A focus on the 5-HT6 receptor

Some recent literature (soon to be published) on the 5-HT6 receptor:

5-HT6 Receptor Antagonists: Potential Efficacy for the Treatment of Cognitive Impairment in Schizophrenia.

5-hydroxytryptamine6 receptor (5-HT6R) antagonists have shown efficacy in animal models for cognitive impairment in multiple cognitive domains relevant for schizophrenia. Improvements were found with 5-HT6R antagonists in preclinical tests for episodic memory, social cognition, executive function, working memory and several other tests for both learning and memory. In contrast, there is little evidence for efficacy on attention. It will be interesting to further investigate 5-HT6R antagonists in neurodevelopmental animal models which are based on prenatal exposure to specific environmental insults, and are characterized by a high level of face, construct and predictive validity for cognitive impairments associated with schizophrenia. It is also important to do more add-on preclinical studies of 5-HT6 antagonists with antipsychotics. Possible mechanisms of action to improve cognition have been described. 5-HT6R antagonists decrease GABA release and GABAergic interneuron excitability, which subsequently disinhibits glutamate and/or acetylcholine release and results in enhancement of synaptic plasticity. Furthermore, cognition could be improved by 5-HT6R antagonists, because these compounds increase the number of NCAM PSA-immunoreactive neurons in the dendate gyrus, inhibit mTOR and Fyn-tyrosine kinase and interact with DARPP-32. Interestingly, there is increasing preclinical evidence that could support additional benefits of 5-HT6R ligands on comorbid conditions in schizophrenia such as drug abuse, depression, anxiety, obesity andantipsychotic-induced EPS. Finally, we briefly give an overview of the 5-HT6R compounds that are currently in clinical development for the treatment of cognitive impairment in both schizophrenia and Alzheimer’s disease.

From: ‘Therapeutic potential of 5-HT6 receptor agonists.’

Studies have shown that both 5-HT6R agonists and antagonists exert similar procognitive activities.

Initial studies performed with 5-HT6R agonists have demonstrated an increase in GABA release across various regions of the rat brain (frontal cortex, hippocampus, and so on) and a decrease in dopamine and 5-HT efflux, which are blocked by an antagonist.

5-HT6R stimulation with an agonist does not lead to the impairment of cognitive processes; rather, it enhances learning and  memory performance in the same manner as a 5-HT6R antagonist. Despite the uncertainty surrounding the precise mechanisms underlying 5-HT6R  modulation, both antagonists and agonists appear to be promising candidates.

“[The] 5-HT6R stimulates Gs and adenylyl cyclase activity, thus liberating cAMP. The coupling of 5-HT6R to Ca2+ signaling has also been reported.The interactions between 5-HT6R and the Src-family Fyn-tyrosine kinase induce the activation of ERK1/2.The activation of these pathways would have a positive impact on cognition, which could partly explain the procognitive influence of 5-HT6R inactivation by an antagonist. Recently, a novel interaction of 5-HT6R with several proteins of the mammalian target of rapamycin (mTOR) pathway has been reported. The same studies have shown a positive effect of 5-HT6R antagonists in the reversal of cognitive impairment induced by mTOR activity. Finally, it has also been demonstrated that 5-HT6R could constitutively  interact with cyclin-dependent  kinase 5 (CdK5) to promote neurite growth. This effect was, however, reported  to be agonist-independent and was prevented by an antagonist.”

There have been few studies of the effects of 5-HT6R agonists in pharmacological models of cognitive deficit in rats, and the results have suggested that a decrease in these deficits might be induced by agonists. 5-HT6R agonists have demonstrated:

  • reversal of  scopolamine and ketamine-induced novel object recognition memory performance deficits
  • reversal of scopolamine and dizocilpine (MK801) induced deficit in contextual fear conditioning in rats.
  • reversal of ketamine-induced deficit in an attentional set-shifting test in rats.

“…results suggest that there is interest in the development of selective 5-HT6R agonists for the correction of cognitive disorders associated with various pathological conditions; this might be especially useful for the treatment of schizophrenia.”

Both 5-HT6R agonists and antagonists may evoke identical responses in animal models of depression and anxiety. However, the possible mechanisms of these effects are diverse and are not clearly understood. 5-HT6R antagonists may elicit anxiolytic effects via contributions of the GABAA/benzodiazepine system.

The 5-HT6R plays a significant role in the action of addictive psychostimulant drugs, such as cocaine. A 5-HT6R agonist attenuated cocaine-evoked conditioned place preference in the rat.

  • 5-HT6 signaling causes balanced activation of opposing medium spiny neurons (MSN) pathways by serotonin in sub-regions of the dorsal striatum [1]
  • Olanzapine augments the effect of selective serotonin reuptake inhibitors by suppressing GABAergic inhibition via antagonism of 5-HT6 receptors in the dorsal raphe nucleus [2]
  • 5-HT6R blockade can rescue a pathological overactivation of the mTOR pathway induced by early life insults in rodents and normalizes the associated social and episodic memory deficits [3]
  • 5-HT6 antagonism has been suggested to have therapeutic potential in the treatment of PTSD [4]
  • a selective 5-HT6 receptor antagonist alters the behavioral and neurochemical effects of ethanol [5]
  • the combination of a 5-HT6 antagonist with low doses of prazosin could have therapeutic potential in the treatment of schizophrenia [6]

A focus on the 5-HT7 receptor

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 [1].

Towards better non-selectivity: the role of 5-HT7 receptors in therapeutic efficacy of a second-generation antipsychotic, lurasidone.

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 [2]. Similarly, a 5-HT7 receptor antagonist reversed ketamine-induced social withdrawal [3].

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 [4].

Downregulation of 5-HT7 receptors by the atypical antipsychotics clozapine and olanzapine has been reported [5].


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]