Both clinical and animal studies demonstrated that seizure-induced respiratory arrest (S-IRA) contributes importantly to sudden unexpected death in epilepsy (SUDEP). It has been shown that enhancing serotonin (5-HT) function relieves S-IRA in animal models of SUDEP, including DBA/1 mice. Direct activation of 5-HT3 and 5-HT4 receptors suppresses S-IRA in DBA/1 mice, indicating that these receptors are involved in S-IRA. However, it remains unknown if other subtypes of 5-HT receptors are implicated in S-IRA in DBA/1 mice. In this study, we investigated the action of an agonist of the 5-HT1A (8-OH-DPAT), 5-HT2A (TCB-2), 5-HT2B (BW723C86), 5-HT2C (MK-212), 5-HT6 (WAY-208466) and 5-HT7 (LP-211) receptor on S-IRA in DBA/1 mice. An agonist of the 5-HT receptor or a vehicle was intraperitoneally administered 30 min prior to acoustic simulation, and the effect of each drug/vehicle on the incidence of S-IRA was videotaped for offline analysis. We found that the incidence of S-IRA was significantly reduced by TCB-2 at 10 mg/kg (30%, n = 10; p < 0.01, Fisher\'s exact test) but was not altered by other agonists compared with the corresponding vehicle controls in DBA/1 mice. Our data demonstrate that 5-HT2A receptors are implicated in S-IRA, and 5-HT1A, 5-HT2B, 5-HT2C, 5-HT6 and 5-HT7 receptors are not involved in S-IRA in DBA/1 mice.

OBJECTIVE: Sudden unexpected death in epilepsy (SUDEP) is an underestimated complication of epilepsy. Previous studies have demonstrated that enhancement of serotonergic neurotransmission suppresses seizure-induced sudden death in evoked seizure models. However, it is unclear whether elevated serotonin (5-HT) function will prevent spontaneous seizure-induced mortality (SSIM), which is characteristic of human SUDEP. We examined the effects of 5-HT-enhancing agents that act by three different pharmacological mechanisms on SSIM in Dravet mice, which exhibit a high incidence of SUDEP, modeling human Dravet syndrome.
METHODS: Dravet mice of both sexes were evaluated for spontaneous seizure characterization and changes in SSIM incidence induced by agents that enhance 5-HT-mediated neurotransmission. Fluoxetine (a selective 5-HT reuptake inhibitor), fenfluramine (a 5-HT releaser and agonist), SR 57227 (a specific 5-HT3 receptor agonist), or saline (vehicle) was intraperitoneally administered over an 8-day period in Dravet mice, and the effect of these treatments on SSIM was examined.
RESULTS: Spontaneous seizures in Dravet mice generally progressed from wild running to tonic seizures with or without SSIM. Fluoxetine at 30 mg/kg, but not at 20 or 5 mg/kg, significantly reduced SSIM compared with the vehicle control. Fenfluramine at 1-10 mg/kg, but not .2 mg/kg, fully protected Dravet mice from SSIM, with all mice surviving. Compared with the vehicle control, SR 57227 at 20 mg/kg, but not at 10 or 5 mg/kg, significantly lowered SSIM. The effect of these drugs on SSIM was independent of sex.
CONCLUSIONS: Our data demonstrate that elevating serotonergic function by fluoxetine, fenfluramine, or SR 57227 significantly reduces or eliminates SSIM in Dravet mice in a sex-independent manner. These findings suggest that deficits in serotonergic neurotransmission likely play an important role in the pathogenesis of SSIM, and fluoxetine and fenfluramine, which are US Food and Drug Administration-approved medications, may potentially prevent SUDEP in at-risk patients.

OBJECTIVE: Lasmiditan holds important potential in treating migraine, but its ideal dose remains elusive. This meta-analysis is conducted based on aggregate data and aims to compare the efficacy of lasmiditan 200 mg versus 100 mg for acute treatment of migraine attack.
METHODS: PubMed, Embase, Web of Science, EBSCO, and Cochrane Library databases were systematically searched, and we included the randomized controlled trials comparing the efficacy of lasmiditan 200 mg versus 100 mg for migraine patients. This meta-analysis was conducted using the random-effect model or fixed-effect model based on the heterogeneity. The primary outcome was pain free at 2 hours. Secondary outcomes included pain relief at 2 hours, pain free at 24 hours, most bothersome symptom free at 2 hours, and adverse events.
RESULTS: Seven randomized controlled trials and 6515 patients were included in this meta-analysis. Compared with lasmiditan 100 mg for migraine patients, lasmiditan 200 mg was able to significantly improve pain free at 2 hours (odd ratio [OR], 1.28; 95% confidence interval [CI], 1.14-1.44; P < 0.0001) and pain free at 24 hours (OR, 1.35; 95% CI, 1.14-1.60; P = 0.0005), but showed no effect on pain relief at 2 hours (OR, 1.00; 95% CI, 0.90-1.12; P = 0.98) or most bothersome symptom free at 2 hours (OR, 0.93; 95% CI, 0.83-1.03; P = 0.17). Lasmiditan 200 mg was associated with the increase in adverse events compared with lasmiditan 100 mg (OR, 1.28; 95% CI, 1.15-1.43; P < 0.0001).
CONCLUSIONS: Lasmiditan 200 mg is more effective to improve pain free at 2 hours and 24 hours than lasmiditan 100 mg for the acute treatment of migraine patients.

BACKGROUND: The ideal dose of lasmiditan for migraine is not clear. This meta-analysis aims to compare the efficacy of lasmiditan 200 mg versus 100 mg for migraine patients.
METHODS: We have searched several databases including PubMed, Embase, Web of Science, EBSCO, and Cochrane Library Databases and selected the randomized controlled trials comparing the efficacy of lasmiditan 200 mg versus 100 mg for migraine patients. This meta-analysis was conducted using the random-effect model.
RESULTS: Five randomized controlled trials were included in this meta-analysis. Compared with lasmiditan 100-mg group in migraine patients, lasmiditan 200-mg group was associated with substantially increased pain free at 2 hours (odds ratio [OR], 1.27; 95% confidence interval [CI], 1.12-1.44; P = 0.0002) and pain free at 24 hours (OR, 1.31; 95% CI, 1.08-1.60; P = 0.007) but demonstrated no obvious impact on pain relief at 2 hours (OR, 1.02; 95% CI, 0.91-1.16; P = 0.72) or MBS free at 2 hours (OR, 0.94; 95% CI, 0.77-1.14; P = 0.52). In addition, the incidence of adverse events was higher in lasmiditan 200-mg group than that in lasmiditan 100-mg group (OR, 1.29; 95% CI, 1.15-1.45; P < 0.0001).
CONCLUSIONS: Lasmiditan 200 mg is better for the treatment of migraine patients than lasmiditan 100 mg.

Cannabinoid CB2R agonists have gained considerable attention as potential novel therapies for psychiatric disorders due to their non-psychoactive nature, in contrast to CB1R agonists. In this study, we employed molecular docking to design and synthesize 23 derivatives of cannabidiol (CBD) with the aim of discovering potent CB2R agonists rather than CB2R antagonists or inverse agonists. Structure-activity relationship (SAR) investigations highlighted the critical importance of the amide group at the C-3\' site and the cycloalkyl group at the C-4\' site for CB2R activation. Interestingly, three CBD derivatives, namely 2o, 6g, and 6h, exhibited substantial partial agonistic activity towards the CB2 receptor, in contrast to the inverse agonistic property of CBD. Among these, 2o acted as a CB2R and 5-HT1AR dual agonist, albeit with some undesired antagonist activity for CB1R. It demonstrated significant CB2R partial agonism while maintaining a level of 5-HT1AR agonistic and CB1R antagonistic activity similar to CBD. Pharmacokinetic experiments confirmed that 2o possesses favorable pharmacokinetic properties. Behavioral studies further revealed that 2o elicits significant antidepressant-like and anxiolytic-like effects while maintaining a good safety profile.

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.

Cognitive impairment is a prominent clinical manifestation of vascular depression (VaDep). The current study aimed to assess the efficacy of tandospirone citrate in VaDep cases with mild cognitive impairment (VaDep-MCI) as well as the role of plasma monoamine neurotransmitters during the treatment. In this single-blind, randomized controlled study, 116 participants were randomly assigned to the tandospirone (tandospirone citrate-escitalopram) and control (escitalopram) groups. The primary endpoints were changes in cognitive test scores from baseline to Week 8, including the Rey Auditory Verbal Learning Test (RAVLT), Semantic Verbal Fluency (SVF) test, Trail Making Test (TMT), Digital Span Test (DST) and Clock Drawing Test (CDT) scores. Generalized estimating equation models were used to examine repeated measures. The results showed that compared with the changes in the control group from baseline to Week 8, the tandospirone group showed more significant changes in SVF score at Weeks 4 (p < 0.05) and 8 (p < 0.001), and TMT (B-A) score at Week 8 (p < 0.05). RAVLT, DST and DCT scores were relatively stable in both groups during the study period. Moreover, mediation analysis showed that these results were not mediated by the alleviation of depression symptoms. Partial Spearman correlation analysis showed that only plasma 5-hydroxytryptamine (5-HT) was positively correlated with Hamilton Depression Rating Scale score after Bonferroni correction (r = 0.347, p < 0.001). Augmentation therapy with tandospirone citrate improved the executive and language functions of VaDep-MCI patients. Additionally, plasma 5-HT levels may serve as a potential biomarker of VaDep severity. These findings may provide clinical insights into the treatment of vascular depression.

Lasmiditan is the first 5-HT1F receptor agonist with potential to address the huge unmet medical needs for the treatment of migraine in China. The CENTURION study was the first phase 3 study of lasmiditan in Caucasian and Chinese patients with migraine. This post hoc analysis further demonstrates the safety profile of lasmiditan in the Chinese population and was urgently needed.
Patients were randomized 1:1:1 to lasmiditan 200 mg lasmiditan 100 mg, or a control group. The incidence of treatment-emergent adverse events (TEAEs), their severity, and incidence by treated attacks for frequently reported TEAEs (≥ 5%) were evaluated. The duration, onset, and relationship of efficacy with very common TEAEs (≥ 10%) was analyzed.
A total of 281 Chinese patients were included in this post hoc analysis. No deaths and no study drug-related treatment emergent serious adverse events (TESAEs) were reported. The incidence of at least one TEAE was higher in patients receiving lasmiditan 200 mg (73.9%) and 100 mg (66.3%) versus placebo (26.6%). TEAEs were generally mild or moderate in severity, and the incidence of frequently reported TEAEs was generally highest during the first attack. Very common TEAEs with lasmiditan included dizziness, asthenia, somnolence, muscular weakness, fatigue, and nausea. The duration of dizziness was longest during the first attack. There were no cardio-cerebrovascular ischemic events and serotonin syndrome. The presence of very common TEAEs (except nausea), and severe dizziness, did not appear to have a negative influence on the efficacy.
In the Chinese population of the CENTURION study, most of the TEAEs were neurologic, of mild or moderate severity, and self-limiting. The distribution of frequently reported TEAEs at the first attack differed from the primary cohort, while the overall safety profile of lasmiditan in the Chinese population was generally consistent with the CENTURION primary cohort. No new safety concerns were observed in the Chinese population.
NCT03670810.
Although there is significant unmet medical need among patients with migraine, there has been no novel compound for treatment of migraine over past two decades in China. These unmet medical needs persist because the current available medications for the acute treatment of migraine are reported to have safety and tolerability issues. Lasmiditan is a new class of acute migraine medication (5-HT receptor agonist with high selectivity for the 5-HT1F receptor) with a proven efficacy and safety in phase 2 and 3 studies. Owing to some differences in clinical practice between China and western countries, there is need to get additional evidence on safety of lasmiditan in the Chinese population to support its usage in clinical practice.This post hoc analysis was conducted to present the detailed safety profile of lasmiditan in the Chinese population using data from the CENTURION study. Approximately half of the analyzed population was not covered in the published primary cohort.The results show that in the Chinese population of the study, most of the treatment-emergent adverse events (TEAEs) were neurologic, of mild or moderate severity, and self-limiting. The distribution of frequently reported TEAEs at the first attack differed from the primary cohort with no new safety concerns observed in the Chinese population. The overall safety profile of lasmiditan in the Chinese population was generally consistent with the primary cohort. The results provide additional evidence and emphasize that lasmiditan may be considered as a useful acute treatment option with acceptable safety profile for patients with migraine in China.

Recent evidence indicates that 5-HT1A receptors play a significant role in mediating maternal behavior in rats. Given that they also modulate the mesocortical dopamine system, we hypothesized that 5-HT1A receptors may mediate maternal behavior, possibly by interacting with the D2 receptor. To address this issue, we used a combination of 5-HT1A agonist (8-OH-DPAT, 0.5 mg/kg) and two D2 drugs (an agonist quinpirole, QUIN, 1.0 mg/kg; a potent D2 antagonist haloperidol, HAL, 0.1 mg/kg) on rat maternal behavior in the home-cage maternal behavior and pup preference tests. We replicated the findings that acute QUIN, HAL, and 8-OH-DPAT disrupted home-cage maternal behavior. When administered in combination, pretreatment with HAL and QUIN worsened 8-OH-DPAT-induced maternal disruption and induced a decrease in the pup preference ratio. Accordingly, 8-OH-DPAT enhanced QUIN\' and HAL\'s disruption of pup retrieval and pup preference, reversed the increase in hovering over pups induced by HAL. These findings suggest that activation of 5-HT1A receptors enhances D2-mediated maternal disruption. Furthermore, given that the combination of D2 drugs and 5-HT1A agonists only produced an additive effect on maternal disruption, 5-HT1A receptors may have a direct effect on maternal behavior independent of their interaction with D2 receptors.

BACKGROUND: Intermittent hypoxia induces increased ventilatory responses in a 5-HT-dependent manner. This study aimed to explore that effect of raphe magnus serotonin 1A receptor (5-HT1A) receptor on the increased ventilatory responses induced by intermittent hypoxia.
METHODS: Stereotaxic surgery was performed in adult male rats, and acute and chronic intermittent hypoxia models were established after recovery from surgery. The experimental group received microinjections of 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) into the raphe magnus nucleus (RMg). Meanwhile, the control group received microinjections of artificial cerebrospinal fluid instead of 8-OH-DPAT. Ventilatory responses were compared among the different groups of oxygen status. 5-HT expressions in the RMg region were assessed by immunohistochemistry after chronic intermittent hypoxia.
RESULTS: Compared with the normoxia group, the acute intermittent hypoxia group exhibited higher ventilatory responses (e.g., shorter inspiratory time and higher tidal volume, frequency of breathing, minute ventilation, and mean inspiratory flow) (P < 0.05). 8-OH-DPAT microinjection partly weakened these changes in the acute intermittent hypoxia group. Further, compared with the acute intermittent hypoxia group, rats in chronic intermittent hypoxia group exhibited higher measures of ventilatory responses after 1 day of intermittent hypoxia (P < 0.05). These effects peaked after 3 days of intermittent hypoxia treatment and then decreased gradually. Moreover, these changes were diminished in the experimental group. 5-HT expression in the RMg region increased after chronic intermittent hypoxia, which was consistent with the changing trend of ventilatory responses. While activation of the 5-HT1A receptor in the RMg region alleviated this phenomenon.
CONCLUSIONS: The results indicate that RMg 5-HT1A receptor, via changing the expression level of 5-HT in the RMg region, is involved in the modulation of the increased ventilatory responses induced by intermittent hypoxia.