HTR1A C-1019G polymorphism (rs6295) and serotonin transporter promoter polymorphism (5-HTTLPR) have been linked with panic disorder (PD) in different ethnic backgrounds. Both these polymorphisms are in the promoter regions. However, results are inconsistent and contrasting evidence makes reliable conclusions even more challenging. A meta-analysis was conducted to test whether C-1019G polymorphism and 5-HTTLPR were involved in the etiology of PD. Articles researching the link between C-1019G, 5-HTTLPR polymorphisms, and PD were retrieved by database searching and systematically selected on the basis of selected inclusion parameters. 21 studies were included that examined the relationship of rs6295,5-HTTLPR polymorphisms with PD risk susceptibility (rs62957 polymorphism - 7 articles, and 5-HTTLPR polymorphism - 14 articles). A significant association was seen between the rs6295 polymorphism and PD pathogenesis, especially in Caucasian PD patients. No significant genetic linkage was found between the 5-HTTLPR polymorphism and PD. C-1019G polymorphism was involved in the etiology of PD in Caucasian patients. The 5-HTTLPR polymorphism was not a susceptibility factor of PD.

The serotonin receptor subtype 1A (5-HT1AR), one of the G-protein-coupled receptor (GPCR) family, has been implicated in several neurological conditions. Understanding the activation and inactivation mechanism of 5-HT1AR at the molecular level is critical for discovering novel therapeutics in many diseases. Recently there has been a growing appreciation for the role of external electric fields (EFs) in influencing the structure and activity of biomolecules. In this study, we used molecular dynamics (MD) simulations to examine conformational features of active states of 5-HT1AR and investigate the effect of an external static EF with 0.02 V/nm applied on the active state of 5-HT1AR. Our results showed that the active state of 5-HT1AR maintained the native structure, while the EF led to structural modifications in 5-HT1AR, particularly inducing the inward movement of transmembrane helix 6 (TM6). Furthermore, it disturbed the conformational switches associated with activation in the CWxP, DRY, PIF, and NPxxY motifs, consequently predisposing an inclination towards the inactive-like conformation. We also found that the EF led to an overall increase in the dipole moment of 5-HT1AR, encompassing TM6 and pivotal amino acids. The analyses of conformational properties of TM6 showed that the changed secondary structure and decreased solvent exposure occurred upon the EF condition. The interaction of 5-HT1AR with the membrane lipid bilayer was also altered under the EF. Our findings reveal the molecular mechanism underlying the transition of 5-HT1AR conformation induced by external EFs, which offer potential novel insights into the prospect of employing structure-based EF applications for GPCRs.

Thrombocytopenia caused by long-term radiotherapy and chemotherapy exists in cancer treatment. Previous research demonstrates that 5-Hydroxtrayptamine (5-HT) and its receptors induce the formation of megakaryocytes (MKs) and platelets. However, the relationships between 5-HT1A receptor (5-HTR1A) and MKs is unclear so far. We screened and investigated the mechanism of vilazodone as a 5-HTR1A partial agonist in promoting MK differentiation and evaluated its therapeutic effect in thrombocytopenia. We employed a drug screening model based on machine learning (ML) to screen the megakaryocytopoiesis activity of Vilazodone (VLZ). The effects of VLZ on megakaryocytopoiesis were verified in HEL and Meg-01 cells. Tg (itga2b: eGFP) zebrafish was performed to analyze the alterations in thrombopoiesis. Moreover, we established a thrombocytopenia mice model to investigate how VLZ administration accelerates platelet recovery and function. We carried out network pharmacology, Western blot, and immunofluorescence to demonstrate the potential targets and pathway of VLZ. VLZ has been predicted to have a potential biological action. Meanwhile, VLZ administration promotes MK differentiation and thrombopoiesis in cells and zebrafish models. Progressive experiments showed that VLZ has a potential therapeutic effect on radiation-induced thrombocytopenia in vivo. The network pharmacology and associated mechanism study indicated that SRC and MAPK signaling are both involved in the processes of megakaryopoiesis facilitated by VLZ. Furthermore, the expression of 5-HTR1A during megakaryocyte differentiation is closely related to the activation of SRC and MAPK. Our findings demonstrated that the expression of 5-HTR1A on MK, VLZ could bind to the 5-HTR1A receptor and further regulate the SRC/MAPK signaling pathway to facilitate megakaryocyte differentiation and platelet production, which provides new insights into the alternative therapeutic options for thrombocytopenia.

UNASSIGNED: Intramuscular (IM) heating-needle therapy, a non-painful thermal therapy, has been found to exert an analgesic effect via the thalamic ventromedial (VM) nucleus, solely by reducing the triggering threshold for descending inhibition; this could be modulated by intracephalic 5-hydroxytryptamine-1A (5-HT1A) receptors, rather than via the regular analgesia pathway. In this study, the effect and the potential serotonergic mechanism of IM heating-needle stimulation at 43°C were explored in the case of the pathological state of lumbar disc herniation (LDH).
UNASSIGNED: A modified classic rat model of LDH, induced via autologous nucleus pulposus implantation, was utilized. IM inner heating-needles were applied at the attachment point of skeletal muscle on both sides of the L4 and L5 spinous processes. WAY-100635 and 8-OH-DAPT, 5-HT1A receptor antagonist and agonist, were separately injected into the bilateral thalamic mediodorsal (MD) and VM nucleus via an intrathalamic catheter. Nociception was assessed by bilateral paw withdrawal reflexes elicited by noxious mechanical and heat stimulation.
UNASSIGNED: IM heating-needle stimulation at a temperature of 43°C for 30 or 45 min significantly relieved both mechanical and heat hyperalgesia in the rat model of LDH (P < 0.05). Heat hyperalgesia was found to be significantly enhanced by administration of WAY-100635 into the thalamic VM nucleus, blocking the effect of heating-needle stimulation in a dose-dependent manner (P < 0.05), while no effects were detected after injection into the thalamic MD nucleus (P > 0.05). Injection of 8-OH-DAPT into the thalamic MD nucleus exerted no modulating effects on either mechanical or heat hyperalgesia (P > 0.05).
UNASSIGNED: IM heating-needle stimulation at 43°C for 30 min may activate 5-HT1A mechanisms, via the thalamic VM nucleus, to attenuate hyperalgesia in a rat model of LDH. This innocuous form of thermal stimulation is speculated to selectively activate the descending inhibition mediated by the thalamic VM nucleus, exerting an analgesic effect, without the involvement of descending facilitation of the thalamic MD nucleus.

General anesthesia is widely used in various clinical practices due to its ability to cause loss of consciousness. However, the exact mechanism of anesthesia-induced unconsciousness remains unclear. It is generally thought that arousal-related brain nuclei are involved. 5-Hydroxytryptamine (5-HT) is closely associated with sleep arousal. Here, we explore the role of the 5-HT system in anesthetic awakening through pharmacological interventions and optogenetic techniques. Our data showed that exogenous administration of 5-hydroxytryptophan (5-HTP) and optogenetic activation of 5-HT neurons in the dorsal raphe nucleus (DR) could significantly shorten the emergence time of sevoflurane anesthesia in mice, suggesting that regulation of the 5-HT system using both endogenous and exogenous approaches could mediate delayed emergence. In addition, we first discovered that the different 5-HT receptors located in the DR, known as 5-HT autoreceptors, are essential for the regulation of general anesthetic awakening, with 5-HT1A and 5-HT2A/C receptors playing a regulatory role. These results can provide a reliable theoretical basis as well as potential targets for clinical intervention to prevent delayed emergence and some postoperative risks.

Parkinson\'s disease (PD) is a pervasive neurodegenerative disease, and levodopa (L-dopa) is its preferred treatment. The pathophysiological mechanism of levodopa-induced dyskinesia (LID), the most common complication of long-term L-dopa administration, remains obscure. Accumulated evidence suggests that the dopaminergic as well as non-dopaminergic systems contribute to LID development. As a 5-hydroxytryptamine 1A/1B receptor agonist, eltoprazine ameliorates dyskinesia, although little is known about its electrophysiological mechanism. The aim of this study was to investigate the cumulative effects of chronic L-dopa administration and the potential mechanism of eltoprazine\'s amelioration of dyskinesia at the electrophysiological level in rats.
Neural electrophysiological analysis techniques were conducted on the acquired local field potential (LFP) data from primary motor cortex (M1) and dorsolateral striatum (DLS) during different pathological states to obtain the information of power spectrum density, theta-gamma phase-amplitude coupling (PAC), and functional connectivity. Behavior tests and AIMs scoring were performed to verify PD model establishment and evaluate LID severity.
We detected exaggerated gamma activities in the dyskinetic state, with different features and impacts in distinct regions. Gamma oscillations in M1 were narrowband manner, whereas that in DLS had a broadband appearance. Striatal exaggerated theta-gamma PAC in the LID state contributed to broadband gamma oscillation, and aperiodic-corrected cortical beta power correlated robustly with aperiodic-corrected gamma power in M1. M1-DLS coherence and phase-locking values (PLVs) in the gamma band were enhanced following L-dopa administration. Eltoprazine intervention reduced gamma oscillations, theta-gamma PAC in the DLS, and coherence and PLVs in the gamma band to alleviate dyskinesia.
Excessive cortical gamma oscillation is a compelling clinical indicator of dyskinesia. The detection of enhanced PAC and functional connectivity of gamma-band oscillation can be used to guide and optimize deep brain stimulation parameters. Eltoprazine has potential clinical application for dyskinesia.

The activation of subcutaneous mast cells (MCs) helps to trigger the analgesic effect induced by acupuncture (AP), a traditional oriental therapy, that has been gradually accepted worldwide. This work aimed to reveal whether the serotonin (5-hydroxytryptamine, 5-HT) released from MCs plays an important role in this process, which has a controversial effect in the mechanism of pain.
In vivo tests, a 20-min session of AP was applied at Zusanli acupuncture point (acupoint) of acute ankle arthritis rats. Pain thresholds of the injured hindpaw were assessed to reflect the pain state, and the targeting substances in the interstitial space of the treated acupoint were sampled by microdialysis. In vitro experiments, exogenous 5-HT (exo-5-HT) was introduced to mediate adenosine triphosphate (ATP) release from cultured MCs.
Needling promoted 5-HT accumulation at the Zusanli acupoint, which was prevented by sodium cromolyn. AP\'s analgesic effect was suppressed by the inhibition of 5-HT receptors at the acupoint, especially 5-HT1A subtype. In vitro tests, mechanical perturbation mimicking needling stimulation induced MCs to release 5-HT. 1 μM and 10 μM of exo-5-HT facilitated ATP release, which was restrained by blocking of 5-HT1 receptors rather than 5-HT3 receptors. As 5-HT, ATP and adenosine were also transiently accumulated in the treated acupoint during needling. Promoting ATP hydrolysis or activation adenosine A1 receptors duplicated AP analgesic effect. Finally, the inhibition of ATP receptors by suramin or pyridoxal phosphate-6-azo tetrasodium salt hydrate (PPADS) prevented AP analgesic effect.
Our results suggest that MC-associated 5-HT release at acupoints contributes to AP analgesia, and the mediation of ATP secretion through 5-HT1A receptors might be the underlying mechanism at play. ATP could facilitate adenosine production or the propagation of needling signals.

UNASSIGNED: This work is to investigate the alterations of the central 5-hydroxytryptamine (5-HT) system in spontaneously hypertensive rats (SHR) and the correlation with the behaviors of SHR, and to explore the effects of glucocorticoid intervention on the central 5-HT system and SHR behaviors.
UNASSIGNED: Three weeks old SHR were chosen as the attention-deficit hyperactivity disorder (ADHD) model and treated with glucocorticoid receptor (GR) agonist or inhibitor, whereas Wista Kyoto rats (WKY) were chosen as the normal control group. Open-field test and Làt maze test were used to evaluate the spontaneous activities and non-selective attention. The levels of 5-HT in the extracellular fluid specimens of the prefrontal cortex of rats were analyzed by high-performance liquid chromatography. The expressions of GR, 5-HT1A receptor (5-HT1AR), and 5-HT2A receptor (5-HT2AR) in the prefrontal cortex were analyzed through immunohistochemistry.
UNASSIGNED: Our study demonstrated that the 5-HT level was lower in the prefrontal cortex of SHR compared to that of WKY. The Open-field test and Làt maze test showed that GR agonist (dexamethasone, DEX) intervention ameliorated attention deficit and hyperactive behavior, whereas GR inhibitor (RU486) aggravated the disorders. With DEX, the expression levels of 5-HT and 5-HT2AR in the prefrontal cortex of SHR were significantly higher than those in the control group, whereas the expression level of 5-HT1AR was lower. However, the expression levels of 5-HT and 5-HT2AR were significantly decreased after the intervention with RU486, while the expression level of 5-HT1AR increased. Results showed that glucocorticoid was negatively correlated with 5-HT1AR and positively correlated with 5-HT2AR.
UNASSIGNED: In the prefrontal cortex of ADHD rats, the down-regulation of 5-HT and 5-HT2AR expressions and the up-regulation of 5-HT1AR, compared with WYK rats, suggested a dysfunctional central 5-HT system in ADHD rats. The GR agonist can upregulate the expression of 5-HT and 5-HT2AR and downregulate the expression of 5-HT1AR in the prefrontal cortex of SHR as well as reduce the hyperactivity and attention deficit behavior in SHR, while the opposite was true for the GR inhibitor. It is suggested that the dysfunction of the 5-HT system in ADHD rats is closely related to glucocorticoid receptor activity.

Somatic symptom disorder (SSD), which occurs in about 5-7 percent of the adult population, involves heightened physical and emotional sensitivity to pain. However, its neural mechanism remains elusive and thus hinders effective clinical intervention. In this study, we employed chronic restraint stress (CRS)-induced hyperalgesia as a mouse model to investigate the neural mechanism underlying SSD and its pharmacological treatment. We found that CRS induced hyperactivity of anterior cingulate cortex (ACC), whereas chemogenetic inhibition of such hyperactivity could prevent CRS-induced hyperalgesia. Systematic application and ACC local infusion of fluoxetine alleviated CRS-induced hyperalgesia. Moreover, we found that fluoxetine exerted its anti-hyperalgesic effects through inhibiting the hyperactivity of ACC and upregulating 5-HT1A receptors. Our study thus uncovers the functional role of 5-HT signaling in modulating pain sensation and provides a neural basis for developing precise clinical intervention for SSD.

Background: Adult hippocampal neurogenesis and synaptic plasticity are necessary for the behavioral response to the selective serotonin reuptake inhibitor (SSRI) fluoxetine, but the molecular mechanisms underlying these effects are only partially understood. Methods: Anxiety and depressive-like behaviors in mice were developed by chronic mild stress (CMS) or chronic corticosterone (CORT) treatment. Pharmacological and genetic approaches were used to investigate the role of the neuronal nitric oxide synthase (nNOS)-carboxy-terminal PDZ ligand of nNOS (CAPON) interaction in behavioral and neuroplasticity effects of serotoninergic system. Molecular biological and morphological studies were performed to examine the mechanisms underlying the behavioral effects of nNOS-CAPON interaction that modulated by 5-HT1A receptor (5-HT1AR). Results: Fluoxetine prevented chronic stress-induced nNOS-CAPON upregulation and coupling in the dentate gyrus (DG), and promoting nNOS-CAPON association weakened the anxiolytic and antidepressant effects of fluoxetine in stressed mice. The chronic fluoxetine elevated 5-HT and 5HT1AR agonist 8-OH-DPAT decreased the expression and binding of nNOS with CAPON, whereas 5-HT1AR antagonist NAN-190 had the opposite effects. Importantly, augmenting nNOS-CAPON binding neutralized 8-OH-DPAT-upregulated spine density of DG granule cells and well-characterized synaptic-related proteins, including brain-derived neurotrophic factor (BDNF) and phosphorylation of extracellular signal regulated kinase (ERK), cAMP-response element binding protein (CREB), and synapsin in the DG and abolished the anxiolytic and antidepressant-like effects of 8-OH-DPAT. In contrast, dissociation of nNOS from CAPON rescued the effects of NAN-190 on behavior and neuroplasticity. Conclusion: Taken together, our results indicated that fluoxetine modifies mood behaviors and hippocampal neuroplasticity by disrupting the nNOS-CAPON interaction that links postsynaptic 5-HT1AR activation.