scholarly journals Lurasidone Sub-Chronically Activates Serotonergic Transmission via Desensitization of 5-HT1A and 5-HT7 Receptors in Dorsal Raphe Nucleus

2019 ◽  
Vol 12 (4) ◽  
pp. 149 ◽  
Author(s):  
Okada ◽  
Fukuyama ◽  
Okubo ◽  
Shiroyama ◽  
Ueda
Keyword(s):  
High Performance ◽  
Dorsal Raphe Nucleus ◽  
Antipsychotic Agent ◽  
Dorsal Raphe ◽  
Raphe Nucleus ◽  
Clinical Effects ◽  
Mediodorsal Thalamic Nucleus ◽  
Nmda Glutamate Receptor ◽  
Receptor Modulators ◽  
Dorsal Raphé

Lurasidone is an atypical mood-stabilizing antipsychotic agent with unique receptor-binding profile, including 5-HT7 receptor (5-HT7R) antagonism. Effects of 5-HT7R antagonism on transmitter systems of schizophrenia and mood disorders, however, have not been well clarified. Thus, this study examined the mechanisms underlying the clinical effects of lurasidone by measuring mesocortical serotonergic transmission. Following systemic and local administrations of lurasidone, MK801 and 5-HT receptor modulators, we determined releases of 5-HT in dorsal raphe nucleus (DRN), mediodorsal thalamic nucleus (MDTN) and medial prefrontal cortex (mPFC) and γ-aminobutyric acid (GABA) in DRN using multiprobe microdialysis with ultra-high-performance liquid chromatography (UHPLC). Serotonergic and GABAergic neurons in the DRN are predominantly regulated by inhibitory 5-HT1A receptor (5-HT1AR) and excitatory 5-HT7R, respectively. Lurasidone acutely generates GABAergic disinhibition by 5-HT7R antagonism, but concomitant its 5-HT1AR agonism prevents serotonergic hyperactivation induced by 5-HT7R inhibition. During treatments with 5-HT1AR antagonist in DRN, lurasidone dose-dependently increased 5-HT release in the DRN, MDTN and mPFC. Contrary, lurasidone chronically enhanced serotonergic transmission and GABAergic disinhibition in the DRN by desensitizing both 5-HT1AR and 5-HT7R. These effects of lurasidone acutely prevented MK801-evoked 5-HT release by GABAergic disinhibition via N-methyl-D-aspartate (NMDA)/glutamate receptor (NMDA-R)-mediated inhibition of 5-HT1AR function, but enhanced MK801-induced 5-HT release by desensitizing 5-HT1AR and 5-HT7R. These results indicate that acutely lurasidone fails to affect 5-HT release, but chronically enhances serotonergic transmission by desensitizing both 5-HT1AR and 5-HT7R. These unique properties of lurasidone ameliorate the dysfunctions of NMDA-R and augment antidepressive effects.

Buspirone-induced changes in the serotonergic and non-serotonergic cells in the dorsal raphe nucleus of rats

2010 ◽  
Vol 473 (2) ◽  
pp. 136-140 ◽  
Author(s):  
Ali Jahanshahi ◽  
Lee Wei Lim ◽  
Harry W.M. Steinbusch ◽  
Veerle Visser-Vandewalle ◽  
Yasin Temel
Keyword(s):  
Dorsal Raphe Nucleus ◽  
Dorsal Raphe ◽  
Raphe Nucleus ◽  
Induced Changes ◽  
Dorsal Raphé

027 GABAergic Neurons in the Dorsal Raphe Nucleus Are under the Influence of GABAergic Inputs from the Nucleus Pontis Oralis

SLEEP ◽  
2021 ◽  
Vol 44 (Supplement_2) ◽  
pp. A12-A12
Author(s):  
Jianhua Zhang ◽  
Mingchu Xi ◽  
Simon Fung ◽  
Charles Tobin ◽  
Sharon Sampogna ◽  
...  
Keyword(s):  
Dorsal Raphe Nucleus ◽  
Dorsal Raphe ◽  
Gabaergic Neurons ◽  
Fluorescent Labeling ◽  
Raphe Nucleus ◽  
Gaba A ◽  
Adult Cats ◽  
Immunohistochemical Techniques ◽  
Fluorescence Immunohistochemistry ◽  
Dorsal Raphé

Abstract Introduction Our previous study has shown that there is a direct connection between GABAergic neurons in the nucleus pontis oralis (NPO) and neurons of the dorsal raphe nucleus (DR), providing a morphological basis for the hypothesis that GABAergic inhibitory processes in NPO play an important role in the generation and maintenance of wakefulness as well as active (REM) sleep through the interaction with neurons in the DR. However, the target of such a GABAergic projection from the NPO within the DR is unknown. In the present study, a double-fluorescent labeling technique was employed to examine the target of GABAergic inputs to the DR. Methods Adult cats were deeply anesthetized and perfused transcardially. Subsequently, the brainstem containing the DR was removed, postfixed and cut into 15 μm coronal sections with a Reichert-Jung cryostat. The sections were immunostained with antibodies against GABA-A or GABA-B receptors and GABA following the procedure of double fluorescence immunohistochemistry. Results Under fluorescence microscopy, a large number of neurons were labeled with antibodies against either GABA-A receptor or GABA-B receptor. In addition, neurons labeled with antibody against GABA were observed in the DR. With double fluorescence immunohistochemical techniques, some neurons labeled by anti-GABA antibody were also stained with antibodies against GABA-A or GABA-B receptors. Conclusion The expression of GABA-A or GABA-B receptors by GABAergic neurons in the DR indicates that GABAergic neurons in the DR receive GABAergic inputs. Our previous study has demonstrated that these GABAergic inputs are from the NPO. These data provide a morphological foundation to support our hypothesis that, during wakefulness, NPO GABAergic “Executive” neurons suppress “Second-Order” GABAergic neurons in the DR, which, in turn, activate (disinhibit) serotonergic wake-on neurons in this nucleus. Support (if any) NS092383

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