Serotonin 5-HT1A Research Articles

Mescaline-induced behavioral alterations are mediated by 5-HT2A and 5-HT2C receptors in rats.

Mescaline is a classical psychedelic compound with a phenylethylamine structure that primarily acts on serotonin 5-HT2A/C receptors, but also binds to 5-HT1A and 5-HT2B receptors. Despite being the first psychedelic ever isolated and synthesized, the precise role of different serotonin receptor subtypes in its behavioral pharmacology is not fully understood. In this study, we aimed to investigate how selective antagonists of 5-HT2A, 5-HT2B, 5-HT2C, and 5-HT1A receptors affect the behavioral changes induced by subcutaneous administration of mescaline (at doses of 10, 20, and 100 mg/kg) in rats. We used adult male Wistar rats in all our experiments. We evaluated locomotor activity using the open field test, and assessed sensorimotor gating deficits by measuring prepulse inhibition (PPI) of acoustic startle reaction (ASR). While the highest dose of mescaline induced hyperlocomotion (p < 0.001), which almost all the other antagonists reversed (p < 0.05-0.001), the PPI deficits were selectively normalized by the 5-HT2A antagonist (p < 0.05-0.01). The 5-HT2C antagonist partially reversed the small PPI deficit induced by lower doses of mescaline (p = 0.0017). Our findings suggest that mescaline-induced changes in behavior are primarily mediated by the 5-HT2A receptor subtype, with less pronounced contributions from the 5-HT2C receptor. The other antagonists had limited effects.

Vilazodone,aNovel SSRI Antidepressant with 5-HT1A Partial Agonist Properties: Diminished Potentiation of Chronic Oral Methylphenidate-Induced Dynorphin Expression in the Striatum in Adolescent Male Rats.

Selective serotonin reuptake inhibitor (SSRI) antidepressants such as fluoxetine are used in combination with the medical psychostimulant methylphenidate (Ritalin) in a variety of treatments in children and adults. Unintended co-exposure to these psychotropic medications also occurs in patients on SSRIs who abuse methylphenidate as a "cognitive enhancer" or recreational drug. Preclinical research shows that SSRIs such as fluoxetine when given in conjunction with methylphenidate potentiate addiction-related gene regulation by methylphenidate in the striatum, consistent with the known facilitatory role for serotonin in psychostimulant-induced neuronal and behavioral changes. Moreover, fluoxetine combined with methylphenidate also facilitated subsequent acquisition of cocaine self-administration in adolescent rats, suggesting an increased addiction liability for methylphenidate. In the present study, we investigated the impact of a novel SSRI, vilazodone, on methylphenidate-induced gene regulation in adolescent male rats. In contrast to prototypical SSRIs such as fluoxetine, vilazodone also acts as a partial 5-HT1A serotonin receptor agonist and is thus proposed to temper serotonin input to the striatum. We compared the effects of chronic treatment (4 weeks) with vilazodone (10mg/kg, twice daily) with those of fluoxetine (5mg/kg, twice daily) on striatal dynorphin expression induced by oral methylphenidate treatment (30/60mg/kg/day in drinking water, 8h access daily). Our results demonstrate that, in contrast to fluoxetine, vilazodone had minimal or no potentiating effects on methylphenidate-induced dynorphin expression. This diminished impact on gene regulation was seen throughout the striatum, including the nucleus accumbens, where increased dynorphin expression has previously been associated with various aspects of addiction. Our findings suggest that vilazodone may serve as a better adjunct SSRI with reduced addiction-facilitating properties.

Design and Synthesis of Potential Multi-Target Antidepressants: Exploration of 1-(4-(7-Azaindole)-3,6-dihydropyridin-1-yl)alkyl-3-(1H-indol-3-yl)pyrrolidine-2,5-dione Derivatives with Affinity for the Serotonin Transporter

We describe the design, synthesis and structure–activity relationship of a novel series of 1-(4-(7-azaindole)-3,6-dihydropyridin-1-yl)alkyl-3-(1H-indol-3-yl)pyrrolidine-2,5-dione derivatives with combined effects on the serotonin (5-HT1A) and dopamine (D2) receptors and the serotonin (5-HT), noradrenaline (NA), and dopamine (DA) transporters as multi-target directed ligands for the treatment of depression. All of the tested compounds demonstrated good affinity for the serotonin transporter (SERT). Among them, compounds 11 and 4 emerged as the lead candidates because of their promising pharmacological profile based on in vitro studies. Compound 11 displayed a high affinity for the 5-HT1A (Ki = 128.0 nM) and D2 (Ki = 51.0 nM) receptors, and the SERT (Ki = 9.2 nM) and DAT (Ki = 288.0 nM) transporters, whereas compound 4 exhibited the most desirable binding profile to SERT/NET/DAT among the series: Ki = 47.0 nM/167.0 nM/43% inhibition at 1 µM. These results suggest that compounds 4 and 11 represent templates for the future development of multi-target antidepressant drugs.

Estimating molecular properties, drug-likeness, cardiotoxic risk, liability profile, and molecular docking study to characterize binding process of key phyto-compounds against serotonin 5-HT2A receptor

Abstract Nowadays, the physiopathological and molecular mechanisms of multiple diseases have been identified, thus helping scientists to provide a clear answer, especially to those ambiguities related to chronic illnesses. This has been accomplished in part through the contribution of a key discipline known as bioinformatics. In this study, the bioinformatics approach was applied on four compounds identified in Centaurea tougourensis, using two axes of research: an in silico study to predict the molecular characteristics, medicinal chemistry attributes as well as the possible cardiotoxicity and adverse liability profile of these compounds. In this context, four compounds were selected and named, respectively, 2,5-monoformal-l-rhamnitol (compound 1), cholest-7-en-3.beta.,5.alpha.-diol-6.alpha.-benzoate (compound 2), 7,8-epoxylanostan-11-ol, 3-acetoxy- (compound 3), and 1H-pyrrole-2,5-dione, 3-ethyl-4-methyl- (compound 4). The second part looked into molecular docking, which objective was to evaluate the possible binding affinity between these compounds and the serotonin 5-hydroxytryptamine 2A (5-HT2A) receptor. Results indicated that compounds 1 and 4 were respecting Pfizer and giant Glaxo-SmithKline rules, while compounds 2 and 3 exhibited an optimal medicinal chemistry evolution 18 score. The structural and molecular features of almost all tested compounds could be considered optimal, indicating that these phyto-compounds may possess drug-likeness capacity. However, only compounds 1 and 4 could be considered non-cardiotoxic, but with a level of confidence more pronounced for compound 1 (80%). In addition, these four biocompounds could preferentially interact with G protein-coupled receptor, ion channel, transporters, and nuclear receptors. However, the heat map was less pronounced for compound 2. Data also indicated that these four compounds could possibly interact with serotonin 5-HT2A receptor, but in an antagonistic way. This research proved once again that plants could be crucial precursors of pharmaceutical substances, which could be helpful to enrich the international pharmacopoeia.

Perry Disease: Current Outlook and Advances in Drug Discovery Approach to Symptomatic Treatment.

Perry disease (PeD) is a rare, neurodegenerative, genetic disorder inherited in an autosomal dominant manner. The disease manifests as parkinsonism, with psychiatric symptoms on top, such as depression or sleep disorders, accompanied by unexpected weight loss, central hypoventilation, and aggregation of DNA-binding protein (TDP-43) in the brain. Due to the genetic cause, no causal treatment for PeD is currently available. The only way to improve the quality of life of patients is through symptomatic therapy. This work aims to review the latest data on potential PeD treatment, specifically from the medicinal chemistry and computer-aided drug design (CADD) points of view. We select proteins that might represent therapeutic targets for symptomatic treatment of the disease: monoamine oxidase B (MAO-B), serotonin transporter (SERT), dopamine D2 (D2R), and serotonin 5-HT1A (5-HT1AR) receptors. We report on compounds that may be potential hits to develop symptomatic therapies for PeD and related neurodegenerative diseases and relieve its symptoms. We use Phase pharmacophore modeling software (version 2023.08) implemented in Schrödinger Maestro as a ligand selection tool. For each of the chosen targets, based on the resolved protein-ligand structures deposited in the Protein Data Bank (PDB) database, pharmacophore models are proposed. We review novel, active compounds that might serve as either hits for further optimization or candidates for further phases of studies, leading to potential use in the treatment of PeD.

Experience-dependent serotonergic signaling in glia regulates targeted synapse elimination.

The optimization of brain circuit connectivity based on initial environmental input occurs during critical periods characterized by sensory experience-dependent, temporally restricted, and transiently reversible synapse elimination. This precise, targeted synaptic pruning mechanism is mediated by glial phagocytosis. Serotonin signaling has prominent, foundational roles in the brain, but functions in glia, or in experience-dependent brain circuit synaptic connectivity remodeling, have been relatively unknown. Here, we discover that serotonergic signaling between glia is essential for olfactory experience-dependent synaptic glomerulus pruning restricted to a well-defined Drosophila critical period. We find that experience-dependent serotonin signaling is restricted to the critical period, with both (1) serotonin production and (2) 5-HT2A receptors specifically in glia, but not neurons, absolutely required for targeted synaptic glomerulus pruning. We discover that glial 5-HT2A receptor signaling limits the experience-dependent synaptic connectivity pruning in the critical period and that conditional reexpression of 5-HT2A receptors within adult glia reestablishes "critical period-like" experience-dependent synaptic glomerulus pruning at maturity. These results reveal an essential requirement for glial serotonergic signaling mediated by 5-HT2A receptors for experience-dependent synapse elimination.

Cariprazine in Psychiatry: A Comprehensive Review of Efficacy, Safety, and Therapeutic Potential.

This article provides a comprehensive review of recent developments regarding a new atypical antipsychotic drug - cariprazine - considering the mechanism of action, efficacy, safety, and promising therapeutic option for various psychiatric disorders, including schizophrenia and bipolar disorder, therapy of addictions, and treatment in the pediatric population. Its distinct pharmacological profile, characterized by partial agonism at dopamine D2 and D3 receptors, as well as serotonin receptors - 5HT1A with a preference for the D3 receptor - sets it apart from other antipsychotics. The unique mechanism of action contributes to cariprazine's positive impact on negative symptoms in schizophrenia and an antidepressant effect. Its relatively low risk of adverse effects, such as sedation, metabolic issues, and hypotension, enhances its tolerability. In bipolar affective disorder, cariprazine exhibits effectiveness in managing both depressive and manic episodes. Ongoing research in pediatric populations suggests potential benefits in schizophrenia, bipolar I disorder, and autism spectrum disorder, but further research is necessary to establish safety and efficacy. Moreover, cariprazine shows promise in addiction therapy, particularly with coexisting psychiatric disorders. Continued research and clinical exploration may discover additional insights, broadening its use in diverse patient populations. This article aims to review the role of cariprazine, a dopamine D2/D3 and serotonin 5-HT1A receptor partial agonist, in the management of psychotic illnesses, including schizophrenia, bipolar disorder, addiction therapy, and pediatric treatment.

The interplay of serotonin 5-HT1A and 5-HT7 receptors in chronic stress.

Serotonin regulates multiple physiological and pathological processes in the brain, including mood and cognition. The serotonin receptors 5-HT1AR (also known as HTR1A) and 5-HT7R (also known as HTR7) have emerged as key players in stress-related disorders, particularly depression. These receptors can form heterodimers, which influence their functions. Here, we explored the developmental dynamics of 5-HT1AR and 5-HT7R expression and validated heterodimerization levels in the brain of control and stressed mice. In control animals, we found that there was an increase in 5-HT1AR expression over 5-HT7R in the prefrontal cortex (PFC) and hippocampus during development. Using a chronic unpredictable stress as a depression model, we found an increase in 5-HT7R expression exclusively in the PFC of resilient animals, whereas no changes in 5-HT1AR expression between control and anhedonic mice were obtained. Quantitative in situ analysis of heterodimerization revealed the PFC as the region exhibiting the highest abundance of 5-HT1AR-5-HT7R heterodimers. More importantly, upon chronic stress, the amount of heterodimers was significantly reduced only in PFC of anhedonic mice, whereas it was not affected in resilient animals. These results suggest an important role of brain-region-specific 5-HT1AR-5-HT7R heterodimerization for establishing depressive-like behaviour and for development of resiliency.

Evaluation of inhibitory actions of antidepressants on muscarinic receptors assessed by a binding assay in the mouse cerebral neocortex

We investigated the inhibitory effects of 32 antidepressants on [3H]N-methylscopolamine ([3H]NMS)-specific binding in the mouse cerebral neocortex to determine which antidepressants should be recommended for patients with Alzheimer's disease (AD). Of those tested, nine antidepressants (10−4 M) exhibited less inhibitory effect on [3H]NMS-specific binding (<35%): tianeptine (a tricyclic); trazodone (a serotonin 5-HT2A blocker); sulpiride (a dopamine D2 blocker); fluvoxamine (a selective serotonin reuptake inhibitor (RI)); milnacipran, levomilnacipran, venlafaxine, and desvenlafaxine (serotonin and noradrenaline RIs); and bupropion (a noradrenaline and dopamine RI). Therefore, these antidepressants show little anticholinergic effect in the brain and are recommended for use in patients with AD.

Dysfunction of the NMDA Receptor in the Pathophysiology of Schizophrenia and/or the Pathomechanisms of Treatment-Resistant Schizophrenia.

For several decades, the dopamine hypothesis contributed to the discovery of numerous typical and atypical antipsychotics and was the sole hypothesis for the pathophysiology of schizophrenia. However, neither typical nor atypical antipsychotics, other than clozapine, have been effective in addressing negative symptoms and cognitive impairments, which are indices for the prognostic and disability outcomes of schizophrenia. Following the development of atypical antipsychotics, the therapeutic targets for antipsychotics expanded beyond the blockade of dopamine D2 and serotonin 5-HT2A receptors to explore the partial agonism of the D2 receptor and the modulation of new targets, such as D3, 5-HT1A, 5-HT7, and metabotropic glutamate receptors. Despite these efforts, to date, psychiatry has not successfully developed antipsychotics with antipsychotic properties proven to be superior to those of clozapine. The glutamate hypothesis, another hypothesis regarding the pathophysiology/pathomechanism of schizophrenia, was proposed based on clinical findings that N-methyl-D-aspartate glutamate receptor (NMDAR) antagonists, such as phencyclidine and ketamine, induce schizophrenia-like psychotic episodes. Large-scale genome-wide association studies (GWASs) revealed that approximately 30% of the risk genes for schizophrenia (the total number was over one hundred) encode proteins associated with glutamatergic transmission. These findings supported the validation of the glutamate hypothesis, which was inspired by the clinical findings regarding NMDAR antagonists. Additionally, these clinical and genetic findings suggest that schizophrenia is possibly a syndrome with complicated pathomechanisms that are affected by multiple biological and genetic vulnerabilities. The glutamate hypothesis has been the most extensively investigated pathophysiology/pathomechanism hypothesis, other than the dopamine hypothesis. Studies have revealed the possibility that functional abnormalities of the NMDAR play important roles in the pathophysiology/pathomechanism of schizophrenia. However, no antipsychotics derived from the glutamatergic hypothesis have yet been approved for the treatment of schizophrenia or treatment-resistant schizophrenia. Considering the increasing evidence supporting the potential pro-cognitive effects of glutamatergic agents and the lack of sufficient medications to treat the cognitive impairments associated with schizophrenia, these previous setbacks cannot preclude research into potential novel glutamate modulators. Given this background, to emphasize the importance of the dysfunction of the NMDAR in the pathomechanism and/or pathophysiology of schizophrenia, this review introduces the increasing findings on the functional abnormalities in glutamatergic transmission associated with the NMDAR.

Structure of tetrameric forms of the serotonin-gated 5-HT3A receptor ion channel

Multimeric membrane proteins are produced in the endoplasmic reticulum and transported to their target membranes which, for ion channels, is typically the plasma membrane. Despite the availability of many fully assembled channel structures, our understanding of assembly intermediates, multimer assembly mechanisms, and potential functions of non-standard assemblies is limited. We demonstrate that the pentameric ligand-gated serotonin 5-HT3A receptor (5-HT3AR) can assemble to tetrameric forms and report the structures of the tetramers in plasma membranes of cell-derived microvesicles and in membrane memetics using cryo-electron microscopy and tomography. The tetrameric structures have near-symmetric transmembrane domains, and asymmetric extracellular domains, and can bind serotonin molecules. Computer simulations, based on our cryo-EM structures, were used to decipher the assembly pathway of pentameric 5-HT3R and suggest a potential functional role for the tetrameric receptors.

Gepirone: A New Extended-Release Oral Selective Serotonin Receptor Agonist for Major Depressive Disorder.

Objective: To evaluate the safety, efficacy, and tolerability of gepirone (Exxua) in the treatment of adult patients with major depressive disorder. Data Sources: A literature search was performed through PubMed, Embase, and PsycINFO using the following terms: Exxua, gepirone, depression, major depressive disorder, anxiety, and anxiety disorders. Study Selection and Data Extraction: Articles that were selected included English-language dominant studies, or studies that could be translated into English by the authors, with terms associated with the safety, efficacy, and/or tolerability of gepirone. Data Synthesis: Gepirone exhibits its antidepressant activity through agonism of 5HT1A serotonin receptors. Phase 3 clinical trials showed that gepirone at a dose of 20 to 80 mg was proven to be effective in the treatment of major depressive disorder in adult patients. Common adverse effects reported in clinical trials included dizziness, nausea, headache, fatigue, and insomnia. Conclusion: This review evaluates the pharmacokinetic, pharmacologic, efficacy, and safety profile of gepirone and includes a discussion on its place in therapy for the treatment of major depressive disorder. Most clinical guidelines recommend second-generation antidepressants consisting of selective serotonin reuptake inhibitors or serotonin norepinephrine reuptake inhibitors as first-line therapy options. Gepirone is expected to receive greater clinical relevance and recommendations when compared to other azapirone medications (buspirone) within practice guidelines. Gepirone could be considered as either an alternative option for patients failing first-line therapies or for initial use to avoid unwanted side effects of other therapy options in the treatment of adult patients with major depressive disorder.

Effect of positive allosteric modulation and orthosteric agonism of dopamine D2-like receptors on respiration in mouse models of Rett syndrome

Rett syndrome (RTT) is an autism spectrum disorder caused by loss-of-function mutations in the methyl-CPG-binding protein 2 (Mecp2) gene. Frequent apneas and irregular breathing are prevalent in RTT, and also occur in rodent models of the disorder, including Mecp2Bird and Mecp2R168X mice. Sarizotan, a serotonin 5-HT1a and dopamine D2-like receptor agonist, reduces the incidence of apneas and irregular breathing in mouse models of RTT (Abdala et al., 2014). Targeting the 5HT1a receptor alone also improves respiration in RTT mice (Levitt et al., 2013). However, the contribution of D2-like receptors in correcting these respiratory disturbances remains untested. PAOPA, a dopamine D2-like receptor positive allosteric modulator, and quinpirole, a dopamine D2-like receptor orthosteric agonist, were used in conjunction with whole-body plethysmography to evaluate whether activation of D2-like receptors is sufficient to improve breathing disturbances in female heterozygous Mecp2Bird/+ and Mecp2R168X/+ mice. PAOPA did not significantly change apnea incidence or irregularity score in RTT mice. PAOPA also had no effect on the ventilatory response to hypercapnia (7 % CO2). In contrast, quinpirole reduced apnea incidence and irregularity scores and improved the hypercapnic ventilatory response in Mecp2R168X/+ and Mecp2Bird/+ mice, while also reducing respiratory rate. These results suggest that D2-like receptors could contribute to the positive effects of sarizotan in the correction of respiratory abnormalities in Rett syndrome. However, positive allosteric modulation of D2-like receptors alone was not sufficient to evoke these effects.

Pharmacodynamic, pharmacokinetic and rat brain receptor occupancy profile of NLX-112, a highly selective 5-HT1A receptor biased agonist.

NLX-112 (i.e., F13640, befiradol) exhibits nanomolar affinity, exceptional selectivity and full agonist efficacy at serotonin 5-HT1A receptors. NLX-112 shows efficacy in rat, marmoset and macaque models of L-DOPA induced dyskinesia (LID) in Parkinson's disease and has shown clinical efficacy in a Phase 2a proof-of-concept study for this indication. Here we investigated, in rats, its pharmacodynamic, pharmacokinetic (PK) and brain 5-HT1A receptor occupancy profiles, and its PK properties in the absence and presence of L-DOPA. Total and free NLX-112 exposure in plasma, CSF and striatal ECF was dose-proportional over the range tested (0.04, 0.16 and 0.63mg/kg i.p.). NLX-112 exposure increased rapidly (Tmax 0.25-0.5h) and exhibited approximately threefold longer half-life in brain than in plasma (1.1 and 3.6h, respectively). At a pharmacologically relevant dose of 0.16 mg/kg i.p., previously shown to elicit anti-LID activity in parkinsonian rats, brain concentration of NLX-112 was 51-63 ng/g from 0.15 to 1h. In microPET imaging experiments, NLX-112 showed dose-dependent reduction of 18F-F13640 (i.e., 18F-NLX-112) brain 5-HT1A receptor labeling in cingulate cortex and striatum, regions associated with motor control and mood, with almost complete inhibition of labeling at the dose of 0.63 mg/kg i.p.. Co-administration of L-DOPA (6mg/kg s.c., a dose used to elicit LID in parkinsonian rats) together with NLX-112 (0.16mg/kg i.p.) did not modify PK parameters in rat plasma and brain of either NLX-112 or L-DOPA. Here, we demonstrate that NLX-112's profile is compatible with 'druggable' parameters for CNS indications, and the results provide measures of brain concentrations and 5-HT1A receptor binding parameters relevant to the anti-dyskinetic activity of the compound.

Preclinical investigation of the effect of stress on the binding of [18F]F13640, a 5-HT1A radiopharmaceutical

Background[18F]F13640 is a new PET radiopharmaceutical for brain molecular imaging of serotonin 5-HT1A receptors. Since we intend to use this radiopharmaceutical in psychiatric studies, it is crucial to establish possible sensitivity modification of 5-HT1A receptors availability during an acute stress exposure. In this study, we first assessed the cerebrometabolic effects of a new animal model of stress with [18F]FDG and then proceeded to test for effects of this model on the cerebral binding of [18F]F13640, a 5-HT1A receptors PET radiopharmaceutical. MethodsFour groups of male Sprague-Dawley were used to identify the optimal model: “stressed group” (n = 10), “post-traumatic stress disorder (PTSD) group” (n = 9) and “restraint group” (n = 8), compared with a control group (n = 8). All rats performed neuroimaging [18F]FDG μPET-CT to decipher which model was the most appropriate to test effects of stress on radiotracer binding. Subsequently, a group of rats (n = 10) underwent two PET imaging acquisitions (baseline and PTSD condition) using the PET radiopharmaceutical [18F]F13640 to assess influence of stress on its binding. Voxel-based analysis was performed to assess [18F]FDG or [18F]F13640 changes. ResultsIn [18F]FDG experiments, the PTSD group showed a pattern of cerebrometabolic activation in various brain regions previously implicated in stress (amygdala, perirhinal cortex, olfactory bulb and caudate). [18F]F13640 PET scans showed increased radiotracer binding in the PTSD condition in caudate nucleus and brainstem. ConclusionsThe present study demonstrated stress-induced cerebrometabolic activation or inhibition of various brain regions involved in stress model. Applying this model to our radiotracer, [18F]F13640 showed few influence of stress on its binding. This will enable to rule out any confounding effect of stress during imaging studies.

Brexpiprazole for Agitation Associated With Dementia Due to Alzheimer's Disease

Alzheimer's disease (AD) is a prevalent neurodegenerative disease characterized by progressive cognitive and functional decline. Nearly all patients with AD develop neuropsychiatric symptoms (NPSs). Agitation is one of the most distressing and challenging NPS. Brexpiprazole is an oral antipsychotic and is the first approved pharmacologic agent in the United States for the treatment of agitation associated with dementia due to AD. Its effect is thought to be from its partial serotonin 5-HT1A and dopamine D2 receptor agonist activity and serotonin 5-HT2A receptor antagonism. Brexpiprazole is a maintenance medication, and it should not be used “as needed” or as a “PRN” treatment for breakthrough agitation. Brexpiprazole is a major substrate of CYP2D6 and CYP3A4. Dose adjustments may be required for drug interactions or impaired renal or hepatic function. Clinical trials found brexpiprazole 2 to 3 mg/d demonstrated significant improvements in agitation, with brexpiprazole showing an approximate 5-point greater reduction on change in the Cohen-Mansfield Agitation Inventory total score at week 12 from baseline compared with placebo. Brexpiprazole is generally well tolerated and safe, and common adverse reactions when used for this indication include dizziness, headaches, insomnia, nasopharyngitis, somnolence, and urinary tract infections. Like other antipsychotics used for agitation in AD, brexpiprazole is associated with higher mortality rates compared with placebo. In a long-term care setting, there are several considerations for its use. Benefits include an oral agent that is well tolerated and clinical data showing statistically significant effects on agitation. However, brexpiprazole has not been studied in head-to-head clinical trials against other antipsychotics, and there are differing opinions if the agitation score reductions translate to a clinically meaningful difference. The approval of brexpiprazole signals favorably for upcoming agents for this indication, including escitalopram and dextromethorphan-bupropion. Both escitalopram and dextromethorphan-bupropion are currently undergoing clinical trials.

Focal pharmacological manipulation of serotonin signaling in the amygdala does not alter social behavior.

Serotonin signaling plays critical roles in social and emotional behaviors. Likewise, decades of research demonstrate that the amygdala is a prime modulator of social behavior. Permanent excitotoxic lesions and transient amygdala inactivation consistently increase social behaviors in non-human primates. In rodents, acute systemic administration of drugs that increase serotonin signaling is associated with decreased social interactions. However, in primates, the direct involvement of serotonin signaling in the amygdala, particularly in affiliative social interaction, remains unexplored. Here, we examined the effects of serotonin manipulations within the amygdala on social behavior in eight pairs of familiar male macaques. We microinfused drugs targeting the serotonin system into either the basolateral (BLA) or central (CeA) amygdala and measured changes in social behavior. Surprisingly, the results demonstrated no significant differences in social behavior following the infusion of a selective serotonin reuptake inhibitor, 5-HT1A agonist or antagonist, 5-HT2A agonist or antagonist, or 5-HT3 agonist or antagonist into either the BLA or CeA. These findings suggest that serotonin signaling in the amygdala does not directly contribute to the regulation of social behavior between familiar conspecifics. Future research should explore alternative mechanisms and potential interactions with other brain regions to gain a comprehensive understanding of the complex neural circuitry governing social behavior.

Structure-function interrelationships and associated neurotransmitter profiles in drug-naïve benign childhood epilepsy with central-temporal spikes patients.

To explore the interrelationships between structural and functional changes as well as the potential neurotransmitter profile alterations in drug-naïve benign childhood epilepsy with central-temporal spikes (BECTS) patients. Structural magnetic resonance imaging (sMRI) and resting-state functional MRI data from 20 drug-naïve BECTS patients and 33 healthy controls (HCs) were acquired. Parallel independent component analysis (P-ICA) was used to identify covarying components among gray matter volume (GMV) maps and fractional amplitude of low-frequency fluctuations (fALFF) maps. Furthermore, we explored the spatial correlations between GMV/fALFF changes derived from P-ICA and neurotransmitter maps in JuSpace toolbox. A significantly positive correlation (p < 0.001) was identified between one structural component (GMV_IC6) and one functional component (fALFF_IC4), which showed significant group differences between drug-naïve BECTS patients and HCs (GMV_IC6: p < 0.01; fALFF_IC4: p < 0.001). GMV_IC6 showed increased GMV in the frontal lobe, temporal lobe, thalamus, and precentral gyrus as well as fALFF_IC4 had enhanced fALFF in the cerebellum in drug-naïve BECTS patients compared to HCs. Moreover, significant correlations between GMV alterations in GMV_IC6 and the serotonin (5HT1a: p < 0.001; 5HT2a: p < 0.001), norepinephrine (NAT: p < 0.001) and glutamate systems (mGluR5: p < 0.001) as well as between fALFF alterations in fALFF_IC4 and the norepinephrine system (NAT: p < 0.001) were detected. The current findings suggest co-altered structural/functional components that reflect the correlation of language and motor networks as well as associated with the serotonergic, noradrenergic, and glutamatergic neurotransmitter systems. The relationship between anatomical brain structure and intrinsic neural activity was evaluated using a multimodal fusion analysis and neurotransmitters which might provide an important window into the multimodal neural and underlying molecular mechanisms of benign childhood epilepsy with central-temporal spikes. Structure-function relationships in drug-naïve benign childhood epilepsy with central-temporal spikes (BECTS) patients were explored. The interrelated structure-function components were found and correlated with the serotonin, norepinephrine, and glutamate systems. Co-altered structural/functional components reflect the correlation of language and motor networks and correlate with the specific neurotransmitter systems.

CBD Versus CBDP: Comparing In Vitro Receptor-Binding Activities.

Phytocannabinoids with seven-carbon alkyl chains (phorols) have gained a lot of attention, as they are commonly believed to be more potent versions of typical cannabinoids with shorter alkyl chains. At the time of this article, cannabidiphorol (CBDP) and tetrahydrocannabiphorol (THCP) can both be purchased in the North American market, even though their biological activities are nearly unknown. To investigate their relative potency, we conducted in vitro receptor-binding experiments with CBDP (cannabinoid CB1/CB2 receptor antagonism, serotonin 5HT-1A agonism, dopamine D2S (short form) agonism, and mu-opioid negative allosteric modulation) and compared the observed activity with that of CBD. To our knowledge, this is the first publication to investigate CBDP's receptor activity in vitro. A similar activity profile was observed for both CBD and CBDP, with the only notable difference at the CB2 receptor. Contrary to common expectations, CBD was found to be a slightly more potent CB2 antagonist than CBDP (p < 0.05). At the highest tested concentration, CBD demonstrated antagonist activity with a 33% maximum response of SR144528 (selective CB2 antagonist/inverse agonist). CBDP at the same concentration produced a weaker antagonist activity. A radioligand binding assay revealed that among cannabinoid and serotonin receptors, CB2 is likely the main biological target of CBDP. However, both CBD and CBDP were found to be significantly less potent than SR144528. The interaction of CBDP with the mu-opioid receptor (MOR) produced unexpected results. Although the cannabidiol family is considered to be a set of negative allosteric modulators (NAMs) of opioid receptors, we observed a significant increase in met-enkephalin-induced mu-opioid internalization when cells were incubated with 3 µM of CBDP and 1 µM met-enkephalin, a type of activity expected from positive allosteric modulators (PAMs). To provide a structural explanation for the observed PAM effect, we conducted molecular docking simulations. These simulations revealed the co-binding potential of CBDP (or CBD) and met-enkephalin to the MOR.

Serotonin and vasovagal syncope.

The goal of this manuscript was to review the biological and clinical evidence that serotonin neurotransmission might play an important role in the physiology and treatment of vasovagal syncope. The authors reviewed PubMed and handsearches of secondary sources for papers related to the Bezold-Jarisch reflex and serotonin, the plausible involvement of the Bezold-Jarisch reflex in vasovagal syncope, and three lines of clinical evidence involving serotonin and the syncope. The Bezold-Jarisch reflex was first described following the infusion of veratrum alkaloids into animals in the 19th century. The reflex is triggered by serotonin stimulation chemoreceptors and mechanoreceptors in the the left ventricle. The afferent component of the reflex is carried by unmyelinated type C vagal nerve fibers, which results in parasympathetic efferent stimulation that causes bradycardia. The similarity of the combination of hypotension and bradycardia in the Bezold-Jarisch reflex and in vasovagal syncope led to the suggestion that the reflex was the cause of the syndrome. Three lines of evidence implicate the serotonin 5HT3 receptors in the heart in the reflex. There is genetic and physiologic evidence for the serotonin 5HT1A and 5HT3 receptors and the serotonin reuptake transporter (SERT). Acute blockade of SERT induces vasovagal syncope in humans undergoing head-up tilt table testing, and SERT inhibition reduces hypotension and bradycardia during spinal anaesthesia. Finally, three randomized clinical trials of SERT inhibitors uniformly reported that they significantly reduce the likelihood of vasovagal syncope recurrences. Multiple lines of evidence implicate serotonin neurotransmission in the cause of vasovagal syncope.