Serotonin 5-HT7 receptors occur in the central and peripheral nervous system. In the brain, the 5-HT7 receptors were detected predominantly in the frontal cortex, thalamus, hypothalamus, and hippocampus. The distribution of 5-HT7 receptors in the central nervous system supports its role in the regulation of cognitive processes, mood states, pain, circadian rhythms, and sleep. Both genetic inactivation and pharmacological blockade of the 5-HT7 receptor led to antidepressant-like effects in animal models of depressive symptomatology.
A number of atypical antipsychotics, including paliperidone, risperidone, ziprasidone, aripiprazole and amisulpride, have high affinities for 5-HT7 receptors. 5-HT7 receptor blockade may play a limited role in the effect of amphetamine or NMDA receptor antagonists on locomotor activity and therefore on psychosis because a number of studies show conflicting results in these animal models. 5HT7 receptor antagonism may be a possible target for the treatment of cognitive impairments in schizophrenia .
Effectiveness of currently available antipsychotic medications is far from satisfactory with many patients showing incomplete therapeutic response even after many trials with different antipsychotic drugs. Hence, there is an ongoing interest in searching for pharmacological mechanisms, which could potentiate therapeutic response to antipsychotic drugs and/or reduce its typical side effects. The primary aim of this mini-review is to summarize available evidence supporting the role of serotonin receptors, especially 5-HT7 receptors, in therapeutic effects of a second-generation antipsychotic drug, lurasidone.
Antagonists of serotonin 5-HT7 receptors have been demonstrated to ameliorate cognitive impairments in pharmacological animal models of schizophrenia that involve blockade of NMDARs. The administration of NMDAR antagonists evokes a broad range of cognitive deficits, including a loss of impulse control. The involvement of 5-HT7 receptors in the modulation of impulsivity has been recently suggested . Similarly, a 5-HT7 receptor antagonist reversed ketamine-induced social withdrawal .
The 5-HT7 receptor appears to facilitate memory processes in a broader cortico-limbic network and not the hippocampus alone. 5-HT7 receptor antagonism plays an important role under poor memory or when the learning or memory is complex. In contrast to the negative regulatory effects of long-term activation of 5-HT7 receptors on NMDA receptor signaling (in vitro), acute activation of 5-HT7 receptors promotes NMDA receptor activity .
Downregulation of 5-HT7 receptors by the atypical antipsychotics clozapine and olanzapine has been reported .
A recent study found that use of lurasidone was superior to quetiapine in terms of cognitive performance.
Lurasidone is “efficacious with comparable efficacy to other agents in the treatment of acute psychosis and prevention of relapse in individuals with schizophrenia. The greater antidepressant and cognitive benefits suggested by its receptor profile need substantiation in robust clinical trials. It is less likely to cause metabolic and cardiac adverse effects than most other second-generation agents and is associated with a modest risk of extrapyramidal side-effects, akathisia, and prolactin elevation.” [review]