Serotonin 1A Receptor Research Articles

Association Study of Serotonin 1A Receptor Gene, Personality, and Anxiety in Women with Alcohol Use Disorder.

Alcohol use disorder is considered a chronic and relapsing disorder affecting the central nervous system. The serotonergic system, mainly through its influence on the mesolimbic dopaminergic reward system, has been postulated to play a pivotal role in the underlying mechanism of alcohol dependence. The study aims to analyse the association of the rs6295 polymorphism of the 5HTR1A gene in women with alcohol use disorder and the association of personality traits with the development of alcohol dependence, as well as the interaction of the rs6295, personality traits, and anxiety with alcohol dependence in women. The study group consisted of 213 female volunteers: 101 with alcohol use disorder and 112 controls. NEO Five-Factor and State-Trait Anxiety Inventories were applied for psychometric testing. Genotyping of rs6295 was performed by real-time PCR. We did not observe significant differences in 5HTR1A rs6295 genotypes (p = 0.2709) or allele distribution (p = 0.4513). The AUD subjects scored higher on the anxiety trait (p < 0.0001) and anxiety state (p < 0.0001) scales, as well as on the neuroticism (p < 0.0001) and openness (p = 0134) scales. Significantly lower scores were obtained by the AUD subjects on the extraversion (p < 0.0001), agreeability (p < 0.0001), and conscientiousness (p < 0.0001) scales. Additionally, we observed a significant effect of 5HTR1A rs6295 genotype interaction and alcohol dependency, or lack thereof, on the openness scale (p = 0.0016). In summary, this study offers a comprehensive overview of alcohol dependence among women. It offers valuable insights into this complex topic, contributing to a more nuanced understanding of substance use among this specific demographic. Additionally, these findings may have implications for developing prevention and intervention strategies tailored to individual genetic and, most importantly, personality and anxiety differences.

Therapeutic potential of fungally derived psilocybin extract in morphine-dependent mice: A research protocol

Introduction: Psilocybin is a naturally occurring tryptamine derivative psychedelic compound potently produced by fungi members of the genus Psilocybe. Previous literature has highlighted psilocybin as a serotonin 2A receptor agonist with striking effects on neural plasticity and cognition. Recent studies explore the usage of psilocybin in addressing addictive behaviours and substance abuse. Small psilocybin doses have shown promising anti-addictive and withdrawal-minimizing properties in alcohol-dependent mice. This study will further investigate this emerging field through a novel lens. We propose a novel study to elucidate psylobicin’s effect on opioid addiction in mouse models. Methods: Morphine-dependent mice will be administered either saline vehicle or differing doses of psilocybin during a morphine-available period to monitor consumption. Though mechanistically ambiguous, psilocybin’s hypothesized entry into serotonin-dependent stress-conciliating pathways supports the hypothesis that mean morphine consumption will decrease in a dose-dependent manner to similar levels to popular opioid receptor agonist therapeutics, such as methadone. Furthermore, we will examine psilocybin's impact on withdrawal behaviour. After morphine deprival on dependent mice, sustained doses of psilocybin, methadone, and positive and negative controls will be administered. Results: By analyzing stress-indicative behaviours in mice, the efficacy of psilocybin as a withdrawal assistance agent can be elucidated. Results from the morphine-dependent mice are expected to consume less morphine than controls, and minimize withdrawal symptoms at a similar level to popular therapeutic options like methadone. Discussion: If successful, psilocybin’s anti-addictive potential will help provide a cheaper, more accessible therapeutic option in addressing the growing opioid crisis. Furthermore, controlled psilocybin dosages have been shown to have lesser dependence potential compared to modern opioid addiction therapeutics. Conclusion: This study’s novel approach will provide meaningful support in exploring the growing field of mycology and its potential to address other substance use disorders. Future research may explore outside the limitations of the mouse model, like the oral administration of the compounds rather than intraperitoneal injection.

CaMKIV-Mediated Phosphorylation Inactivates Freud-1/CC2D1A Repression for Calcium-Dependent 5-HT1A Receptor Gene Induction.

Calcium calmodulin-dependent protein kinase (CaMK) mediates calcium-induced neural gene activation. CaMK also inhibits the non-syndromic intellectual disability gene, Freud-1/CC2D1A, a transcriptional repressor of human serotonin-1A (5-HT1A) and dopamine-D2 receptor genes. The altered expression of these Freud-1-regulated genes is implicated in mental illnesses such as major depression and schizophrenia. We hypothesized that Freud-1 is blocked by CaMK-induced phosphorylation. The incubation of purified Freud-1 with either CaMKIIα or CaMKIV increased Freud-1 phosphorylation that was partly prevented in Freud-1-Ser644Ala and Freud-1-Thr780Ala CaMK site mutants. In human SK-N-SH neuroblastoma cells, active CaMKIV induced the serine and threonine phosphorylation of Freud-1, and specifically increased Freud-1-Thr780 phosphorylation in transfected HEK-293 cells. The activation of purified CaMKIIα or CaMKIV reduced Freud-1 binding to its DNA element on the 5-HT1A and dopamine-D2 receptor genes. In SK-N-SH cells, active CaMKIV but not CaMKIIα blocked the Freud-1 repressor activity, while Freud-1 Ser644Ala, Thr780Ala or dual mutants were resistant to inhibition by activated CaMKIV or calcium mobilization. These results indicate that the Freud-1 repressor activity is blocked by CaMKIV-induced phosphorylation at Thr780, resulting in the up-regulation of the target genes, such as the 5-HT1A receptor gene. The CaMKIV-mediated inhibition of Freud-1 provides a novel de-repression mechanism to induce 5-HT1A receptor expression for the regulation of cognitive development, behavior and antidepressant response.

Psilocybin reduces heroin seeking behavior and modulates inflammatory gene expression in the nucleus accumbens and prefrontal cortex of male rats.

Preclinical and human studies indicate psilocybin may reduce perseverant maladaptive behaviors, including nicotine and alcohol seeking. Such studies in the opioid field are lacking, though opioids are involved in more >50% of overdose deaths. Psilocybin is an agonist at the serotonin 2A receptor (5-HT2AR), a well-documented target for modulation of drug seeking, and evidence suggests 5-HT2AR agonists may dampen motivation for opioids. We sought to investigate the therapeutic efficacy of psilocybin in mediating cessation of opioid use and maintenance of long-lasting abstinence from opioid seeking behavior in a rat model of heroin self-administration (SA). Psilocybin or 5-HT2AR antagonists ketanserin and volinanserin were administered systemically to rats prior to SA of 0.075 mg/kg/infusion of heroin, or relapse following forced abstinence. Psilocybin did not alter heroin taking, but a single exposure to 3.0 mg/kg psilocybin 4-24 hours prior to a relapse test blunted cue-induced heroin seeking. Conversely, 5-HT2AR antagonists exacerbated heroin relapse. To begin to elucidate mechanisms of psilocybin, drug-naïve rats received psilocybin and/or ketanserin, and tissue was collected from the prefrontal cortex (PFC), a region critical for drug seeking and responsive to psilocybin, 24 hours later for RNA-sequencing. 3.0 mg/kg psilocybin regulated ~2-fold more genes in the PFC than 1.0 mg/kg, including genes involved in the cytoskeleton and cytokine signaling. Ketanserin blocked >90% of psilocybin-regulated genes, including the IL-17a cytokine receptor, Il17ra. Psychedelic compounds have reported anti-inflammatory properties, and therefore we performed a gene expression array to measure chemokine/cytokine molecules in the PFC of animals that displayed psilocybin-mediated inhibition of heroin seeking. Psilocybin regulated 4 genes, including Il17a, and a subset of genes correlated with relapse behavior. Selective inhibition of PFC IL-17a was sufficient to reduce heroin relapse. We conclude that psilocybin reduces heroin relapse and highlight IL-17a signaling as a potential downstream pathway of psilocybin that also reduces heroin seeking.

N-(4-Bromo-2,5-Dimethoxyphenethyl)-6-(4-Phenylbutoxy)Hexan-1-Amine (XOB): A Novel Phenylalkylamine Antagonist of Serotonin 2A Receptors and Voltage-Gated Sodium Channels.

Bipolar disorder impacts millions of patients in the United States but the mechanistic understanding of its pathophysiology and therapeutics is incomplete. Atypical antipsychotic serotonin2A (5-HT2A) receptor antagonists, such as quetiapine and olanzapine, and mood-stabilizing voltage-gated sodium channel (VGSC) blockers, such as lamotrigine, carbamazepine, and valproate, show therapeutic synergy and are often prescribed in combination for the treatment of bipolar disorder. Combination therapy is a complex task for clinicians and patients, often resulting in unexpected difficulties with dosing, drug tolerances, and decreased patient compliance. Thus, an unmet need for bipolar disorder treatment is to develop a therapeutic agent that targets both 5-HT2A receptors and VGSCs. Toward this goal, we developed a novel small molecule that simultaneously antagonizes 5-HT2A receptors and blocks sodium current. The new compound, N-(4-bromo-2,5-dimethoxyphenethyl)-6-(4-phenylbutoxy)hexan-1-amine (XOB) antagonizes 5-HT-stimulated, Gq-mediated, calcium flux at 5-HT2A receptors at low micromolar concentrations while displaying negligible affinity and activity at 5-HT1A, 5-HT2B, and 5-HT2C receptors. At similar concentrations, XOB administration inhibits sodium current in heterologous cells and results in reduced action potential (AP) firing and VGSC-related AP properties in mouse prefrontal cortex layer V pyramidal neurons. Thus, XOB represents a new, proof-of-principle tool that can be used for future preclinical investigations and therapeutic development. This polypharmacology approach of developing a single molecule to act upon two targets, which are currently independently targeted by combination therapies, may lead to safer alternatives for the treatment of psychiatric disorders that are increasingly being found to benefit from the simultaneous targeting of multiple receptors. SIGNIFICANCE STATEMENT: The authors synthesized a novel small molecule (XOB) that simultaneously antagonizes two key therapeutic targets of bipolar disorder, 5-HT2A receptors and voltage-gated sodium channels, in heterologous cells, and inhibits the intrinsic excitability of mouse prefrontal cortex layer V pyramidal neurons in brain slices. XOB represents a valuable new proof-of-principle tool for future preclinical investigations and provides a novel molecular approach to the pharmacological treatment of complex neuropsychiatric disease, which often requires a combination of therapeutics for sufficient patient benefit.

Association between hearing ability and cortical morphology in the elderly: multiparametric mapping, cognitive relevance, and neurobiological underpinnings

Hearing impairment is a common condition in the elderly. However, a comprehensive understanding of its neural correlates is still lacking. We recruited 284 elderly adults who underwent structural MRI, magnetic resonance spectroscopy, audiometry, and cognitive assessments. Individual hearing abilities indexed by pure tone average (PTA) were correlated with multiple structural MRI-derived cortical morphological indices. For regions showing significant correlations, mediation analyses were performed to examine their role in the relationship between hearing ability and cognitive function. Finally, the correlation maps between hearing ability and cortical morphology were linked with publicly available connectomic gradient, transcriptomic, and neurotransmitter maps. Poorer hearing was related to cortical thickness (CT) reductions in widespread regions and gyrification index (GI) reductions in the right Area 52 and Insular Granular Complex. The GI in the right Area 52 mediated the relationship between hearing ability and executive function. This mediating effect was further modulated by glutamate and N-acetylaspartate levels in the right auditory region. The PTA-CT correlation map followed microstructural connectomic hierarchy, were related to genes involved in certain biological processes (e.g., glutamate metabolic process), cell types (e.g., excitatory neurons and astrocytes), and developmental stages (i.e., childhood to young adulthood), and covaried with dopamine receptor 1, dopamine transporter, and fluorodopa. The PTA-GI correlation map was related to 5-hydroxytryptamine receptor 2a. Poorer hearing is associated with cortical thinning and folding reductions, which may be engaged in the relationship between hearing impairment and cognitive decline in the elderly and have different neurobiological substrates. See the Acknowledgements section.

RE104: Synthesis and Activity of a Novel Serotonergic Psychedelic Prodrug of 4-Hydroxy-N,N-diisopropyltryptamine.

Results from randomized clinical trials of psilocybin in depressive disorders highlight the therapeutic potential of serotonergic psychedelic compounds in mental health disorders. The synthetic 5-hydroxytryptamine 2A receptor agonist 4-hydroxy-N,N-diisopropyltryptamine (4-OH-DiPT) is structurally similar to psilocin but is reported to have a shorter duration (2-3 h) of psychedelic effects, suggesting the potential for psilocybin-like therapeutic activity with reduced clinical resource burden. Here, we describe the preclinical and translational characterization of RE104, a 4-OH-DiPT prodrug comprising a glutarate moiety designed to cleave rapidly in situ and thus provide reasonable bioavailability of the active drug. Plasma concentration of 4-HO-DiPT over time in PK experiments in rats was correlated with head-twitch intensity. The half-life of 4-OH-DiPT was 40 min after subcutaneous administration of RE104 in rats. In a forced swim test, a single dose of RE104 (1 mg/kg) significantly reduced mean immobility time at 1 week compared with vehicle (P < 0.001), confirming translational antidepressant potential. Taken together, these data with RE104 show that the glutarate ester can act as an efficient prodrug strategy for 4-HO-DiPT, a unique short-duration psychedelic with potential in depressive disorders.

Patients with uncontrolled hypertension subjected to cardiopulmonary bypass have altered coronary vasomotor responses to serotonin

BackgroundWe previously found that cardioplegic arrest and cardiopulmonary bypass are associated with altered coronary arteriolar response to serotonin in patients undergoing cardiac surgery. In this study, we investigated the effects of hypertension on coronary microvascular vasomotor tone in response to serotonin and alterations in serotonin receptor protein expression in the setting of cardioplegic arrest and cardiopulmonary bypass. MethodsCoronary arterioles were dissected from harvested pre– and post–cardioplegic arrest and cardiopulmonary bypass right atrial tissue samples of patients undergoing cardiac surgery with normotension, well-controlled hypertension, and uncontrolled hypertension. Vasomotor tone was assessed by video-myography, and protein expression was measured with immunoblotting. ResultsPre–cardioplegic arrest and cardiopulmonary bypass, serotonin induced moderate relaxation responses of coronary arterioles in normotension and well-controlled hypertension patients, whereas serotonin caused moderate contractile responses in uncontrolled hypertension patients. Post–cardioplegic arrest and cardiopulmonary bypass, serotonin caused contractile responses of coronary arterioles in all 3 groups. The post–cardioplegic arrest and cardiopulmonary bypass contractile response to serotonin was significantly higher in the uncontrolled hypertension group compared with the normotension or well-controlled hypertension groups (P < .05). Pre–cardioplegic arrest and cardiopulmonary bypass, expression of the serotonin 1A receptor was significantly lower in the uncontrolled hypertension group compared with the well-controlled hypertension and normotension groups (P = .01 and P < .001). Serotonin 1B receptor expression was higher in the uncontrolled hypertension group compared with the normotension or well-controlled hypertension groups post–cardioplegic arrest and cardiopulmonary bypass (P = .03 and P = .046). ConclusionUncontrolled hypertension is associated with an increased coronary contractile response of coronary microvessels to serotonin and altered serotonin receptor protein expression after cardioplegic arrest and cardiopulmonary bypass. These findings may contribute to a worse postoperative coronary spasm and worsened recovery of coronary perfusion in patients with uncontrolled hypertension after cardioplegic arrest and cardiopulmonary bypass and cardiac surgery.

The Analgesic Potential of Litsea Species: A Systematic Review.

Various plant species from the Litsea genus have been claimed to be beneficial for pain relief. The PRISMA approach was adopted to identify studies that reported analgesic properties of plants from the Litsea genus. Out of 450 records returned, 19 primary studies revealed the analgesic potential of nine Litsea species including (1) Litsea cubeba, (2) Litsea elliptibacea, (3) Litsea japonica, (4) Litsea glutinosa, (5) Litsea glaucescens, (6) Litsea guatemalensis, (7) Litsea lancifolia, (8) Litsea liyuyingi and (9) Litsea monopetala. Six of the species, 1, 3, 4, 7, 8 and 9, demonstrated peripheral antinociceptive properties as they inhibited acetic-acid-induced writhing in animal models. Species 1, 3, 4, 8 and 9 further showed effects via the central analgesic route at the spinal level by increasing the latencies of heat stimulated-nocifensive responses in the tail flick assay. The hot plate assay also revealed the efficacies of 4 and 9 at the supraspinal level. Species 6 was reported to ameliorate hyperalgesia induced via partial sciatic nerve ligation (PSNL). The antinociceptive effects of 1 and 3 were attributed to the regulatory effects of their bioactive compounds on inflammatory mediators. As for 2 and 5, their analgesic effect may be a result of their activity with the 5-hydroxytryptamine 1A receptor (5-HT1AR) which disrupted the pain-stimulating actions of 5-HT. Antinociceptive activities were documented for various major compounds of the Litsea plants. Overall, the findings suggested Litsea species as good sources of antinociceptive compounds that can be further developed to complement or substitute prescription drugs for pain management.

Multimodal brain age prediction using machine learning: combining structural MRI and 5-HT2AR PET-derived features

To better assess the pathology of neurodegenerative disorders and the efficacy of neuroprotective interventions, it is necessary to develop biomarkers that can accurately capture age-related biological changes in the human brain. Brain serotonin 2A receptors (5-HT2AR) show a particularly profound age-related decline and are also reduced in neurodegenerative disorders, such as Alzheimer’s disease. This study investigates whether the decline in 5-HT2AR binding, measured in vivo using positron emission tomography (PET), can be used as a biomarker for brain aging. Specifically, we aim to (1) predict brain age using 5-HT2AR binding outcomes, (2) compare 5-HT2AR-based predictions of brain age to predictions based on gray matter (GM) volume, as determined with structural magnetic resonance imaging (MRI), and (3) investigate whether combining 5-HT2AR and GM volume data improves prediction. We used PET and MR images from 209 healthy individuals aged between 18 and 85 years (mean = 38, std = 18) and estimated 5-HT2AR binding and GM volume for 14 cortical and subcortical regions. Different machine learning algorithms were applied to predict chronological age based on 5-HT2AR binding, GM volume, and the combined measures. The mean absolute error (MAE) and a cross-validation approach were used for evaluation and model comparison. We find that both the cerebral 5-HT2AR binding (mean MAE = 6.63 years, std = 0.74 years) and GM volume (mean MAE = 6.95 years, std = 0.83 years) predict chronological age accurately. Combining the two measures improves the prediction further (mean MAE = 5.54 years, std = 0.68). In conclusion, 5-HT2AR binding measured using PET might be useful for improving the quantification of a biomarker for brain aging.

Discovery and Structure-Activity Relationships of 2,5-Dimethoxyphenylpiperidines as Selective Serotonin 5-HT2A Receptor Agonists.

Classical psychedelics such as psilocybin, lysergic acid diethylamide (LSD), and N,N-dimethyltryptamine (DMT) are showing promising results in clinical trials for a range of psychiatric indications, including depression, anxiety, and substance abuse disorder. These compounds are characterized by broad pharmacological activity profiles, and while the acute mind-altering effects can be ascribed to their shared agonist activity at the serotonin 2A receptor (5-HT2AR), their apparent persistent therapeutic effects are yet to be decidedly linked to activity at this receptor. We report herein the discovery of 2,5-dimethoxyphenylpiperidines as a novel class of selective 5-HT2AR agonists and detail the structure-activity investigations leading to the identification of LPH-5 [analogue (S)-11] as a selective 5-HT2AR agonist with desirable drug-like properties.

Changes in Induced-Antipredation Defense Traits and Transcriptome Regulations of Daphnia magna in Response to 5-HT1A Receptor Antagonist.

The serotonin signaling system plays a crucial role in regulating the ontogeny of crustaceans. Here, we describe the effects of different concentrations of the 5-hydroxytryptamine 1A receptor antagonist (WAY-100635) on the induced antipredation (Rhodeus ocellatus as the predator), morphological, behavioral, and life-history defenses of Daphnia magna and use transcriptomics to analyze the underlying molecular mechanisms. Our results indicate that exposure to WAY-100635 leads to changes in the expression of different defensive traits in D. magna when faced with fish predation risks. Specifically, as the length of exposure to WAY-100635 increases, high concentrations of WAY-100635 inhibit defensive responses associated with morphological and reproductive activities but promote the immediate negative phototactic behavioral defense of D. magna. This change is related to the underlying mechanism through which WAY-100635 interferes with gene expression of G-protein-coupled GABA receptors by affecting GABBR1 but promotes serotonin receptor signaling and ecdysteroid signaling pathways. In addition, we also find for the first time that fish kairomone can significantly activate the HIF-1α signaling pathway, which may lead to an increase in the rate of immediate movement. These results can help assess the potential impacts of serotonin-disrupting psychotropic drugs on zooplankton in aquatic ecosystems.

Parenting behaviors, inhibitory control, and aggression: Moderation by serotonin receptor 2A haplotypes.

Despite the well-established relationship between parenting and child aggression, the mechanisms by which children incur this risk and whether genetic sources contribute to the heterogeneity in their vulnerability are not entirely clear. This study utilized a longitudinal sample of adolescents (n = 1,047, 50.2% females, Mage = 13.32 ± 0.48 years at Time 1) to examine the effects of positive and negative parenting on aggression, as mediated by inhibitory control and moderated by the serotonin receptor 2A (5-HTR2A) haplotype. Mediation analysis revealed that inhibitory control indirectly mediated the link between both positive and negative parenting and overt aggression but not relational aggression. Further, the indirect effect of negative parenting on overt aggression via inhibitory control was moderated by the 5-HTR2A haplotype. Compared to adolescents carrying zero copies of Thymine-Thymine haplotype, those with one copy of Thymine-Thymine haplotype had better inhibitory control when experiencing less negative parenting, which buffers the risk for overt aggression. However, the mediating role of inhibitory control did not hold in the positive parenting model. These findings elucidate the manner by which adolescents with different genetic predispositions develop aggressive behaviors in the context of family and suggest different etiology of overt and relational aggression. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Side effects and cognitive benefits of buspirone: A systematic review and meta-analysis

Buspirone, a 5-hydroxytryptamine 1A (5-HT1A) receptor agonist, has been investigated for its use in various diseases. However, knowledge about its side effects and potential cognitive benefits in different conditions is limited. Cognitive impairment is also a prevalent symptom in many diseases, yet effective treatments are still lacking. Therefore, to explore the potential side effects of buspirone and the possible cognitive benefits of buspirone, we conducted a comprehensive search of several databases, including PubMed, Embase, Web of Science, Cochrane Review, Cochrane Trial, and ClinicalTrials.gov, to identify eligible randomized clinical trials. Our primary outcome measures included both side effects (adverse events) and cognitive benefits. For continuous variables, we utilized effect size with a 95% confidence interval (CI), whereas for dichotomous variables, we used odds ratios (OR) with a 95% CI. In total, 16 studies were included in this analysis, with 13 studies reporting on buspirone's side effects and 4 studies focusing on cognitive tasks. In terms of side effects, buspirone exhibited a higher rate of dizziness (OR = 4.66, 95% CI: 2.07–10.47), constipation (OR = 4.11, 95% CI: 1.34–12.55), and gastric distress (OR = 1.97, 95% CI: 1.03–3.78) than the placebo group. Regarding cognitive functions, buspirone showed significant benefits (g = 0.20, 95% CI: 0.06–0.34) while the placebo did not. Subgroup analysis indicated superior performance in visual learning and memory (g = 0.49, 95% CI: 0.21–0.78), logical reasoning (g = 0.42, 95% CI: 0.14–0.71), and attention (g = 0.37, 95% CI: 0.13–0.61) when compared to placebo. Our findings indicated that participants in the buspirone group experienced side effects of dizziness, constipation, and gastric distress in different diseases. Despite these adverse events, however, buspirone demonstrated significant cognitive benefits, particularly in the domains of visual learning and memory, logical reasoning, and attention.

The Association Between the 5-Hydroxytryptamine Receptor 2A Gene Variants rs6311 and rs6313 and Obstructive Sleep Apnea in the Iranian Kurdish Population.

Introduction: Sleep is one of the most significant parts of everyone's life. Most people sleep for about one-third of their lives. Sleep disorders negatively impact the quality of life. Obstructive sleep apnea (OSA) is a severe sleep disorder that significantly impacts the patient's life and their family members. This study aimed to investigate the relationship between rs6313 and rs6311 polymorphisms in the serotonin receptor type 2A gene and OSA in the Kurdish population. Materials and Methods: The study's population comprises 100 OSAsufferers and 100 healthy people. Polysomnography diagnostic tests were done on both the patient and control groups. The polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP) was used to investigate the relationship between OSAand LEPR gene polymorphisms. Results: Statistical analysis showed a significant relationship between genotype frequencies of patient and control groups of rs6311 with OSAin dominant [odds ratio (OR) = 5.203, p < 0.001) and codominant models (OR = 9.7, p < 0.001). Also, there was a significant relationship between genotype frequencies of patient and control groups of rs6313 with OSAin dominant (OR = 10.565, p < 0.001) and codominant models (OR = 5.938, p < 0.001). Conclusions: Findings from the study demonstrated that the two polymorphisms rs6311 and rs6313 could be effective at causing OSA; however, there was no correlation between the severity of the disease and either of the two polymorphisms.

The novel psychoactive substance 25E-NBOMe induces reward-related behaviors via dopamine D1 receptor signaling in male rodents.

Novel psychoactive substances (NPSs) are new psychotropic drugs designed to evade substance regulatory policies. 25E-NBOMe (2-(4-ethyl-2,5-dimethoxyphenyl)-N-(2-methoxybenzyl)ethanamine) has recently been identified as an NPS, and its recreational misuse has been reported to be rapidly increasing. However, the psychopharmacological effects and mechanisms of 25E-NBOMe have not been studied. We examined the abuse potential of 25E-NBOMe using the conditioned place preference in male mice and self-administration paradigms in male rats. Additionally, immunoblot assay, enzyme-linked immunosorbent assay, and microdialysis were used to determine the molecular effects of 25E-NBOMe in the nucleus accumbens (NAc). Our data demonstrated that 25E-NBOMe induces conditioned place preference, and the dopaminergic signaling in the NAc mediates these. Following 25E-NBOMe administration, expression of dopamine transporter and dopamine D1 receptor (D1DR) were enhanced in the NAc of male mice, and NAc dopamine levels were reduced in both male mice and rats. Induction of intracellular dopaminergic pathways, DARPP32, and phosphorylation of CREB in the NAc of male mice was also observed. Significantly, pharmacological blockade of D1DR or chemogenetic inhibition of D1DR-expressing medium spiny neurons in the NAc attenuated 25E-NBOMe-induced conditioned place preference in male mice. We also examined the hallucinogenic properties of 25E-NBOMe using the head twitch response test in male mice and found that this behavior was mediated by serotonin 2A receptor activity. Our findings demonstrate that D1DR signaling may govern the addictive potential of 25E-NBOMe. Moreover, our study provides new insights into the potential mechanisms of substance use disorder and the improvement of controlled substance management.

Cannabidiol Exerts Anticonvulsant Effects Alone and in Combination with Δ9-THC through the 5-HT1A Receptor in the Neocortex of Mice.

Cannabinoids have shown potential in drug-resistant epilepsy treatment; however, we lack knowledge on which cannabinoid(s) to use, dosing, and their pharmacological targets. This study investigated (i) the anticonvulsant effect of Cannabidiol (CBD) alone and (ii) in combination with Delta-9 Tetrahydrocannabinol (Δ9-THC), as well as (iii) the serotonin (5-HT)1A receptor's role in CBD's mechanism of action. Seizure activity, induced by 4-aminopyridine, was measured by extracellular field recordings in cortex layer 2/3 of mouse brain slices. The anticonvulsant effect of 10, 30, and 100 µM CBD alone and combined with Δ9-THC was evaluated. To examine CBD's mechanism of action, slices were pre-treated with a 5-HT1A receptor antagonist before CBD's effect was evaluated. An amount of ≥30 µM CBD alone exerted significant anticonvulsant effects while 10 µM CBD did not. However, 10 µM CBD combined with low-dose Δ9-THC (20:3 ratio) displayed significantly greater anticonvulsant effects than either phytocannabinoid alone. Furthermore, blocking 5-HT1A receptors before CBD application significantly abolished CBD's effects. Thus, our results demonstrate the efficacy of low-dose CBD and Δ9-THC combined and that CBD exerts its effects, at least in part, through 5-HT1A receptors. These results could address drug-resistance while providing insight into CBD's mechanism of action, laying the groundwork for further testing of cannabinoids as anticonvulsants.

Therapeutic-like activity of cannabidiolic acid methyl ester in the MK-801 mouse model of schizophrenia: Role for cannabinoid CB1 and serotonin-1A receptors.

Schizophrenia is a psychotic disorder with an increasing prevalence and incidence over the last two decades. The condition presents with a diverse array of positive, negative, and cognitive impairments. Conventional treatments often yield unsatisfactory outcomes, especially with negative symptoms. We investigated the role of prefrontocortical (PFC) N-methyl-D-aspartate receptors (NMDARs) in the pathophysiology and development of schizophrenia. We explored the potential therapeutic effects of cannabidiolic acid (CBDA) methyl ester (HU-580), an analogue of CBDA known to act as an agonist of the serotonin-1A receptor (5-HT1AR) and an antagonist of cannabinoid type 1 receptor (CB1R). C57BL/6 mice were intraperitoneally administered the NMDAR antagonist, dizocilpine (MK-801, .3mg/kg) once daily for 17 days. After 7days, they were concurrently given HU-580 (.01 or .05 μg/kg) for 10days. Behavioural deficits were assessed at two time points. We conducted enzyme-linked immunosorbent assays to measure the concentration of PFC 5-HT1AR and CB1R. We found that MK-801 effectively induced schizophrenia-related behaviours including hyperactivity, social withdrawal, increased forced swim immobility, and cognitive deficits. We discovered that low-dose HU-580 (.01 μg/kg), but not the high dose (.05 μg/kg), attenuated hyperactivity, forced swim immobility and cognitive deficits, particularly in female mice. Our results revealed that MK-801 downregulated both CB1R and 5-HT1AR, an effect that was blocked by both low- and high-dose HU-580. This study sheds light on the potential antipsychotic properties of HU-580, particularly in the context of NMDAR-induced dysfunction. Our findings could contribute significantly to our understanding of schizophrenia pathophysiology and offer a promising avenue for exploring the therapeutic potential of HU-580 and related compoundsin alleviating symptoms.

Exploring Novel Antidepressants Targeting G Protein-Coupled Receptors and Key Membrane Receptors Based on Molecular Structures.

Major Depressive Disorder (MDD) is a complex mental disorder that involves alterations in signal transmission across multiple scales and structural abnormalities. The development of effective antidepressants (ADs) has been hindered by the dominance of monoamine hypothesis, resulting in slow progress. Traditional ADs have undesirable traits like delayed onset of action, limited efficacy, and severe side effects. Recently, two categories of fast-acting antidepressant compounds have surfaced, dissociative anesthetics S-ketamine and its metabolites, as well as psychedelics such as lysergic acid diethylamide (LSD). This has led to structural research and drug development of the receptors that they target. This review provides breakthroughs and achievements in the structure of depression-related receptors and novel ADs based on these. Cryo-electron microscopy (cryo-EM) has enabled researchers to identify the structures of membrane receptors, including the N-methyl-D-aspartate receptor (NMDAR) and the 5-hydroxytryptamine 2A (5-HT2A) receptor. These high-resolution structures can be used for the development of novel ADs using virtual drug screening (VDS). Moreover, the unique antidepressant effects of 5-HT1A receptors in various brain regions, and the pivotal roles of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) and tyrosine kinase receptor 2 (TrkB) in regulating synaptic plasticity, emphasize their potential as therapeutic targets. Using structural information, a series of highly selective ADs were designed based on the different role of receptors in MDD. These molecules have the favorable characteristics of rapid onset and low adverse drug reactions. This review offers researchers guidance and a methodological framework for the structure-based design of ADs.

Modulation of neuronal morphology by antipsychotic drug: Involvement of serotonin receptor 7

Antipsychotic drugs (APDs) are the primary pharmacological treatment for schizophrenia, a complex disorder characterized by altered neuronal connectivity. Atypical or second-generation antipsychotics, such as Risperidone (RSP) and Clozapine (CZP) predominantly block dopaminergic D2 and serotonin receptor 2A (5-HT2A) neurotransmission. Both compounds also exhibit affinity for the 5-HT7R, with RSP acting as an antagonist and CZP as an inverse agonist. Our study aimed to determine whether RSP and CZP can influence neuronal morphology through a 5-HT7R-mediated mechanism. Here, we demonstrated that CZP promotes neurite outgrowth of early postnatal cortical neurons, and the 5-HT7R mediates its effect. Conversely, RSP leads to a reduction of neurite length of early postnatal cortical neurons, in a 5-HT7R-independent way.Furthermore, we found that the effects of CZP, mediated by 5-HT7R activation, require the participation of ERK and Cdk5 kinase pathways. At the same time, the modulation of neurite length by RSP does not involve these pathways.In conclusion, our findings provide valuable insights into the morphological changes induced by these two APDs in neurons and elucidate some of the associated molecular pathways. Investigating the 5-HT7R-dependent signaling pathways underlying the neuronal morphogenic effects of APDs may contribute to the identification of novel targets for the treatment of schizophrenia.