Synthesis and Structure-Activity Relationships of 2,5-Dimethoxy-4-Substituted Phenethylamines and the Discovery of CYB210010: A Potent, Orally Bioavailable and Long-Acting Serotonin 5-HT2 Receptor Agonist.

Structure-activity studies of 4-substituted-2,5-dimethoxyphenethylamines led to the discovery of 2,5-dimethoxy-4-thiotrifluoromethylphenethylamines, including CYB210010, a potent and long-acting serotonin 5-HT2 receptor agonist. CYB210010 exhibited high agonist potency at 5-HT2A and 5-HT2C receptors, modest selectivity over 5-HT2B, 5-HT1A, 5-HT6, and adrenergic α2A receptors, and lacked activity at monoamine transporters and over 70 other proteins. CYB210010 (0.1-3 mg/kg) elicited a head-twitch response (HTR) and could be administered subchronically at threshold doses without behavioral tolerance. CYB210010 was orally bioavailable in three species, readily and preferentially crossed into the CNS, engaged frontal cortex 5-HT2A receptors, and increased the expression of genes involved in neuroplasticity in the frontal cortex. CYB210010 represents a new tool molecule for investigating the therapeutic potential of 5-HT2 receptor activation. In addition, several other compounds with high 5-HT2A receptor potency, yet with little or no HTR activity, were discovered, providing the groundwork for the development of nonpsychedelic 5-HT2A receptor ligands.

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 OSA sufferers 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 OSA and LEPR gene polymorphisms. Results: Statistical analysis showed a significant relationship between genotype frequencies of patient and control groups of rs6311 with OSA in 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 OSA in 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 'PSILAUT' protocol: an experimental medicine study of autistic differences in the function of brain serotonin targets of psilocybin.

BACKGROUND: The underlying neurobiology of the complex autism phenotype remains obscure, although accumulating evidence implicates the serotonin system and especially the 5HT2A receptor. However, previous research has largely relied upon association or correlation studies to link differences in serotonin targets to autism. To directly establish that serotonergic signalling is involved in a candidate brain function our approach is to change it and observe a shift in that function. We will use psilocybin as a pharmacological probe of the serotonin system in vivo. We will directly test the hypothesis that serotonergic targets of psilocybin - principally, but not exclusively, 5HT2A receptor pathways-function differently in autistic and non-autistic adults. METHODS: The 'PSILAUT' "shiftability" study is a case-control study autistic and non-autistic adults. How neural responses 'shift' in response to low doses (2 mg and 5 mg) of psilocybin compared to placebo will be examined using multimodal techniques including functional MRI and EEG. Each participant will attend on up to three separate visits with drug or placebo administration in a double-blind and randomized order. RESULTS: This study will provide the first direct evidence that the serotonin targets of psilocybin function differently in the autistic and non-autistic brain. We will also examine individual differences in serotonin system function. CONCLUSIONS: This work will inform our understanding of the neurobiology of autism as well as decisions about future clinical trials of psilocybin and/or related compounds including stratification approaches. TRIAL REGISTRATION: NCT05651126.

Fibroblast expression of neurotransmitter receptor HTR2A associates with inflammation in rheumatoid arthritis joint.

The study of neuroimmune crosstalk and the involvement of neurotransmitters in inflammation and bone health has illustrated their significance in joint-related conditions. One important mode of cell-to-cell communication in the synovial fluid (SF) is through extracellular vesicles (EVs) carrying microRNAs (miRNAs). The role of neurotransmitter receptors in the pathogenesis of inflammatory joint diseases, and whether there are specific miRNAs regulating differentially expressed HTR2A, contributing to the inflammatory processes and bone metabolism is unclear. Expression of neurotransmitter receptors and their correlated inflammatory molecules were identified in rheumatoid arthritis (RA) and osteoarthritis (OA) synovium from a scRNA-seq dataset. Immunohistochemistry staining of synovial tissue (ST) from RA and OA patients was performed for validation. Expression of miRNAs targeting HTR2A carried by SF EVs was screened in low- and high-grade inflammation RA from a public dataset and validated by qPCR. HTR2A reduction by target miRNAs was verified by miRNAs mimics transfection into RA fibroblasts. HTR2A was found to be highly expressed in fibroblasts derived from RA synovial tissue. Its expression showed a positive correlation with the degree of inflammation observed. 5 miRNAs targeting HTR2A were decreased in RA SF EVs compared to OA, three of which, miR-214-3p, miR-3120-5p and miR-615-3p, mainly derived from monocytes in the SF, were validated as regulators of HTR2A expression. The findings suggest that fibroblast HTR2A may play a contributory role in inflammation and the pathogenesis of RA. Additionally, targeting miRNAs that act upon HTR2A could present novel therapeutic strategies for alleviating inflammation in RA.

Intranasal delivery of shRNA to knockdown the 5HT-2A receptor enhances memory and alleviates anxiety.

Short-hairpin RNAs (shRNA), targeting knockdown of specific genes, hold enormous promise for precision-based therapeutics to treat numerous neurodegenerative disorders. However, whether shRNA constructed molecules can modify neuronal circuits underlying certain behaviors has not been explored. We designed shRNA to knockdown the human HTR2A gene in vitro using iPSC-differentiated neurons. Multi-electrode array (MEA) results showed that the knockdown of the 5HT-2A mRNA and receptor protein led to a decrease in spontaneous electrical activity. In vivo, intranasal delivery of AAV9 vectors containing shRNA resulted in a decrease in anxiety-like behavior in mice and a significant improvement in memory in both mice (104%) and rats (92%) compared to vehicle-treated animals. Our demonstration of a non-invasive shRNA delivery platform that can bypass the blood-brain barrier has broad implications for treating numerous neurological mental disorders. Specifically, targeting the HTR2A gene presents a novel therapeutic approach for treating chronic anxiety and age-related cognitive decline.

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.

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).

The 5-HT2A, 5-HT5A, and 5-HT6 serotonergic receptors in the medial prefrontal cortex behave differently in extinction learning: Does social support play a role?

Studies on the social modulation of fear have revealed that in social species, individuals in a distressed state show better recovery from aversive experiences when accompanied - referred to as social buffering. However, the underlying mechanisms remain unknown, hindering the understanding of such an approach. Our previous data showed that the presence of a conspecific during the extinction task inhibited the retrieval of fear memory without affecting the extinction memory in the retention test. Here, we investigate the role of serotonergic receptors (5-HTRs), specifically 5-HT2A, 5-HT5A, and 5-HT6 in the medial prefrontal cortex (mPFC), In the retention of extinction after the extinction task, in the absence or presence of social support. Extinction training was conducted on 60-day-old male Wistar rats either alone or with a conspecific (a familiar cagemate, non-fearful). The antagonists for these receptors were administered directly into the mPFC immediately after the extinction training. The results indicate that blocking 5-HT5A (SB-699551-10 µg/side) and 5-HT6 (SB-271046A - 10 µg/side) receptors in the mPFC impairs the consolidation of CFC in the social support group. Interestingly, blocking 5-HT2A receptors (R65777 - 4 µg/side) in the mPFC led to impaired CFC specifically in the group undergoing extinction training alone. These findings contribute to a better understanding of brain mechanisms and neuromodulation associated with social support during an extinction protocol. They are consistent with previously published research, suggesting that the extinction of contextual fear conditioning with social support involves distinct neuromodulatory processes compared to when extinction training is conducted alone.

Effect of Bulky N-Dibenzofuranylmethyl Substitution on the 5-HT2 Receptor Affinity and Efficacy of a Psychedelic Phenethylamine.

The introduction of arylmethyl substituents on the amine nitrogen atom of phenethylamines and tryptamines often results in profound increases in their affinity and functional activity at 5-HT2 serotonin receptors. To probe the sensitivity of this effect to substantially larger N-substituents, ten derivatives of the well-characterized psychedelic phenethylamine 2C-B were prepared by appending different dibenzo[b,d]furylmethyl (DBFM) moieties to the basic nitrogen. The DBFM group attached to the amino group through its 1-, -2-, or 3-position decreased affinity and agonist activity at the 5-HT2A/2C receptors. Substitution through the 4-position usually favored affinity for all three 5-HT2 receptor subtypes with compound 5 exhibiting 10- and 40-fold higher affinities at the 5-HT2A and 5-HT2C receptors, respectively, but less than fourfold selectivity among the three receptor subtypes. Nevertheless, all were relatively weak partial 5-HT2AR agonists, mostly in the low micromolar range, but full or nearly full agonists at the 5-HT2C subtype as determined in a calcium mobilization assay. Molecular docking simulations suggested that the dibenzofuryl portion dives more deeply into the orthosteric binding site of the 5-HT2A than the 5-HT2C receptor, interacting with the Trp3366.48 toggle switch associated with its activation, while the phenylamine moiety lies close to the extracellular side of the receptor. In conclusion, a very bulky N-substituent on a phenethylamine 5-HT2 receptor agonist is tolerated and may increase affinity if its orientation is appropriate. However, the Gq protein-mediated potencies are generally low, with low efficacy (relative to 5-HT) at the 5-HT2A receptor, somewhat higher efficacy at the 5-HT2B subtype, and full or nearly full efficacy at the 5-HT2C subtype.

Psychedelic-like Activity of Norpsilocin Analogues.

Primary metabolites of mushroom tryptamines, psilocybin and baeocystin (i.e., psilocin and norpsilocin), exhibit potent agonist activity at the serotonin 2A receptor (5-HT2A) in vitro but differ in their 5-HT2A-mediated effects in vivo. In particular, psilocin produces centrally mediated psychedelic effects in vivo, whereas norpsilocin, differing only by the loss of an N-methyl group, is devoid of psychedelic-like effects. These observations suggest that the secondary methylamine group in norpsilocin impacts its central nervous system (CNS) bioavailability but not its receptor pharmacodynamics. To test this hypothesis, eight norpsilocin derivatives were synthesized with varied secondary alkyl-, allyl-, and benzylamine groups, primarily aiming to increase their lipophilicity and brain permeability. Structure-activity relationships for the norpsilocin analogues were evaluated using the mouse head-twitch response (HTR) as a proxy for CNS-mediated psychedelic-like effects. HTR studies revealed that extending the N-methyl group of norpsilocin by a single methyl group, to give the corresponding secondary N-ethyl analogue (4-HO-NET), was sufficient to produce psilocin-like activity (median effective dose or ED50 = 1.4 mg/kg). Notably, N-allyl, N-propyl, N-isopropyl, and N-benzyl derivatives also induced psilocin-like HTR activity (ED50 = 1.1-3.2 mg/kg), with variable maximum effects (26-77 total HTR events). By contrast, adding bulkier tert-butyl or cyclohexyl groups in the same position did not elicit psilocin-like HTRs. Pharmacological assessments of the tryptamine series in vitro demonstrated interactions with multiple serotonin receptor subtypes, including 5-HT2A, and other CNS signaling proteins (e.g., sigma receptors). Overall, our data highlight key structural requirements for CNS-mediated psychedelic-like effects of norpsilocin analogues.

5-HT2A Receptor Knockout Mice Show Sex-Dependent Differences following Acute Noribogaine Administration.

Noribogaine (noribo) is the primary metabolite from ibogaine, an atypical psychedelic alkaloid isolated from the root bark of the African shrub Tabernanthe iboga. The main objective of this study was to test the hypothesis that molecular, electrophysiological, and behavioral responses of noribo are mediated by the 5-HT2A receptor (5-HT2AR) in mice. In that regard, we used male and female, 5-HT2AR knockout (KO) and wild type (WT) mice injected with a single noribo dose (10 or 40 mg/kg; i.p.). After 30 min., locomotor activity was recorded followed by mRNA measurements by qPCR (immediate early genes; IEG, glutamate receptors, and 5-HT2AR levels) and electrophysiology recordings of layer V pyramidal neurons from the medial prefrontal cortex. Noribo 40 decreased locomotion in male, but not female WT. Sex and genotype differences were observed for IEG and glutamate receptor expression. Expression of 5-HT2AR mRNA increased in the mPFC of WT mice following Noribo 10 (males) or Noribo 40 (females). Patch-clamp recordings showed that Noribo 40 reduced the NMDA-mediated postsynaptic current density in mPFC pyramidal neurons only in male WT mice, but no effects were found for either KO males or females. Our results highlight that noribo produces sexually dimorphic effects while the genetic removal of 5HT2AR blunted noribo-mediated responses to NMDA synaptic transmission.

Antidepressant-like effects of psychedelics in a chronic despair mouse model: is the 5-HT2A receptor the unique player?

Major depressive disorder (MDD) is one of the most disabling psychiatric disorders in the world. First-line treatments such as selective serotonin reuptake inhibitors (SSRIs) still have many limitations, including a resistance to treatment in 30% of patients and a delayed clinical benefit that is observed only after several weeks of treatment. Increasing clinical evidence indicates that the acute administration of psychedelic agonists of the serotonin 5-HT2A receptor (5-HT2AR), such as psilocybin, to patients with MDD induce fast antidepressant effects, which persist up to five weeks after the treatment. However, the involvement of the 5-HT2AR in these antidepressant effects remains controversial. Furthermore, whether the hallucinogenic properties of 5-HT2AR agonists are mandatory to their antidepressant activity is still an open question. Here, we addressed these issues by investigating the effect of two psychedelics of different chemical families, DOI and psilocybin, and a non-hallucinogenic 5-HT2AR agonist, lisuride, in a chronic despair mouse model exhibiting a robust depressive-like phenotype. We show that a single injection of each drug to wild type mice induces anxiolytic- and antidepressant-like effects in the novelty-suppressed feeding, sucrose preference and forced swim tests, which last up to 15 days. DOI and lisuride administration did not produce antidepressant-like effects in 5-HT2A-/- mice, whereas psilocybin was still effective. Moreover, neither 5-HT1AR blockade nor dopamine D1 or D2 receptor blockade affected the antidepressant-like effects of psilocybin in 5-HT2A-/- mice. Collectively, these findings indicate that 5-HT2AR agonists can produce antidepressant-like effects independently of hallucinogenic properties through mechanisms involving or not involving the receptor.

The novel non-hallucinogenic compound DM506 (3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole) induces sedative- and anxiolytic-like activity in mice by a mechanism involving 5-HT2A receptor activation.

The anxiolytic and sedative-like effects of 3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (DM506), a non-hallucinogenic compound derived from ibogamine, were studied in mice. The behavioral effects were examined using Elevated O-maze and novelty suppressed feeding (NSFT) tests, open field test, and loss of righting reflex (LORR) test. The results showed that 15 mg/kg DM506 induced acute and long-lasting anxiolytic-like activity in naive and stressed/anxious mice, respectively. Repeated administration of 5 mg/kg DM506 did not cause cumulative anxiolytic activity or any side effects. Higher doses of DM506 (40 mg/kg) induced sedative-like activity, which was inhibited by a selective 5-HT2A receptor antagonist, volinanserin. Electroencephalography results showed that 15 mg/kg DM506 fumarate increased the transition from a highly alert state (fast γ wavelength) to a more synchronized deep-sleeping activity (δ wavelength), which is reflected in the sedative/anxiolytic activity in mice but without the head-twitch response observed in hallucinogens. The functional, radioligand binding, and molecular docking results showed that DM506 binds to the agonist sites of human 5-HT2A (Ki = 24 nM) and 5-HT2B (Ki = 16 nM) receptors and activates them with a potency (EC50) of 9 nM and 3 nM, respectively. DM506 was relatively less potent and behaved as a partial agonist (efficacy <80%) for both receptor subtypes compared to the full agonist DOI (2,5-dimethoxy-4-iodoamphetamine). Our study showed for the first time that the non-hallucinogenic compound DM506 induces anxiolytic- and sedative-like activities in naïve and stressed/anxious mice in a dose-, time-, and volinanserin-sensitive manner, likely through mechanisms involving 5-HT2A receptor activation.

Serotonin 2A Receptor (5-HT2AR) Agonists: Psychedelics and Non-Hallucinogenic Analogues as Emerging Antidepressants.

Psychedelics make up a group of psychoactive compounds that induce hallucinogenic effects by activating the serotonin 2A receptor (5-HT2AR). Clinical trials have demonstrated the traditional psychedelic substances like psilocybin as a class of rapid-acting and long-lasting antidepressants. However, there is a pressing need for rationally designed 5-HT2AR agonists that possess optimal pharmacological profiles in order to fully reveal the therapeutic potential of these agonists and identify safer drug candidates devoid of hallucinogenic effects. This Perspective provides an overview of the structure-activity relationships of existing 5-HT2AR agonists based on their chemical classifications and discusses recent advancements in understanding their molecular pharmacology at a structural level. The encouraging clinical outcomes of psychedelics in depression treatment have sparked drug discovery endeavors aimed at developing novel 5-HT2AR agonists with improved subtype selectivity and signaling bias properties, which could serve as safer and potentially nonhallucinogenic antidepressants. These efforts can be significantly expedited through the utilization of structure-based methods and functional selectivity-directed screening.

A role for the serotonin 2A receptor in the expansion and functioning of human transmodal cortex.

Integrating independent but converging lines of research on brain function and neurodevelopment across scales, this article proposes that serotonin 2A receptor (5-HT2AR) signalling is an evolutionary and developmental driver and potent modulator of the macroscale functional organization of the human cerebral cortex. A wealth of evidence indicates that the anatomical and functional organization of the cortex follows a unimodal-to-transmodal gradient. Situated at the apex of this processing hierarchy-where it plays a central role in the integrative processes underpinning complex, human-defining cognition-the transmodal cortex has disproportionately expanded across human development and evolution. Notably, the adult human transmodal cortex is especially rich in 5-HT2AR expression and recent evidence suggests that, during early brain development, 5-HT2AR signalling on neural progenitor cells stimulates their proliferation-a critical process for evolutionarily-relevant cortical expansion. Drawing on multimodal neuroimaging and cross-species investigations, we argue that, by contributing to the expansion of the human cortex and being prevalent at the apex of its hierarchy in the adult brain, 5-HT2AR signalling plays a major role in both human cortical expansion and functioning. Owing to its unique excitatory and downstream cellular effects, neuronal 5-HT2AR agonism promotes neuroplasticity, learning and cognitive and psychological flexibility in a context-(hyper)sensitive manner with therapeutic potential. Overall, we delineate a dual role of 5-HT2ARs in enabling both the expansion and modulation of the human transmodal cortex.

Established sensitization of ethanol-induced locomotor activity is not reversed by psilocybin or the 5-HT2A receptor agonist TCB-2 in male DBA/2J mice.

RATIONALE: Psychedelic drugs, which share in common 5-HT2A receptor agonist activity, have shown promise in treating alcohol-use disorders (AUDs). Repeated exposure to ethanol (EtOH) induces molecular and behavioural changes reflective of neuroadaptations that may contribute to addiction. Psychedelic drugs can induce neuroplasticity also, raising the possibility that their potential clinical effects in AUD may involve an action to reverse or offset effects of long-term changes induced by EtOH. This possibility was examined by investigating whether psilocybin, or the 5-HT2A receptor agonist TCB-2, counteracted established sensitization of EtOH-induced locomotor activity. METHODS: Male DBA/2J mice received repeated injections of 2.2 g/kg EtOH to induce a sensitized locomotor activity response. In two experiments separate groups of mice were then injected with psilocybin (0, 0.3 and 1 kg/kg) or TCB-2 (0, 1 and 3 mg/kg) on 5 consecutive days. Next, mice were challenged with 1.8 g/kg EtOH and locomotor activity measured for 15 min. RESULTS: Relative to naïve controls, previously sensitized mice showed enhanced locomotor activity to the challenge dose. Despite reducing locomotor activity in their own right psilocybin and TCB-2 did not alter the strength of this sensitized response. CONCLUSION: Psilocybin and TCB-2 at behaviourally effective doses did not reverse sensitization of EtOH-induced activity. This suggests that mechanisms involved in mediating short-term reductions in EtOH intake by psilocybin or TCB-2 may not involve a capacity of these drugs to offset enduring changes in behaviour and any underlying neural adaptations induced by repeated intermittent exposure to EtOH.

Identification of 5-HT2A receptor signaling pathways associated with psychedelic potential.

Serotonergic psychedelics possess considerable therapeutic potential. Although 5-HT2A receptor activation mediates psychedelic effects, prototypical psychedelics activate both 5-HT2A-Gq/11 and ß-arrestin2 transducers, making their respective roles unclear. To elucidate this, we develop a series of 5-HT2A-selective ligands with varying Gq efficacies, including ß-arrestin-biased ligands. We show that 5-HT2A-Gq but not 5-HT2A-ß-arrestin2 recruitment efficacy predicts psychedelic potential, assessed using head-twitch response (HTR) magnitude in male mice. We further show that disrupting Gq-PLC signaling attenuates the HTR and a threshold level of Gq activation is required to induce psychedelic-like effects, consistent with the fact that certain 5-HT2A partial agonists (e.g., lisuride) are non-psychedelic. Understanding the role of 5-HT2A Gq-efficacy in psychedelic-like psychopharmacology permits rational development of non-psychedelic 5-HT2A agonists. We also demonstrate that ß-arrestin-biased 5-HT2A receptor agonists block psychedelic effects and induce receptor downregulation and tachyphylaxis. Overall, 5-HT2A receptor Gq-signaling can be fine-tuned to generate ligands distinct from classical psychedelics.

In Vivo Serotonin 5-HT2A Receptor Availability and Its Relationship with Aggression Traits in Healthy Individuals: A Positron Emission Tomography Study with C-11 MDL100907.

Serotonergic neurotransmission has been associated with aggression in several psychiatric disorders. Human aggression is a continuum of traits, ranging from normal to pathological phenomena. However, the individual differences in serotonergic neurotransmission and their relationships with aggression traits in healthy individuals remain unclear. In this study, we explored the relationship between 5-HT2A receptor availability in vivo and aggression traits in healthy participants. Thirty-three healthy participants underwent 3-Tesla magnetic resonance imaging and positron emission tomography (PET) with [11C]MDL100907, a selective radioligand for 5-HT2A receptors. To quantify 5-HT2A receptor availability, the binding potential (BPND) was derived using the basis function implementation of the simplified reference tissue model, with the cerebellum as the reference region. The participants' aggression levels were assessed using the Buss-Perry Aggression Questionnaire. The voxel-based correlation analysis with age and sex as covariates revealed that the total aggression score was significantly positively correlated with [11C]MDL100907 BPND in the right middle temporal gyrus (MTG) pole, left fusiform gyrus (FUSI), right parahippocampal gyrus, and right hippocampus. The physical aggression subscale score had significant positive correlations with [11C]MDL100907 BPND in the left olfactory cortex, left orbital superior frontal gyrus (SFG), right anterior cingulate and paracingulate gyri, left orbitomedial SFG, left gyrus rectus, left MTG, left inferior temporal gyrus, and left angular gyrus. The verbal aggression subscale score showed significant positive correlations with [11C]MDL100907 BPND in the bilateral SFG, right medial SFG, left FUSI, and right MTG pole. Overall, our findings suggest the possibility of positive correlations between aggression traits and in vivo 5-HT2A receptor availability in healthy individuals. Future research should incorporate multimodal neuroimaging to investigate the downstream effects of 5-HT2A receptor-mediated signaling and integrate molecular and systems-level information in relation to aggression traits.

Beyond the 5-HT2A Receptor: Classic and Nonclassic Targets in Psychedelic Drug Action.

Serotonergic psychedelics, such as psilocybin and LSD, have garnered significant attention in recent years for their potential therapeutic effects and unique mechanisms of action. These compounds exert their primary effects through activating serotonin 5-HT2A receptors, found predominantly in cortical regions. By interacting with these receptors, serotonergic psychedelics induce alterations in perception, cognition, and emotions, leading to the characteristic psychedelic experience. One of the most crucial aspects of serotonergic psychedelics is their ability to promote neuroplasticity, the formation of new neural connections, and rewire neuronal networks. This neuroplasticity is believed to underlie their therapeutic potential for various mental health conditions, including depression, anxiety, and substance use disorders. In this mini-review, we will discuss how the 5-HT2A receptor activation is just one facet of the complex mechanisms of action of serotonergic psychedelics. They also interact with other serotonin receptor subtypes, such as 5-HT1A and 5-HT2C receptors, and with neurotrophin receptors (e.g., tropomyosin receptor kinase B). These interactions contribute to the complexity of their effects on perception, mood, and cognition. Moreover, as psychedelic research advances, there is an increasing interest in developing nonhallucinogenic derivatives of these drugs to create safer and more targeted medications for psychiatric disorders by removing the hallucinogenic properties while retaining the potential therapeutic benefits. These nonhallucinogenic derivatives would offer patients therapeutic advantages without the intense psychedelic experience, potentially reducing the risks of adverse reactions. Finally, we discuss the potential of psychedelics as substrates for post-translational modification of proteins as part of their mechanism of action.

5-HT1A receptor in the central amygdala and 5-HT2A receptor in the basolateral amygdala are involved in social hierarchy in male mice.

Most social animals self-organize into dominance hierarchies that strongly influence their behavior and health. The serotonin (5-HT) system is believed to play an important role in the formation of social hierarchy. 5-HT receptors are abundantly expressed in the amygdala, which is considered as the central node for the perception and learning of social hierarchy. In this study, we assessed the functions of various 5-HT receptor subtypes related to social rank determination in different subregions of the amygdala using the confrontation tube test in mice. We revealed that most adult C57BL/6 J male mice exhibited a linear social rank after a few days of cohousing. The tube test ranks were slightly related to anxiety-like behavioral performance. After the tube test, the amygdala and 5-HT neurons in the dorsal raphe nucleus were activated in lower-rank individuals. Quantitative real-time polymerase chain reaction analysis revealed that despite the high expression of 5-HT1A receptor mRNA in the central amygdala (CeA), 5-HT2A receptor mRNA expression was downregulated in the basolateral amygdala (BLA) in higher-rank individuals. The dominant-subordinate relationship between mouse pairs could be switched via pharmacological modulation of these receptors in CeA and BLA, suggesting that these expression changes are essential for establishing social ranks. Our findings provide novel insights into the divergent functions of 5-HT receptors in the amygdala related to social hierarchy, which is closely related to our health and welfare.