Serotonin 1A Receptor Research Articles

Creatine Activity as a Neuromodulator in the Central Nervous System.

Creatine is a nutritional compound that potentially influences cognitive processing and neuroprotection. Recent evidence has demonstrated that similar to neurotransmitters, creatine is released in an excitotoxic and action potential-dependent manner and acts as a neuromodulator. Creatine deficiency syndromes are characterized by severe mental and developmental disorders. Studies have reported that brain creatine content could be enhanced with creatine supplementation. Nevertheless, there is still limited knowledge about the effects of creatine on the central nervous system. However, ample evidence has proved the neuroprotective effects of creatine on various mental aspects, such as cognition, memory skills, and spatial memory. The present review aimed to review available experimental data and clinical observations confirming creatine roles in the central transmission process.A systematic search in the literature was performed in PubMed, Scopus, Embase, Cochrane Library, Web of Science, and Google Scholar database using all available MeSH terms for Creatine, Phosphocreatine, Bioenergetics, Nervous system, Brain, Cognition, and Neuroprotection. Electronic database searches were combined and duplicates were removed. Here, first, creatine and its potential influence on cognitive health and performance were briefly reviewed. Next, the existing experimental and clinical evidence was specifically explored to understand how creatine could interact as a neurotransmitter in the nervous system. Studies have revealed that exogenous creatine supplementation decreases neuronal cell loss in experimental paradigms of neurological diseases. It was observed that creatine could interact with the N-methyl-D-aspartate receptor, Na+-K+-ATPase enzyme, GABAA receptor, serotonin 1A receptors, and presumably α1-adrenoceptor and play critical roles in the central transmission process which implies that creatine can be considered a neuromodulator.

Structure-Activity Assessment and In-Depth Analysis of Biased Agonism in a Set of Phenylalkylamine 5-HT2A Receptor Agonists.

Serotonergic psychedelics are described to have activation of the serotonin 2A receptor (5-HT2A) as their main pharmacological action. Despite their relevance, the molecular mechanisms underlying the psychedelic effects induced by certain 5-HT2A agonists remain elusive. One of the proposed hypotheses is the occurrence of biased agonism, defined as the preferential activation of certain signaling pathways over others. This study comparatively monitored the efficiency of a diverse panel of 4-position-substituted (and N-benzyl-derived) phenylalkylamines to induce recruitment of β-arrestin2 (βarr2) or miniGαq to the 5-HT2A, allowing us to assess structure-activity relationships and biased agonism. All test compounds exhibited agonist properties with a relatively large range of both EC50 and Emax values. Interestingly, the lipophilicity of the 2C-X phenethylamines was correlated with their efficacy in both assays but yielded a stronger correlation in the miniGαq- than in the βarr2-assay. Molecular docking suggested that accommodation of the 4-substituent of the 2C-X analogues in a hydrophobic pocket between transmembrane helices 4 and 5 of 5-HT2A may contribute to this differential effect. Aside from previously used standard conditions (lysergic acid diethylamide (LSD) as a reference agonist and a 2 h activation profile to assess a compound's activity), serotonin was included as a second reference agonist, and the compounds' activities were also assessed using the first 30 min of the activation profile. Under all assessed circumstances, the qualitative structure-activity relationships remained unchanged. Furthermore, the use of two reference agonists allowed for the estimation of both "benchmark bias" (relative to LSD) and "physiology bias" (relative to serotonin).

Ameliorating the Role of Aripiprazole in Memory Deficits Induced by Intracerebroventricular Streptozotocin-Induced Dementia of Alzheimer's Type.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder causing immense suffering for the patients. Dopamine D2 and 5-hydroxytryptamine receptor 1A (5-HT1A) receptors' activation has been reported to play a crucial role in managing neurological outcomes in the brain and other health disorders. This study aimed to investigate the role of aripiprazole, a dopamine D2 and 5-HT1A selective receptors' activator, in the restoration of memory deficit induced by streptozotocin in mice. The cognitive functions of animals were determined using the Morris water maze. Brain sections were stained with hematoxylin and eosin and Congo red to examine the structural deviations. Brain oxidative stress (thiobarbituric acid reactive substance and glutathione), acetylcholinesterase activity, IL-6, and IL-10 were measured to assess biochemical alterations. Activation of D2 and 5-HT1A with aripiprazole attenuated STZ-induced cognitive deficit, increased brain GSH levels, reduced TBARS levels, AChE activity, IL-6 levels, and IL-10 levels and prevented STZ-induced brain anomalies in mice. Hence, the present study concluded that aripiprazole mitigated STZ-induced memory impairment and can be used as an efficacious therapeutic target for the management of AD.

Neurotransmitter Gene Polymorphisms Are Associated with Symptom Clusters in Patients Undergoing Radiation Therapy

Purpose was to evaluate for associations between the severity of three distinct symptom clusters (ie, sickness-behavior, mood-cognitive, treatment-related) and polymorphisms for 16 genes involved in catecholaminergic, GABAergic, and serotonergic neurotransmission. Patients with breast and prostate cancer (n = 157) completed study questionnaires at the completion of radiation therapy. Memorial Symptom Assessment Scale was used to assess the severity of 32 common symptoms. Three distinct symptom clusters were identified using exploratory factor analysis. Associations between the symptom cluster severity scores and neurotransmitter gene polymorphisms were evaluated using regression analyses. Severity scores for the sickness-behavior symptom cluster were associated with polymorphisms for solute carrier family 6 (SLC6A) member 2 (SLC6A2), SLC6A3, SLC6A1, and 5-hydroxytryptamine receptor (HTR) 2A (HTR2A) genes. For the mood-cognitive symptom cluster, severity scores were associated with polymorphisms for adrenoreceptor alpha 1D, SLC6A2, SLC6A3, SLC6A1, HTR2A, and HTR3A. Severity scores for the treatment-related symptom cluster were associated with polymorphisms for SLC6A2, SLC6A3, catechol-o-methyltransferase, SLC6A1, HTR2A, SLC6A4, and tryptophan hydroxylase 2. Findings suggest that polymorphisms for several neurotransmitter genes are involved in the severity of sickness-behavior, mood-cognitive, and treatment-related symptom clusters in oncology patients at the completion of radiation therapy. Four genes with various associated polymorphisms were common across the three distinct symptom clusters (ie, SLC6A2, SLC6A3, SLC6A1, HTR2A) which suggest that these clusters have common underlying mechanisms.

Neuroprotective Effects of a Serotonin Receptor Peptide Following Sham vs. Mild Traumatic Brain Injury in the Zucker Rat.

Accelerated cognitive decline frequently complicates traumatic brain injury. Obesity and type 2 diabetes mellitus drive peripheral inflammation which may accelerate traumatic brain injury-associated neurodegeneration. The Zucker rat harbors G-protein coupled receptor agonist IgG autoantibodies and in vitro neurotoxicity caused by these autoantibodies was prevented by a novel synthetic fragment of the serotonin 2A receptor. The aim of the present study was to test whether genetic obesity manifested in Zucker diabetic fatty rat is associated with greater spatial memory impairment before and after mild traumatic brain injury compared to Zucker lean rats. Furthermore, we investigated whether these neurodegenerative complications can be lessened by administration of a novel putative neuroprotective peptide comprised of a fragment of the second extracellular loop of the serotonin 2A receptor. Age-matched lean and fatty diabetic Zucker rats were tested in the Morris water maze (spatial memory) prior to receiving a sham-injury or lateral fluid percussion (LFP) mild traumatic brain injury. Behavioral testing was repeated at 1-week, 1-month, and 3-month intervals following injury. A synthetic peptide consisting of a portion of the 5-hydroxytryptamine (serotonin) 2A receptor (2 mg/kg) (vehicle, or an inactive scrambled version of the peptide (2 mg/kg)) was administered via intraperitoneal route every other day for 7 days after sham or LFP injury to lean rats or 7 days before and after sham or LFP injury to fatty rats. Mild traumatic brain injury impaired recall of spatial memory in fatty and lean rats. Zucker fatty rats subjected to sham-injury or mild TBI experienced a significantly greater longitudinal decline in recall of spatial memory compared to lean Zucker rats. A synthetic peptide fragment of the 5-hydroxytryptamine 2A receptor significantly enhanced acquisition of spatial learning and it appeared to strengthen recall of spatial learning (one-week) after sham injury in Zucker rats. These data suggest that the Zucker diabetic fatty rat is a suitable animal model to investigate the role of metabolic factor(s) in accelerated cognitive decline. A novel synthetic peptide comprised of a fragment of the second extracellular loop of the human serotonin 2A receptor appeared to have neuroprotective effects on both acquisition and recall of spatial memory in subsets of Zucker rats, with relatively greater benefit in sham-injured, lean Zucker rats.

Brain serotonin 1A receptor binding: relationship to peripheral blood DNA methylation, recent life stress and childhood adversity in unmedicated major depression.

Childhood and lifetime adversity may reduce brain serotonergic (5-HT) neurotransmission by epigenetic mechanisms. We tested the relationships of childhood adversity and recent stress to serotonin 1A (5-HT1A) receptor genotype, DNA methylation of this gene in peripheral blood monocytes and in vivo 5-HT1A receptor binding potential (BPF) determined by positron emission tomography (PET) in 13 a priori brain regions, in participants with major depressive disorder (MDD) and healthy volunteers (controls). Medication-free participants with MDD (n = 192: 110 female, 81 male, 1 other) and controls (n = 88: 48 female, 40 male) were interviewed about childhood adversity and recent stressors and genotyped for rs6295. DNA methylation was assayed at three upstream promoter sites (-1019, -1007, -681) of the 5-HT1A receptor gene. A subgroup (n = 119) had regional brain 5-HT1A receptor BPF quantified by PET. Multi-predictor models were used to test associations between diagnosis, recent stress, childhood adversity, genotype, methylation and BPF. Recent stress correlated positively with blood monocyte methylation at the -681 CpG site, adjusted for diagnosis, and had positive and region-specific correlations with 5-HT1A BPF in participants with MDD, but not in controls. In participants with MDD, but not in controls, methylation at the -1007 CpG site had positive and region-specific correlations with binding potential. Childhood adversity was not associated with methylation or BPF in participants with MDD. These findings support a model in which recent stress increases 5-HT1A receptor binding, via methylation of promoter sites, thus affecting MDD psychopathology.

Neuromodulatory mechanisms of N,N-dimethyltryptamine

N,N-dimethyltryptamine (DMT) is the simplest psychedelic tryptamine and is produced naturally by many plant and animal species, including humans. While classical psychedelics, such as lysergic acid diethylamide, or psilocybin, are gaining interest because of their therapeutic potential, DMT has yet to be fully investigated. However, preliminary clinical evidence suggests that DMT and/or ayahuasca, a DMT-containing psychoactive beverage, both possess antidepressive, anxiolytic, and antiaddictive properties. In addition, the subjective effects of DMT are particularly potent. Both subjective and therapeutic cues can be largely explained via the neuromodulatory properties of DMT. In addition, DMT interacts with several neurochemical systems, including the glutamatergic, monoaminergic, and cholinergic systems. Consequently, large-scale brain dynamics can suffer acute and dramatic shifts in several networks, including visual and auditive networks, and the default-mode network. More broadly, top-down cognitive processes (predictive and contextual processing) can become restricted while bottom-up and stimuli-related processing is enhanced. Furthermore, the acute effects of DMT can crystallize to some extent by virtue of its plastogenic effects which are mediated by sigma 1 receptor, brain-derived neurotrophic factor, tropomyosin receptor kinase B, and serotonin receptor 2A. DMT-induced plasticity has been related mental well-being and therapeutic benefits. Here, I provide an updated review of the neuromodulatory effects of DMT and the mechanisms that underlie these effects. I consider the molecular targets that influence neurochemical systems, changes in large-scale cortical function and structure, and DMT-dependent neuroplasticity. Finally, I highlight the therapeutic relevance and/or risks associated with the neuromodulatory mechanisms of DMT.

Psilocybin for treatment-resistant depression without psychedelic effects: study protocol for a 4-week, double-blind, proof-of-concept randomised controlled trial.

Randomised controlled trials (RCTs) of psilocybin have reported large antidepressant effects in adults with major depressive disorder and treatment-resistant depression (TRD). Given psilocybin's psychedelic effects, all published studies have included psychological support. These effects depend on serotonin 2A (5-HT2A) receptor activation, which can be blocked by 5-HT2A receptor antagonists like ketanserin or risperidone. In an animal model of depression, ketanserin followed by psilocybin had similar symptomatic effects as psilocybin alone. To conduct a proof-of-concept RCT to (a) establish feasibility and tolerability of combining psilocybin and risperidone in adults with TRD, (b) show that this combination blocks the psychedelic effects of psilocybin and (c) provide pilot data on the antidepressant effect of this combination (compared with psilocybin alone). In a 4-week, three-arm, 'double dummy' trial, 60 adults with TRD will be randomised to psilocybin 25 mg plus risperidone 1 mg, psilocybin 25 mg plus placebo, or placebo plus risperidone 1 mg. All participants will receive 12 h of manualised psychotherapy. Measures of feasibility will include recruitment and retention rates; tolerability and safety will be assessed by rates of drop-out attributed to adverse events and rates of serious adverse events. The 5-Dimensional Altered States of Consciousness Rating Scale will be a secondary outcome measure. This trial will advance the understanding of psilocybin's mechanism of antidepressant action. This line of research could increase acceptability and access to psilocybin as a novel treatment for TRD without the need for a psychedelic experience and continuous monitoring.

Psilocybin therapy: A novel approach to treating depression

Psilocybin therapy: A novel approach to treating depression

Expression of the serotonin 1A receptor in the horse brain

Expression of the serotonin 1A receptor in the horse brain

The Serotonin 1A (5-HT1A) Receptor as a Pharmacological Target in Depression.

Clinical depression is a common, debilitating and heterogenous disorder. Existing treatments for depression are inadequate for a significant minority of patients and new approaches are urgently needed. A wealth of evidence implicates the serotonin1A (5-HT1A) receptor in the pathophysiology of depression. Stimulation of the 5-HT1A receptor is an existing therapeutic target for treating depression and anxiety, using drugs such as buspirone and tandospirone. However, activation of 5-HT1A raphe autoreceptors has also been suggested to be responsible for the delay in the therapeutic action of conventional antidepressants such as selective serotonin reuptake inhibitors (SSRIs). This narrative review provides a brief overview of the 5-HT1A receptor, the evidence implicating it in depression and inthe effects of conventional antidepressant treatment. We highlight that pre- and post-synaptic 5-HT1A receptors may have divergent roles in the pathophysiology and treatment of depression. To date, developing this understanding to progress therapeutic discovery has been limited, partly due to a paucity of specific pharmacological probes suitable for use in humans. The development of 5-HT1A 'biased agonism', using compounds such as NLX-101, offers the opportunity to further elucidate the roles of pre- and post-synaptic 5-HT1A receptors. We describe how experimental medicine approaches can be helpful in profiling the effectsof 5-HT1A receptor modulation on the different clinical domains of depression, and outline some potential neurocognitive models that could be used to test the effects of 5-HT1A biased agonists.

Influences of neurotransmission-related genetic polymorphisms on depression, anxiety and stress

Over 10% of the world population suffer from mental disorders. In particular, depression causes about 800,000 suicide cases annually, while anxiety is the most common mental disorder. Stresses from work, life, and health have been identified as the common triggers for the two mental disorders. Eventhough mental disorders are treatable and validated tools are available to diagnose, many individuals are left untreated due to different factors, such as a lack of trained personnel and stigma. Neuroscience research indicates that mental disorders could be hereditary, where genes involved in determining behavioural variants. Disturbance in brain communication, resulting from abnormalities in neurogenesis, neurotransmission, and enzymatic degradation, have led to negative emotional states. This mini-review will highlight some important genes in the neurotransmitter systems and explore the relationship between gene polymorphisms and emotional states (i.e., depression, anxiety, and stress). The genes that will be discussed in this mini-review include brain-derived neurotrophic factor (BDNF) which is involved in neuron development, serotonin-transporter-linked polymorphic region (5-HTTLPR) and 5-hydroxytryptamine receptor 1A (5-HT1A) which are involved in serotonin neurotransmitter action potential propagation, and monoamine oxidase A (MAOA) and catechol-O-methyltransferase (COMT), which are involved in neurotransmitter catabolism.

Association between single nucleotide polymorphisms in serotonin receptor 2A and melatonin receptor 1A genes and pain after root canal treatment.

This study aimed to investigate whether single nucleotide polymorphisms (SNPs) in the genes encoding 5-HTR2A (5-Hydroxytryptamine (serotonin) receptor 2A) and MTNR1A (melatonin receptor 1A) may contribute to postoperative pain perception after root canal treatment. We hypothesised that SNPs in HTR2A and MTNR1A genes were associated with postoperative pain after root canal treatment. This genetic cohort study enrolled patients with single-rooted teeth diagnosed with pulp necrosis and asymptomatic apical periodontitis before root canal treatment. Root canal treatment was performed in one session using a standardised protocol. Postoperative pain and tenderness were assessed using a visual analogue scale (recorded every day for seven days and on the 14th and 30th days after root canal treatment). Genomic DNA was extracted from saliva and used to genotype the SNPs in HTR2A (rs4941573 and rs6313) and MTNR1A (rs6553010, rs6847693, and rs13140012) using real-time polymerase chain reaction. Genotypes were compared using univariate and multivariate Poisson regression with generalised estimating equations (p<0.05). In total, 108 patients were enrolled in this study. The SNPs rs6553010 (MTNR1A), rs4941573, and rs6313 (HTR2A) were associated with an increased risk of developing pain after root canal treatment (p<0.05). This study suggests that SNPs in HTR2A and MTNR1A influence pain response after root canal treatment.

Development of a novel senolysis approach targeting the senescent fibroblast marker HTR2A via antibody-dependent cellular cytotoxicity.

Abnormal remodeling of collagen and extracellular matrix caused by the accumulation of senescent fibroblasts in the dermis is the most likely cause of skin aging. Therefore, the application of "senolysis," in which only senescent cells are cleared from the body, has a potential in the development of antiaging treatments for skin. However, markers that label senescent fibroblasts only reflect the state of senescence, and it is important to develop markers as therapeutic targets to aid senolysis application. We investigated the potential of serotonin 2A receptor (HTR2A), which is involved in melanin production in response to UV light, as a senescent cell marker. The results showed that HTR2A is upregulated in aging dermal fibroblasts but is expressed at low levels in proliferating young cells. Flow cytometry demonstrated the presence of many HTR2A-positive cells in the aging cell population and few in the young cells. Furthermore, antibody-dependent cytotoxicity assays revealed that HTR2A preferentially sensitizes senescent fibroblasts and specifically damages only senescent cells by NK cells that recognize it. In conclusion, selective labeling of the novel senescent cell marker, HTR2A, could preferentially eliminate senescent cells and may contribute to the future development of novel skin senolysis approaches.

Repeated Traumatic Brain Injury is Associated with Neurotoxic Plasma Autoantibodies Directed against the Serotonin 2A and Alpha 1 Adrenergic Receptors.

Traumatic brain injury (TBI) was associated with increased plasma agonist autoantibodies targeting the serotonin 2A receptor. Repeated TBI exposure is associated with high risk for neurodegenerative and neuropsychiatric complications. Here we tested a hypothesis that repeated TBI is associated with plasma agonist autoantibodies targeting more than one kind of catecholamine G-protein coupled receptor. Protein-A affinity chromatography was used to isolate the IgG fraction of plasma in forty-two middle-aged and older adults who had experienced one or more TBI exposures. The Ig (1/40th dilution=7.5 ug/mL) were tested for neurotoxicity in mouse neuroblastoma cells using an acute neurite retraction assay indicative of Gq11/IP3/Ca2+ and RhoA/Rho kinase signaling pathways' activation. Three different linear synthetic peptides corresponding to the second extracellular loop of the alpha 1A, alpha 2A or serotonin 2A receptors were used as target antigen in different enzyme-linked immunoassays. The second extracellular loop receptor peptides themselves (alpha 1A, alpha 2A) or a fragment (serotonin 2A) were tested for ability to prevent Ig-induced neurite retraction. Patients who had experienced either repeated TBI (N=10) or a single TBI with a co-morbid autoimmune disease (N=5) were significantly more likely to harbor neurotoxic plasma autoantibodies targeting both alpha 1 adrenergic and serotonin 2A receptors vs. patients having only a single TBI. Ig-induced neurotoxicity was significantly prevented by co-incubation with either 850 nM prazosin (alpha 1 adrenergic receptor) and/or 500 nM M100907 (serotonin 2A receptor) antagonists. Alpha 1 adrenergic receptor and serotonin 2A receptor Ig immunoreactive level and titer were significantly increased in repeated TBI and single TBI/autoimmune patients (N=7-8) compared to age-matched TBI patients without neurotoxic plasma Ig (N=4). SN.8, a linear synthetic peptide corresponding to a conserved region of the second extracellular loop (ECL) of the serotonin 2A receptor completely prevented neurite retraction induced by repeated TBI plasma Ig. A repeated TBI patient harboring alpha adrenergic receptor AAB alone experienced prospective steep decline in cognitive function over two years. Repeated TBI and TBI with associated autoimmunity harbored more than one kind of neurotoxic catecholaminergic agonist GPCR autoantibody each associated with high risk for steep rate of cognitive decline. Specific immunoassays using the second extracellular receptor loop as target antigen are needed to detect each specific different GPCR autoantibody. A fragment of the second ECL of the serotonin 2A receptor (SN.8) neutralized Ig-induced neurotoxicity in repeated TBI or TBI with associated systemic autoimmunity.

On the construction of LIECE models for the serotonin receptor 5-HT_{text {2A}}R

Computer-aided approaches to ligand design need to balance accuracy with speed. This is particularly true for one of the key parameters to be optimized during ligand development, the free energy of binding (DeltaG_{text {bind}}). Here, we developed simple models based on the Linear Interaction Energy approximation to free energy calculation for a G protein-coupled receptor, the serotonin receptor 2A, and critically evaluated their accuracy. Several lessons can be taken from our calculations, providing information on the influence of the docking software used, the conformational state of the receptor, the cocrystallized ligand, and its comparability to the training/test ligands.

Bimodal modulation of L1 interneuron activity in anterior cingulate cortex during fear conditioning.

The anterior cingulate cortex (ACC) plays a crucial role in encoding, consolidating and retrieving memories related to emotionally salient experiences, such as aversive and rewarding events. Various studies have highlighted its importance for fear memory processing, but its circuit mechanisms are still poorly understood. Cortical layer 1 (L1) of the ACC might be a particularly important site of signal integration, since it is a major entry point for long-range inputs, which is tightly controlled by local inhibition. Many L1 interneurons express the ionotropic serotonin receptor 3a (5HT3aR), which has been implicated in post-traumatic stress disorder and in models of anxiety. Hence, unraveling the response dynamics of L1 interneurons and subtypes thereof during fear memory processing may provide important insights into the microcircuit organization regulating this process. Here, using 2-photon laser scanning microscopy of genetically encoded calcium indicators through microprisms in awake mice, we longitudinally monitored over days the activity of L1 interneurons in the ACC in a tone-cued fear conditioning paradigm. We observed that tones elicited responses in a substantial fraction of the imaged neurons, which were significantly modulated in a bidirectional manner after the tone was associated to an aversive stimulus. A subpopulation of these neurons, the neurogliaform cells (NGCs), displayed a net increase in tone-evoked responses following fear conditioning. Together, these results suggest that different subpopulations of L1 interneurons may exert distinct functions in the ACC circuitry regulating fear learning and memory.

Non-clinical pharmacology and toxicology studies of LPM6690061, a novel 5-hydroxytryptamine (5-HT)2A receptor inverse agonist.

LPM6690061 is a novel compound with 5-HT2A receptor antagonist and inverse agonist activities. To support the clinical trial and marketing application of LPM6690061, a series of pharmacology and toxicology studies have been conducted. In vitro and in vivo pharmacology studies showed that LPM6690061 had high inverse agonism and antagonism activities against human 5-HT2A receptors, and demonstrated significant antipsychotic-like effects in two rat models: the DOI-induced head-twitch model and the MK-801-induced hyperactivity model, which was more effective than the control drug pimavanserin. LPM6690061 did not have detectable side effects on the neurobehavioral activities and respiratory function in rats, or on the ECG or blood pressure in dogs at the doses of 2 and 6mg/kg. The half maximal inhibitory concentration (IC50) of LPM6690061 for inhibiting hERG current was 1.02μM. Three in vivo toxicology studies were conducted. In the single dose toxicity study in rats and dogs, the maximum tolerated dose of LPM6690061 was 100mg/kg. In the 4-week repeat dose toxicity study in rats, the main detectable toxic reactions of LPM6690061 included moderate artery wall hypertrophy, minimal to mild mixed cell inflammation and increased macrophages in the lung, which generally recovered after a 4-week drug withdrawal period. In the 4-week repeat dose toxicity study in dogs, no detectable toxicity was observed. The doses of no-observed-adverse-effect-level (NOAEL) in rats and dogs were 10mg/kg and 20mg/kg, respectively. In conclusion, both in vitro and in vivo pharmacological and toxicological studies showed that LPM6690061 was a safe and efficacious 5-HT2A receptor antagonist/inverse agonist which supports the clinical development as a novel antipsychotic drug.

Psychedelics promote plasticity by directly binding to BDNF receptor TrkB

Psychedelics produce fast and persistent antidepressant effects and induce neuroplasticity resembling the effects of clinically approved antidepressants. We recently reported that pharmacologically diverse antidepressants, including fluoxetine and ketamine, act by binding to TrkB, the receptor for BDNF. Here we show that lysergic acid diethylamide (LSD) and psilocin directly bind to TrkB with affinities 1,000-fold higher than those for other antidepressants, and that psychedelics and antidepressants bind to distinct but partially overlapping sites within the transmembrane domain of TrkB dimers. The effects of psychedelics on neurotrophic signaling, plasticity and antidepressant-like behavior in mice depend on TrkB binding and promotion of endogenous BDNF signaling but are independent of serotonin 2A receptor (5-HT2A) activation, whereas LSD-induced head twitching is dependent on 5-HT2A and independent of TrkB binding. Our data confirm TrkB as a common primary target for antidepressants and suggest that high-affinity TrkB positive allosteric modulators lacking 5-HT2A activity may retain the antidepressant potential of psychedelics without hallucinogenic effects.

Imbalance of multiple neurotransmitter pathways leading to depression-like behavior and cognitive dysfunction in the triple transgenic mouse model of Alzheimer disease.

Depression is among the most frequent psychiatric comorbid conditions in Alzheimer disease (AD). However, pharmacotherapy for depressive disorders in AD is still a big challenge, and the data on the efffcacy of current antidepressants used clinically for depressive symptoms in patients with AD remain inconclusive. Here we investigated the mechanism of the interactions between depression and AD, which we believe would aid in the development of pharmacological therapeutics for the comorbidity of depression and AD. Female APP/PS1/Tau triple transgenic (3×Tg-AD) mice at 24 months of age and age- and sex-matched wild-type (WT) mice were used. The shuttle-box passive avoidance test (PAT) were implemented to assess the abilities of learning and memory, and the open field test (OFT) and the tail suspension test (TST) were used to assess depression-like behavior. High-performance liquid chromatography coupled to tandem mass spectrometry (HPLC-MS/MS) was used to detect the level of neurotransmitters related to depression in the hippocampus of mice. The data was identified by orthogonal projections to latent structures discriminant analysis (OPLS-DA). Most neurotransmitters exert their effects by binding to the corresponding receptor, so the expression of relative receptors in the hippocampus of mice was detected using Western blot. Compared to WT mice, 3×Tg-AD mice displayed significant cognitive impairment in the PAT and depression-like behavior in the OFT and TST. They also showed significant decreases in the levels of L-tyrosine, norepinephrine, vanillylmandelic acid, 5-hydroxytryptamine, and acetylcholine, in contrast to significant increases in 5-hydroxyindoleacetic acid, L-histidine, L-glutamine, and L-arginine in the hippocampus. Moreover, the expression of the alpha 1a adrenergic receptor (ADRA1A), serotonin 1A receptor (5HT1A), and γ-aminobutyric acid A receptor subunit alpha-2 (GABRA2) was significantly downregulated in the hippocampus of 3×Tg-AD mice, while histamine H3 receptor (H3R) expression was significantly upregulated. In addition, the ratio of phosphorylated cAMP-response element-binding protein (pCREB) and CREB was significantly decreased in the hippocampus of 3×Tg-AD mice than WT mice. We demonstrated in the present study that aged female 3×Tg-AD mice showed depression-like behavior accompanied with cognitive dysfunction. The complex and diverse mechanism appears not only relevant to the imbalance of multiple neurotransmitter pathways, including the transmitters and receptors of the monoaminergic, GABAergic, histaminergic, and cholinergic systems, but also related to the changes in L-arginine and CREB signaling molecules.