Rationale
The 5-HT
7
receptor is a more recently discovered G-protein-coupled receptor for serotonin. The functions and possible clinical relevance of this receptor are not yet fully understood.
...Objective
The present paper reviews to what extent the use of animal models of human psychiatric and neurological disorders have implicated the 5-HT
7
receptor in such disorders. The studies have used a combination of pharmacological and genetic tools targeting the receptor to evaluate effects on behavior.
Results
Models of anxiety and schizophrenia have yielded mixed results with no clear role for the 5-HT
7
receptor described in these disorders. Some data are available for epilepsy, migraine, and pain but it is still very early to draw any definitive conclusions. There is a considerable amount of evidence supporting a role for the 5-HT
7
receptor in depression. Both blockade and inactivation of the receptor have resulted in an antidepressant-like profile in models of depression. Supporting evidence has also been obtained in sleep studies. Especially interesting are the augmented effects achieved by combining antidepressants and 5-HT
7
receptor antagonists. The antidepressant effect of amisulpride has been shown to most likely be mediated by the 5-HT
7
receptor.
Conclusions
The use of pharmacological and genetic tools in preclinical animal models strongly supports a role for the 5-HT
7
receptor in depression. Indirect evidence exists showing that 5-HT
7
receptor antagonism is clinically useful in the treatment of depression. Available data also indicate a possible involvement of the 5-HT
7
receptor in anxiety, epilepsy, pain, and schizophrenia.
The hippocampus has been implicated in aspects of spatial memory. Its ability to generate new neurons has been suggested to play a role in memory formation. Hippocampal serotonin (5-HT) ...neurotransmission has also been proposed as a contributor to memory processing. Studies have shown that the 5-HT(7) receptor is present in the hippocampus in relatively high abundance. Thus the aim of the present study was to investigate the possible role of the 5-HT(7) receptor in spatial memory using 5-HT(7) receptor-deficient mice (5-HT(7)(-/-)). A hippocampus-associated spatial memory deficit in 5-HT(7)(-/-) mice was demonstrated using a novel location/novel object test. A similar reduction in novel location exploration was observed in C57BL/6J mice treated with the selective 5-HT(7) receptor antagonist SB-269970. These findings prompted an extended analysis using the Barnes maze demonstrating that 5-HT(7)(-/-) mice were less efficient in accommodating to changes in spatial arrangement than 5-HT(7)(+/+) mice. 5-HT(7)(-/-) mice had specific impairments in memory compilation required for resolving spatial tasks, which resulted in impaired allocentric spatial memory whereas egocentric spatial memory remained intact after the mice were forced to switch back from striatum-dependent egocentric to hippocampus-dependent allocentric memory. To further investigate the physiological bases underlining these behaviors we compared hippocampal neurogenesis in 5-HT(7)(+/+) and 5-HT(7)(-/-) mice employing BrdU immunohistochemistry. The rate of cell proliferation in the dentate gyrus was identical in the two genotypes. From the current data we conclude that the 5-HT(7)(-/-) mice performed by remembering a simple sequence of actions that resulted in successfully locating a hidden target in a static environment.
Since its discovery in the 1940s in serum, the mammalian intestinal mucosa, and in the central nervous system, serotonin (5-HT) has been shown to be involved in virtually all cognitive and behavioral ...human functions, and alterations in its neurochemistry have been implicated in the etiology of a plethora of neuropsychiatric disorders. The cloning of 5-HT receptor subtypes has been of importance in enabling them to be classified as specific protein molecules encoded by specific genes. The 5-HT(7) receptor is the most recently classified member of the serotonin receptor family. Since its identification, it has been the subject of intense research efforts driven by its presence in functionally relevant regions of the brain. The availability of some selective antagonists and agonists, in combination with genetically modified mice lacking the 5-HT(7) receptor, has allowed for a better understanding of the pathophysiological role of this receptor. This paper reviews data on localization and pharmacological properties of the 5-HT(7) receptor, and summarizes the results of structure-activity relationship studies aimed at the discovery of selective 5-HT(7) receptor ligands. Additionally, an overview of the potential therapeutic applications of 5-HT(7) receptor agonists and antagonists in central nervous system disorders is presented.
Major depression is a common psychiatric disorder associated with high symptomatic and functional burdens. Pharmacological treatment is often effective, but there remain substantial unmet needs in ...the form of non-responders, delayed onset of clinical effect, and side effects. Recent studies have positioned the serotonin 5-HT7 receptor as a new target for the treatment of depression. Preclinical studies have shown that antagonists induce an antidepressant-like response, a phenotype that can also be observed in mice lacking the receptor. Lurasidone is a new atypical antipsychotic agent with very high affinity for the 5-HT7 receptor. Patients in clinical trials have reported improved scores in depression ratings. We have tested lurasidone in both acute and chronic mouse models of depression. In the tail suspension and forced swim tests lurasidone decreased immobility, an antidepressant-like response. The effect required functional 5-HT7 receptors as it was absent in mice lacking the receptor. In the repeated open-space swim test lurasidone was able to reverse the despair induced by repeated swims in a manner similar to the commonly used antidepressant citalopram. The results provide evidence that lurasidone can act as a 5-HT7 receptor antagonist and provide a possible explanation for the antidepressant effect data currently emerging from lurasidone clinical trials. Additionally, the results give further support for targeting the 5-HT7 receptor in the treatment of depression. It will be of interest to clinically evaluate lurasidone as an antidepressant either as monotherapy or as an adjunctive therapy to available drugs.
► Lurasidone has high affinity for 5-HT7 receptors, a proposed target for depression. ► Lurasidone acted antidepressant-like in the tail suspension and forced swim tests. ► The effect of lurasidone was absent in mice lacking the 5-HT7 receptor. ► In the repeated open-space swim test lurasidone had an effect similar to citalopram. ► Lurasidone acts as a 5-HT7 receptor antagonist and can be used as an antidepressant.
Mucosal inflammation in conditions ranging from infective acute enteritis or colitis to inflammatory bowel disease is accompanied by alteration in serotonin (5-hydroxytryptamine 5-HT) content in the ...gut. Recently, we have identified an important role of 5-HT in the pathogenesis of experimental colitis. 5-HT type 7 (5-HT7) receptor is one of the most recently identified members of the 5-HT receptor family, and dendritic cells express this receptor. In this study, we investigated the effect of blocking 5-HT7 receptor signaling in experimental colitis with a view to develop an improved therapeutic strategy in intestinal inflammatory disorders. Colitis was induced with dextran sulfate sodium (DSS) or dinitrobenzene sulfonic acid (DNBS) in mice treated with selective 5-HT7 receptor antagonist SB-269970, as well as in mice lacking 5-HT7 receptor (5-HT7(-/-)) and irradiated wild-type mice reconstituted with bone marrow cells harvested from 5-HT7(-/-) mice. Inhibition of 5-HT7 receptor signaling with SB-269970 ameliorated both acute and chronic colitis induced by DSS. Treatment with SB-269970 resulted in lower clinical disease, histological damage, and proinflammatory cytokine levels compared with vehicle-treated mice post-DSS. Colitis severity was significantly lower in 5-HT7(-/-) mice and in mice reconstituted with bone marrow cells from 5-HT7(-/-) mice compared with control mice after DSS colitis. 5-HT7(-/-) mice also had significantly reduced DNBS-induced colitis. These observations provide us with novel information on the critical role of the 5-HT7 receptor in immune response and inflammation in the gut, and highlight the potential benefit of targeting this receptor to alleviate the severity of intestinal inflammatory disorders such as inflammatory bowel disease.
The 5-HT7 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-HT7 receptor. Immobility despair in the tail suspension test and the forced swim test was evaluated in mice lacking the 5-HT7 receptor (5-HT7 a/a) and in wild-type controls (5-HT7 +/+) 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-HT7 +/+ and 5-HT7 a/a mice. Combining doses of citalopram and the 5-HT7 receptor antagonist SB-269970 that by themselves did not affect behavior, reduced immobility in 5-HT7 +/+ mice in both the tail suspension test and the forced swim test. No effect was seen in 5-HT7 a/a mice. Desipramine and reboxetine, two norepinephrine reuptake inhibitors, dose-dependently reduced immobility in the tail suspension test in 5-HT7 +/+ mice, but had no effect in 5-HT7 a/a mice. A synergistic effect between desipramine and SB-269970 was found in both behavioral tests in 5-HT7 +/+ 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-HT7 +/+ mice, but not in 5-HT7 a/a mice. The results show that the 5-HT7 receptor is required for the observed interaction between this receptor and antidepressants such as citalopram. The data furthermore support the hypothesis that the 5-HT7 receptor might be a suitable target for treating depression.
The 5-hydroxytryptamine7 receptor (5-HT7) is implicated in circadian rhythm phase resetting, and 5-HT7 receptor-selective antagonists alter rapid eye movement (REM) sleep parameters in a pattern ...opposite from those in patients with clinical depression.
As sleep, circadian rhythm, and mood regulation are related, we examined 5-HT7 receptor knockout mice in two behavioral models of depression. The forced swim and tail suspension tests are highly predictive for antidepressant drug activity.
Unmedicated 5-HT7-/- mice showed decreased immobility in both tests, consistent with an antidepressantlike behavior. The selective 5-HT7 receptor antagonist SB-269970 also decreased immobility. The selective serotonin reuptake inhibitor citalopram, a widely used antidepressant, decreased immobility in both 5-HT7+/+ and 5-HT7-/- mice in the tail suspension test, suggesting that it utilizes an independent mechanism. The 5-HT7-/- mice spent less time in and had less frequent episodes of REM sleep, also consistent with an antidepressantlike state.
The 5-HT7 receptor might have a role in mood disorders and antagonists might have therapeutic value as antidepressants.
Rationale
Amisulpride is approved for clinical use in treating schizophrenia in a number of European countries and also for treating dysthymia, a mild form of depression, in Italy. Amisulpride has ...also been demonstrated to be an antidepressant for patients with major depression in many clinical trials. In part because of the selective D
2
/D
3
receptor antagonist properties of amisulpride, it has long been widely assumed that dopaminergic modulation is the proximal event responsible for mediating its antidepressant and antipsychotic properties.
Objectives
The purpose of these studies was to determine if amisulpride’s antidepressant actions are mediated by off-target interactions with other receptors.
Materials and Methods
We performed experiments that: (1) examined the pharmacological profile of amisulpride at a large number of central nervous system (CNS) molecular targets and, (2) after finding high potency antagonist affinity for human 5-HT
7a
serotonin receptors, characterized the actions of amisulpride as an antidepressant in wild-type and 5-HT
7
receptor knockout mice.
Results
We discovered that amisulpride was a potent competitive antagonist at 5-HT
7a
receptors and that interactions with no other molecular target investigated in this paper could explain its antidepressant actions in vivo
.
Significantly, and in contrast to their wild-type littermates, 5-HT
7
receptor knockout mice did not respond to amisulpride in two widely used rodent models of depression, the tail suspension test and the forced swim test.
Conclusions
These results indicate that 5-HT
7a
receptor antagonism, and not D
2
/D
3
receptor antagonism, likely underlies the antidepressant actions of amisulpride.
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