Current Limitations and Candidate Potential of 5-HT7 Receptor Antagonism in Psychiatric Pharmacotherapy

Okubo, Ruri; Hasegawa, Toshiki; Fukuyama, Kouji; Shiroyama, Takashi; Okada, Motohiro

doi:10.3389/fpsyt.2021.623684

Cited by 35 publications

(55 citation statements)

References 195 publications

(122 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Similar to CLZ and QTP, the serotonin receptor binding profile of BPZ displays the feature of atypical antipsychotic agent, since BPZ is a potent partial agonist of serotonin 5-HT1A receptor and serotonin 5-HT2A receptors antagonism [ 1 , 5 ], but BPZ is the dopamine D2 receptor partial agonist [ 90 , 91 ]. Activation of dopamine D2 receptor suppresses Akt signaling leading to disinhibition of glucose glycogen synthase kinase 3 [ 92 , 93 ].…”

Section: Discussionmentioning

confidence: 99%

“…Modulations of various monoamine receptors have provided the development of a number of atypical antipsychotics for the treatment of schizophrenia and affective disorders [ 1 , 2 , 3 ], whereas approximately two-thirds of patients with schizophrenia and affective disorders lack to achieve an adequate response to first-choice pharmacotherapy using conventional atypical antipsychotics, and ultimately as many as one-third of patients remain unwell even after several adequate trials of antipsychotics [ 1 , 2 , 3 , 4 , 5 ]. Therefore, a number of psychiatrists and pharmacologists have been exploring the novel therapeutic strategies associated without monoaminergic hypothesis for the treatment of patients with schizophrenia and affective disorders [ 1 , 2 , 3 , 6 ]. Recent neuropharmacological studies suggest that functional abnormalities of tripartite synaptic transmission possibly contribute to pathophysiology of schizophrenia, affective disorder, epilepsy and their associated cognitive impairments [ 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 ].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Effects of Atypical Antipsychotics, Clozapine, Quetiapine and Brexpiprazole on Astroglial Transmission Associated with Connexin43

Fukuyama

Okada

2021

IJMS

Self Cite

View full text Add to dashboard Cite

Recently, accumulating preclinical findings suggest the possibility that functional abnormalities of tripartite synaptic transmission play important roles in the pathophysiology of schizophrenia and affective disorder. Therefore, to explore the novel mechanisms of mood-stabilizing effects associated with tripartite synaptic transmission, the present study determined the effects of mood-stabilizing antipsychotics, clozapine (CLZ), quetiapine (QTP) and brexpiprazole (BPZ), on the astroglial l-glutamate release and expression of connexin43 (Cx43) in the astroglial plasma membrane using cortical primary cultured astrocytes. Neither acute (for 120 min) nor subchronic (for 7 days) administrations of CLZ, QTP and BPZ affected basal astroglial l-glutamate release, whereas both acute and subchronic administration of CLZ, QTP and BPZ concentration-dependently enhanced astroglial l-glutamate release through activated hemichannels. Subchronic administration of therapeutic-relevant concentration of valproate (VPA), a histone deacetylase inhibiting mood-stabilizing antiepileptic drug, enhanced the stimulatory effects of therapeutic-relevant concentration of CLZ, QTP and BPZ on astroglial l-glutamate release through activated hemichannel. Subchronic administration of therapeutic-relevant concentration of CLZ, QTP and BPZ did not affect Cx43 protein expression in the plasma membrane during resting stage. After subchronic administration of VPA, acute and subchronic administration of therapeutic-relevant concentrations of CLZ increased Cx43 protein expression in the plasma membrane. Both acute administrations of therapeutic-relevant concentrations of QTP and BPZ did not affect, but subchronic administrations enhanced Cx43 protein expression in the astroglial plasma membrane. Furthermore, protein kinase B (Akt) inhibitor suppressed the stimulatory effects of CLZ and QTP, but did not affect Cx43 protein expression in the astroglial plasma membrane. These results suggest that three mood-stabilizing atypical antipsychotics, CLZ, QTP and BPZ enhance tripartite synaptic glutamatergic transmission due to enhancement of astroglial Cx43 containing hemichannel activities; however, the Cx43 activating mechanisms of these three mood-stabilizing antipsychotics were not identical. The enhanced astroglial glutamatergic transmission induced by CLZ, QTP and BPZ is, at least partially, involved in the actions of these three mood-stabilizing antipsychotics.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Effects of Atypical Antipsychotics, Clozapine, Quetiapine and Brexpiprazole on Astroglial Transmission Associated with Connexin43

Fukuyama

Okada

2021

IJMS

Self Cite

View full text Add to dashboard Cite

show abstract

“…Vortioxetine is a high affinity inhibitor of the human 5-HT transporter, 5-HT 3 and 5-HT 7 receptors, and a 5-HT 1A agonist [281]. Although the affinity of vortioxetine for the rat 5-HT 7 receptor is lower compared to the human receptor [282], subacute administration (within 3 days) of an effective dose of vortioxetine rapidly lowers rat 5-HT 7 receptor levels [283].…”

Section: The 5-ht 7 Receptorsmentioning

confidence: 99%

5-HT Receptors and the Development of New Antidepressants

Ślifirski

Król

Turło

2021

IJMS

View full text Add to dashboard Cite

Serotonin modulates several physiological and cognitive pathways throughout the human body that affect emotions, memory, sleep, and thermal regulation. The complex nature of the serotonergic system and interactions with other neurochemical systems indicate that the development of depression may be mediated by various pathomechanisms, the common denominator of which is undoubtedly the disturbed transmission in central 5-HT synapses. Therefore, the deliberate pharmacological modulation of serotonergic transmission in the brain seems to be one of the most appropriate strategies for the search for new antidepressants. As discussed in this review, the serotonergic system offers great potential for the development of new antidepressant therapies based on the combination of SERT inhibition with different pharmacological activity towards the 5-HT system. The aim of this article is to summarize the search for new antidepressants in recent years, focusing primarily on the possibility of benefiting from interactions with various 5-HT receptors in the pharmacotherapy of depression.

show abstract

“…In addition, the antagonism of the 5-HT7 further enhances serotonergic transmission with a synergistic antidepressant effects. 38 …”

Section: Mechanism Of Actionmentioning

confidence: 99%

Vortioxetine as a new frontier in the treatment of chronic neuropathic pain: a review and update

Adamo

Calabria

Coppola

et al. 2021

Therapeutic Advances in Psychopharmacology

View full text Add to dashboard Cite

Chronic neuropathic pain (CNP) is a disabling medical condition that impairs the health-related quality-of-life of affected patients. A high prevalence of anxiety, depression, sleep disturbance and cognitive impairment has frequently been reported in association with CNP, making the management of this disease complex and often multidisciplinary. Dual-acting agents such as selective serotonin and noradrenalin reuptake inhibitors (SNRIs) are considered particularly useful in the modulation of pain and in treatment of the mood disorders frequently associated with CNP. Recent evidence suggests that the top-down inhibitory control of pain involves the engagement and enhancement of descending endogenous opioidergic, cannabinoid and serotonergic systems, with the effect of serotonin being particularly related to the receptor subtypes that are preferentially activated; indeed serotonin induces analgesia via activation of 5-HT7 receptors and hyperalgesia via activation of 5-HT3 receptors. Vortioxetine (VO) is a novel multimodal serotonergic antidepressant with a unique mechanism of action. It has been demonstrated recently in experimental and clinical studies to have efficacy on pain hypersensitivity and on mood disorders. This drug inhibits the serotonin transporter with a high affinity, antagonises the 5-HT3, 5-HT1D and 5HT7 serotonin receptors, and activates the 5-HT1A and 5-HT1B receptors. In clinical studies, VO has proved effective at a dose of 10–20 mg/daily in short- and long-term treatment of patients with chronic orofacial pain, demonstrating a higher rate of clinical response and remission, a better acceptability, safety rate and tolerability, and a lower latency of action compared with other antidepressants. In the light of these recent findings, VO may be considered as a new pharmacological treatment also in relation to various types of CNP, particularly in elderly patients with concomitant mood disorders and cognitive impairment. The purpose of this review is to provide an up-to-date overview of the pharmacology and clinical applications of VO and to highlight its potential therapeutic properties and advantages in the management of CNP.

show abstract

Current Limitations and Candidate Potential of 5-HT7 Receptor Antagonism in Psychiatric Pharmacotherapy

Cited by 35 publications

References 195 publications

Effects of Atypical Antipsychotics, Clozapine, Quetiapine and Brexpiprazole on Astroglial Transmission Associated with Connexin43

Effects of Atypical Antipsychotics, Clozapine, Quetiapine and Brexpiprazole on Astroglial Transmission Associated with Connexin43

5-HT Receptors and the Development of New Antidepressants

Vortioxetine as a new frontier in the treatment of chronic neuropathic pain: a review and update

Contact Info

Product

Resources

About