5-HT 7 receptor is required for the observed interaction between this receptor and antidepressants such as citalopram. The data furthermore support the hypothesis that the 5-HT 7 receptor might be a suitable target for treating depression.

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

“…Additionally, Abbas et al (2009) demonstrated that, in contrast to their wild-type littermates, 5-HT 7 receptor knock-out mice did not respond to amisulpride in the FST and the tail suspension test. This indicates that 5-HT 7 receptor antagonism may underly, at least in part, the antidepressant-like actions of antipsychotics such as amisulpride and aripiprazole (Abbas et al, 2009;Sarkisyan et al, 2010). Taken together, these data suggest that 5-HT 7 receptor antagonists are of potential interest for the treatment of both depression and anxiety.…”

“…This group reported that an intrahippocampal injection of SB-269970 also reduces immobility time, suggesting that the hippocampus is one of the brain structures involved in the beneficial action of 5-HT 7 antagonism (Wesolowska et al, 2006). It has also been reported that both pharmacological inhibition and genetic inactivation of 5-HT 7 receptors induce antidepressant-like behavior in the mouse tail suspension test (Hedlund et al, 2005;Bonaventure et al, 2007;Sarkisyan et al, 2010), as well as an antianxiety effect in the Vogel drinking test in rats, the elevated plus maze in rats, and in the four-plate test in mice (Wesolowska et al, 2006). Interestingly, a dose of 2 mg/kg of SB-269970 had no detectable effect in the present study by itself, suggesting a lack of modification of 5-HT release as previously shown (Bonaventure et al, 2007), it counteracted the anxiogenic-like effect of acute administration of fluoxetine in the illuminated open field (Figure 1).…”

The Serotonin-7 Receptor as a Novel Therapeutic Target

“…[10][11][12][13][14][15][16][17] In particular, several of the compounds listed in Table 1 are effective antidepressants, and in animal models, the antidepressant efficacy of aripiprazole is reversed in animals lacking 5-HT 7 receptors, 8 and the serotonin release and antidepressant actions of selective serotonin reuptake inhibitors (SSRIs) are enhanced by selective 5-HT 7 antagonists. 3,5,8 Three novel agents characterized as antipsychotics have 5-HT 7 antagonist properties among their most potent pharmacologic actions ( Figure 1), 2,10,13,14 and 1 of these, lurasidone, in late-stage clinical development as an antipsychotic, is actually "5-HT 7 preferring, " with 5-HT 7 antagonism its most potent property. 13 Of these, amisulpride (not available in the United States) is a proven antidepressant.…”

“…[3][4][5]8 Given the recent positive results as an antidepressant for the melatonergic/ serotonergic agent agomelatine, which resets circadian rhythms, 18 combining novel 5-HT 7 antagonists with melatonin agonism may also enhance the antidepressant actions of 5-HT 7 antagonists. In addition, preclinical studies 3,5,8,9 suggest the possibility that agents with potent 5-HT 7 antagonism may improve cognition, so cognition in depression, schizophrenia, and other illnesses is a theoretically attractive clinical target, for 5-HT 7 antagonists as well. …”

“…1,2 Now comes the 5-HT 7 receptor onto the scene, 2-17 not just because of the development of specific compounds allowing characterization of this receptor, 3,5,[7][8][9] but also because of the discovery that several of the known antidepressants and antipsychotics block 5-HT 7 receptors, and that this 5-HT 7 antagonism may account in part for the therapeutic properties of these drugs, especially antidepressant actions. [10][11][12][13][14][15][16][17] Localization and Function of 5-HT 7 Receptors Serotonin-7 receptors are postsynaptic G protein-linked receptors that may regulate serotonin-glutamate interactions.…”