5-HT1A Receptor Function Research Articles

Altered brain serotonin 5-HT1A receptor expression and function in juvenile Fmr1 knockout mice

There are no approved pharmacotherapies for fragile X syndrome (FXS), a rare neurodevelopmental disorder caused by a mutation in the FMR1 promoter region that leads to various symptoms, including intellectual disability and auditory hypersensitivity. The gene that encodes inhibitory serotonin 1A receptors (5-HT1ARs) is differentially expressed in embryonic brain tissue from individuals with FXS, and 5-HT1ARs are highly expressed in neural systems that are disordered in FXS, providing a rationale to focus on 5-HT1ARs as targets to treat symptoms of FXS. We examined agonist-labeled 5-HT1AR densities in male and female Fmr1 knockout mice and found no differences in whole-brain 5-HT1AR expression in adult control compared to Fmr1 knockout mice. However, juvenile Fmr1 knockout mice had lower whole-brain 5-HT1AR expression than age-matched controls. Consistent with these results, juvenile Fmr1 knockout mice showed reduced behavioral responses elicited by the 5-HT1AR agonist (R)-8-OH-DPAT, effects blocked by the selective 5-HT1AR antagonist, WAY-100635. Also, treatment with the selective 5-HT1AR agonist, NLX-112, dose-dependently prevented audiogenic seizures (AGS) in juvenile Fmr1 knockout mice, an effect reversed by WAY-100635. Suggestive of a potential role for 5-HT1ARs in regulating AGS, compared to males, female Fmr1 knockout mice had a lower prevalence of AGS and higher expression of antagonist-labeled 5-HT1ARs in the inferior colliculus and auditory cortex. These results provide preclinical support that 5-HT1AR agonists may be therapeutic for young individuals with FXS hypersensitive to auditory stimuli.

18F]F13640: a selective agonist PET radiopharmaceutical for imaging functional 5-HT1A receptors in humans

PurposeF13640 (a.k.a. befiradol, NLX-112) is a highly selective 5-HT1A receptor ligand that was selected as a PET radiopharmaceutical-candidate based on animal studies. Due to its high efficacy agonist properties, [18F]F13640 binds preferentially to functional 5-HT1A receptors, which are coupled to intracellular G-proteins. Here, we characterize brain labeling of 5-HT1A receptors by [18F]F13640 in humans and describe a simplified model for its quantification.MethodsPET/CT and PET-MRI scans were conducted in a total of 13 healthy male volunteers (29 ± 9 years old), with arterial input functions (AIF) (n = 9) and test–retest protocol (n = 8). Several kinetic models were compared (one tissue compartment model, two-tissue compartment model, and Logan); two models with reference region were also evaluated: simplified reference tissue model (SRTM) and the logan reference model (LREF).Results[18F]F13640 showed high uptake values in raphe nuclei and cortical regions. SRTM and LREF models showed a very high correlation with kinetic models using AIF. As concerns test–retest parameters and the prolonged binding kinetics of [18F]F13640, better reproducibility, and reliability were found with the LREF method. Cerebellum white matter and frontal lobe white matter stand out as suitable reference regions.ConclusionThe favorable brain labeling and kinetic profile of [18F]F13640, its high receptor specificity and its high efficacy agonist properties open new perspectives for studying functionally active 5-HT1A receptors, unlike previous radiopharmaceuticals that act as antagonists. [18F]F13640’s kinetic properties allow injection outside of the PET scanner with delayed acquisitions, facilitating the design of innovative longitudinal protocols in neurology and psychiatry.Trial Registration.Trial Registration EudraCT 2017–002,722-21.

Effects of low-doses of methamphetamine on d-fenfluramine-induced head-twitch response (HTR) in mice during ageing and c-fos expression in the prefrontal cortex

BackgroundThe head-twitch response (HTR) in mice is considered a behavioral model for hallucinogens and serotonin 5-HT2A receptor function, as well as Tourette syndrome in humans. It is mediated by 5-HT2A receptor agonists such as ( ±)− 2,5-dimethoxy-4-iodoamphetamine (DOI) in the prefrontal cortex (PFC). The 5-HT2A antagonist EMD 281014, can prevent both DOI-induced HTR during ageing and c-fos expression in different regions of PFC. Moreover, the nonselective monoamine releaser methamphetamine (MA) suppressed DOI-induced HTR through ageing via concomitant activation of inhibitory 5-HT1A receptors, but enhanced DOI-evoked c-fos expression. d-Fenfluramine is a selective 5-HT releaser and induces HTR in mice, whereas MA does not. Currently, we investigated whether EMD 281014 or MA would alter: (1) d-fenfluramine-induced HTR frequency in 20-, 30- and 60-day old mice, (2) d-fenfluramine-evoked c-fos expression in PFC, and (3) whether blockade of inhibitory serotonergic 5-HT1A- or adrenergic ɑ2-receptors would prevent suppressive effect of MA on d-fenfluramine-induced HTR.ResultsEMD 281014 (0.001–0.05 mg/kg) or MA (0.1–5 mg/kg) blocked d-fenfluramine-induced HTR dose-dependently during ageing. The 5-HT1A antagonist WAY 100635 countered the inhibitory effect of MA on d-fenfluramine-induced HTR in 30-day old mice, whereas the adrenergic ɑ2 antagonist RS 79948 reversed MA’s inhibitory effect in both 20- and 30- day old mice. d-Fenfluramine significantly increased c-fos expressions in PFC regions. MA (1 mg/kg) pretreatment significantly increased d-fenfluramine-evoked c-fos expression in different regions of PFC. EMD 281014 (0.05 mg/kg) failed to prevent d-fenfluramine-induced c-fos expression, but significantly increased it in one PFC region (PrL at − 2.68 mm).ConclusionEMD 281014 suppressed d-fenfluramine-induced HTR but failed to prevent d-fenfluramine-evoked c-fos expression which suggest involvement of additional serotonergic receptors in the mediation of evoked c-fos. The suppressive effect of MA on d-fenfluramine-evoked HTR is due to well-recognized functional interactions between stimulatory 5-HT2A- and the inhibitory 5-HT1A- and ɑ2-receptors. MA-evoked increases in c-fos expression in PFC regions are due to the activation of diverse monoaminergic receptors through increased synaptic concentrations of 5-HT, NE and/or DA, which may also account for the additive effect of MA on d-fenfluramine-evoked changes in c-fos expression. Our findings suggest potential drug receptor functional interaction during development when used in combination.

Altered Serotonin 2A (5-HT2A) Receptor Signaling Underlies Mild TBI-Elicited Deficits in Social Dominance.

Various forms of traumatic brain injury (TBI) are a leading cause of disability in the United States, with the generation of neuropsychiatric complications such as depression, anxiety, social dysfunction, and suicidality being common comorbidities. Serotonin (5-HT) signaling is linked to psychiatric disorders; however, the effects of neurotrauma on normal, homeostatic 5-HT signaling within the central nervous system (CNS) have not been well characterized. We hypothesize that TBI alters specific components of 5-HT signaling within the CNS and that the elucidation of specific TBI-induced alterations in 5-HT signaling may identify novel targets for pharmacotherapies that ameliorate the neuropsychiatric complications of TBI. Herein, we provide evidence that closed-head blast-induced mild TBI (mTBI) results in selective alterations in cortical 5-HT2A receptor signaling. We find that mTBI increases in vivo cortical 5-HT2A receptor sensitivity and ex vivo radioligand binding at time points corresponding with mTBI-induced deficits in social behavior. In contrast, in vivo characterizations of 5-HT1A receptor function revealed no effect of mTBI. Notably, we find that repeated pharmacologic activation of 5-HT2A receptors post-injury reverses deficits in social dominance resulting from mTBI. Cumulatively, these studies provide evidence that mTBI drives alterations in cortical 5-HT2A receptor function and that selective targeting of TBI-elicited alterations in 5-HT2A receptor signaling may represent a promising avenue for the development of pharmacotherapies for TBI-induced generation of neuropsychiatric disorders.

Effect of Central Administration of Brain-Derived Neurotrophic Factor (BDNF) on Behavior and Brain Monoamine Metabolism in New Recombinant Mouse Lines Differing by 5-HT1A Receptor Functionality.

Experiments were carried out on recombinant B6.CBA-D13Mit76C (B6-M76C) and B6.CBA-D13Mit76B (B6-M76B) mouse lines created by transferring a 102.73–118.83 Mbp fragment of chromosome 13, containing the 5-HT1A receptor gene, from CBA or C57BL/6 strains to a C57BL/6 genetic background, correspondingly. We have recently shown different levels of 5-HT1A receptor functionality in these mouse lines. The administration of BDNF (300 ng/mouse, i.c.v.) increased the levels of exploratory activity and intermale aggression only in B6-M76B mice, without affecting depressive-like behavior in both lines. In B6-M76B mice the behavioral alterations were accompanied by a decrease in the 5-HT2A receptor functional activity and the augmentation of levels of serotonin and its main metabolite, 5-HIAA (5-hydroxyindoleacetic acid), in the midbrain. Moreover, the levels of dopamine and its main metabolites, HVA (homovanillic acid) and DOPAC (3,4-dihydroxyphenylacetic acid), were also elevated in the striatum of B6-M76B mice after BDNF treatment. In B6-M76C mice, central BDNF administration led only to a reduction in the functional activity of the 5-HT1A receptor and a rise in DOPAC levels in the midbrain. The obtained data suggest the importance of the 102.73–118.83 Mbp fragment of mouse chromosome 13, which contains the 5-HT1A receptor gene, for BDNF-induced alterations in behavior and the brain monoamine system.

Influence of 5-HT2A receptor function on anxiety-like behavior induced by a combination treatment with doxorubicin and cyclophosphamide in rats.

Anxiety-like behavior induced by a combination of doxorubicin and cyclophosphamide may be mediated by serotonin (5-HT)2A receptor hyperactivity. The anxiolytic effects of fluoxetine may be inhibited by this combination. The present study examined the mechanisms underlying anxiety-like behavior induced by the combination doxorubicin and cyclophosphamide in rats. Anxiety-like behavior was induced during a light-dark test by the doxorubicin and cyclophosphamide treatment (once a week for 2weeks). 5-HT2A receptor and 5-HT2A receptor-mediated extracellular signal-related kinase (ERK)1/2 levels were measured using Western blotting. 5-HT reuptake activity in fluoxetine-treated rats was also examined using microdialysis. ( ±)-1-(2,5-Dimethoxy-4-iodophenyl)-2-aminopropane, a 5-HT2A receptor agonist, induced anxiety-like behavior. The fluoxetine treatment increased extracellular 5-HT concentrations in the hippocampus of vehicle- and doxorubicin and cyclophosphamide-treated rats. 5-HT transporter levels in the hippocampus were not affected by chemotherapy. The doxorubicin and cyclophosphamide treatment did not alter 5-HT2A receptor levels in the frontal cortex. However, chemotherapy increased 5-HT2A receptor-mediated ERK1/2 phosphorylation levels significantly more than the vehicle treatment. The present results suggest that anxiety-like behavior induced by the combination of doxorubicin and cyclophosphamide is mediated by 5-HT2A receptor hyperactivity without an increase in 5-HT2A receptor levels in rats.

5-HT4 Receptors Are Not Involved in the Effects of Fluoxetine in the Corticosterone Model of Depression.

Clinical and preclinical studies report the implication of 5-hydroxytryptamine 4 receptors (5-HT4Rs) in depression and anxiety. Here, we tested whether the absence of 5-HT4Rs influences the response to the antidepressant fluoxetine in mice subjected to chronic corticosterone administration, an animal model of depression and anxiety. Therefore, the effects of chronic administration of fluoxetine in corticosterone-treated wild-type (WT) and 5-HT4R knockout (KO) mice were evaluated in the open-field and novelty suppressed feeding tests. As 5-HT1A receptor (5-HT1AR) and brain-derived neurotrophic factor (BDNF) are critically involved in depression and anxiety, we further evaluated 5-HT1A receptor functionality by [35S]GTPγS autoradiography and BDNF mRNA expression by in situ hybridization techniques. We found that 5-HT4R KO and WT mice displayed anxiety- and depressive-like behavior following chronic administration of corticosterone, as evidenced in the open-field and novelty suppressed feeding tests. In the open-field, a decreased central activity was observed in naïve and corticosterone-treated mice of both genotypes following chronic fluoxetine administration. In the novelty suppressed feeding test, a predictive paradigm of antidepressant activity, chronic treatment with fluoxetine reverted the latency to eat in both genotypes. The antidepressant also potentiated the corticosterone-induced desensitization of the 5-HT1AR in the dorsal raphe nucleus. Further, chronic fluoxetine increased BDNF mRNA expression in the dentate gyrus of the hippocampus in corticosterone-treated mice of both genotypes. Therefore, our findings indicate that the behavioral effects of fluoxetine in the corticosterone model of depression and anxiety appear not to be dependent on 5-HT4Rs.

Increased behavioral and neuronal responses to a hallucinogenic drug after adolescent toluene exposure in mice: Effects of antipsychotic treatment

Toluene has been characterized as a non-classical hallucinogen drug through activation of 5-HT2A receptors and antagonism of NMDA receptors. It remains unclear whether psychotic symptoms after long-term and intense toluene exposure are associated with abnormalities in 5-HT2A receptor function. The present study examined whether the responses to a hallucinogenic 5-HT2A receptor agonist 2,5-dimethoxy-4-iodoamphetamine (DOI) were altered in a mouse model of toluene psychosis. Male NMRI mice were subchronically treated with toluene during adolescence. Reciprocal social interaction test and novel object recognition test were conducted to confirm the persistent behavioral deficits in adulthood. Subsequently, DOI-induced head twitch, c-Fos and Egr-2 expression, field potentials in the medial prefrontal cortex (mPFC), and the levels of 5-HT2A, 5-HT1A and mGlu2 receptors in the mPFC were monitored. Toluene exposure during adolescence produced social and memory impairments and enhanced DOI–induced behavioral, molecular and electrophysiological responses, but did not change the levels of 5-HT2A, 5-HT1A or mGlu2 receptors in the mPFC. Moreover, the effects of haloperidol and risperidone on the behavioral deficits and hyper-responsiveness to DOI after adolescent toluene exposure were compared. When administered after adolescent toluene exposure, risperidone could reverse social withdrawal, cognitive impairment and hypersensitivity to DOI, whereas haloperidol was only beneficial for social withdrawal. These findings suggest that increased functionality of 5-HT2A receptors may play a critical role in solvent-induced psychosis and recommend the antipsychotics with more selective 5-HT2A receptor antagonism as the first-line treatment for solvent-induced psychosis.

Key role of 5-HT1A receptors in the modulation of the neuronal network underlying the respiratory rhythm generation in lampreys.

In mammals, 5-HTexcitatory respiratory effects imply 5-HT1A receptor-mediated disinhibition of pre-Bötzinger complex neurons. In the lamprey, 5-HT1A receptors are involved in the neural control of locomotion, but their role in the respiratory regulation, particularly at the level of the putative respiratory rhythm generator, the paratrigeminal respiratory group (pTRG), is not known. We here investigate the respiratory function of inhibitory 5-HT1A receptors within the pTRG of the isolated brainstem of the adult lamprey. The 5-HT1A receptor agonists either bath applied or microinjected into the pTRG did not cause significant effects. However, the selective 5-HT1A receptor antagonist (S)-WAY 100135 bath applied or microinjected into the pTRG induced depressing respiratory effects or even apnoea, thus revealing that 5-HT exerts a 5-HT1A receptor-mediated potent tonic influence on respiration and contributes to maintain baseline levels of respiratory activity. Microinjections of strychnine or bicuculline, either alone or in combination, into the pTRG prevented (S)-WAY 100135-induced apnoea. In addition, immunohistochemical studies corroborate the present findings suggesting that 5-HT1A receptors are widely expressed in close apposition to the soma of glycine-immunoreactive cells located within the pTRG region. The results show that in the lamprey respiratory network, 5-HT exerts a tonic influence on respiration by a potent inhibitory control on both GABAergic and glycinergic mechanisms. The observed disinhibitory effects resemble the excitatory respiratory modulation exerted by 5-HT1A receptor-mediated inhibition of glycinergic and/or GABAergic neurons present in mammals, supporting the notion that some features of the neuronal network subserving respiratory rhythm generation are highly conserved throughout phylogeny.

β-Catenin Role in the Vulnerability/Resilience to Stress-Related Disorders Is Associated to Changes in the Serotonergic System

We previously reported that the inactivation (cKO) or the stabilization (cST) of β-catenin in cells expressing the astrocyte-specific glutamate aspartate transporter (GLAST) is associated with the vulnerability or resilience to exhibit anxious/depressive-like behaviors, respectively, and to changes in hippocampal proliferation. Here, we used these cKO and cST β-catenin mice to study the serotonergic system functionality associated with their behavioral/molecular phenotype. The activity of 5-HT1A receptors was assessed by (+)-8-OH-DPAT-induced hypothermia and [35S]GTPγS binding autoradiography. The animals' response to acute stress and the levels of extracellular serotonin (5-HT) in the medial prefrontal cortex (mPFC) were also assessed. cKO mice presented higher 5-HT1A autoreceptor functionality, lower 5-HT1A heteroreceptor functionality, and a decrease in extracellular 5-HT levels in the mPFC. These neurochemical changes were accompanied with a blunted physiological response to stress-induced hyperthermia. In contrast, cST mice showed a reduced 5-HT1A autoreceptor functionality and higher extracellular 5-HT levels in the mPFC after fluoxetine administration. Moreover, cST mice subjected to chronic corticosterone administration did not show a blunted response to fluoxetine. Our findings suggest the existence of a link between β-catenin levels and 5-HT1A receptor functionality, which may be relevant to understand the neurobiological bases underlying the vulnerability or resilience to stress-related disorders.

Enhanced aggressive phenotype of Tph2 knockout rats is associated with diminished 5-HT1A receptor sensitivity

Brain serotonin (5-HT) plays a key role in aggressive behaviours and related psychopathologies, but its precise mechanism of action remains elusive. Genetic animal models may provide a tool to elucidate the relationship between aggression and serotonin. The present study showed that tryptophan hydroxylase 2 (Tph2) knockout (KO) rats, which exhibit profoundly diminished extracellular serotonin levels, display increased aggressiveness compared to their Tph2 wildtype (WT) counterparts. However, the level of aggression in Tph2 KO rats did not equal that of feral wild type Groningen (WTG) rats. To investigate whether enhanced 5-HT1A receptor functionality may be present in Tph2 KO rats, we tested the acute anti-aggressive potency of the highly selective 5-HT1A receptor full agonist NLX-112 (a.k.a. befiradol or F13640). Data show that compared to Tph2 WT and WTG rats, the NLX-112 dose-effect curve was shifted to the right in Tph2 KO animals. These results suggest that, unlike previous reports in Tph2 KO mice, Tph2 KO rats have a decreased 5-HT1A receptor sensitivity compared to both Tph2 WT and WTG animals.

PET Neuroimaging Reveals Serotonergic and Metabolic Dysfunctions in the Hippocampal Electrical Kindling Model of Epileptogenesis

Glucose metabolism and serotonergic neurotransmission have been reported to play an important role in epileptogenesis. We therefore aimed to use neuroimaging to evaluate potential alterations in serotonin 5-HT1A receptor and glucose metabolism during epileptogenesis in the rat electrical kindling model.To achieve this goal, we performed positron emission tomography (PET) imaging in a rat epileptogenesis model triggered by electrical stimulation of the hippocampus using 2-deoxy-2-[18F]fluoro-D-glucose (18F-FDG), a radiolabeled analog of glucose, and 2′-methoxyphenyl-(N-2′-pyridinyl)-p-18F-fluoro-benzamidoethylpiperazine (18F-MPPF), a radiolabeled 5-HT1A receptor ligand, to evaluate brain metabolism and 5-HT1A receptor functionality. Since the 5-HT1A receptor is also highly expressed in astrocytes, glial fibrillary acidic protein (GFAP) immunofluorescence was performed to detect astrogliosis arising from the kindling procedure once the study was finalized. Lastly, in vitro18F-MPPF autoradiography was performed to evaluate changes in 5HT1A receptor expression.18F-FDG PET showed reduction of glucose uptake in cortical structures, whereas 18F-MPPF PET revealed an enhancement of tracer binding potential (BPND) in key areas rich in 5-HT1A receptor involved in epilepsy, including septum, hippocampus and entorhinal cortex of kindled animals compared to controls. However, in vitro 5-HT1A receptor autoradiography showed no changes in densitometric signal in any brain region, suggesting that the augmentation in BPND found by PET could be caused by reduction of synaptic serotonin. Importantly, astroglial activation was detected in the hippocampus of kindled rats.Overall, electrical kindling induced hypometabolism, astrogliosis and serotonergic alterations in epilepsy-related regions. Furthermore, the present findings point to 5-HT1A receptor as a valuable epileptogenesis biomarker candidate and a potential therapeutic target.

5-Hydroxytryptamine1a receptors on tumour cells induce immune evasion in lung adenocarcinoma patients with depression via autophagy/pSTAT3

BackgroundCancer patients frequently suffer from fatigue and depression. Dysregulation of the immune system, tumour recurrence and metastasis are more common in cancer patients with depression. 5-Hydroxytryptamine (5-HT), a neurotransmitter, contributes to immune evasion in lung adenocarcinoma patients by activating 5-HTRs, but the mechanism for this phenomenon is still unclear. In this study, we examined the function of 5-HT1a receptors (5-HT1aRs) in immune evasion in a mouse model and in samples from lung adenocarcinomas patients. Experimental designSixty-four human lung adenocarcinoma patients with depression and 64 lung adenocarcinoma patients without depression were recruited for this study. The expression of 5-HT receptors on lung adenocarcinoma cells from tumour tissues were detected by using immunohistochemistry (IHC) and fluorescence-activated cell sorting (FACS). The depression models were established in vitro and in vivo. The effects of immunosuppression were evaluated by testing the function of cytotoxic lymphocyte (CTLs) and Tregs, measuring tumour weight or volume, assessing the survival of mice and staining of tissues by IHC. Changes in the expression of immunoregulatory factor genes were assessed to elucidate the mechanism of immune evasion induced by the 5- hydroxytryptamine receptor (HTRs). ResultsHigher levels of 5-HT, increased expression of 5-HT1Rs and decreased overall survival were observed in lung adenocarcinomas patients with depression compared with those without depression. Moreover, 5-HT1aR, a critical factor for increasing the number of CD4+CD25+Foxp3+ Treg cells and decreasing the ratio of Th1/Th2 cells, which suggested immune system dysregulation. In addition, expression of 5-HT1aR on tumour cells was also negatively associated with CTL activity in both peripheral blood and tumour infiltrating lymphocytes. In a depressive state, 5-HT1aR activates p-signal transducer and activator of transcription 3 (STAT3) and autophagy, and programmed death ligand-1, a downstream gene of autophagy/p-STAT3 signalling, mediates an immunosuppressive environment. Moreover, in both the mouse model and lung adenocarcinoma patients, the activation of 5HT1aR and the elevated tumour autophagy/p-STAT3 axis were associated with reduced overall survival. ConclusionsThe 5-HT1aR/autophagy/p-STAT3 axis influences both tumour cells and immune cells, resulting in immunosuppression in lung adenocarcinomas patients with depression.

The adrenergic receptor antagonist carvedilol interacts with serotonin 2A receptors both in vitro and in vivo

There is increasing support for the potential clinical use of compounds that interact with serotonin 2A (5-HT2A) receptors. It is therefore of interest to discover novel compounds that interact with 5-HT2A receptors. In the present study, we used computational chemistry to identify critical ligand structural features of 5-HT2A receptor binding and function. Query of compound databases using those ligand features revealed the adrenergic receptor antagonist carvedilol as a high priority match. As carvedilol is used clinically for cardiovascular diseases, we conducted experiments to assess whether it has any interactions with 5-HT2A receptors. In vitro experiments demonstrated that carvedilol has high nanomolar affinity for 5-HT2A receptors. In vivo experiments demonstrated that carvedilol increases the ethanol-induced loss of the righting reflex and suppresses operant responding in mice, and that these effects are attenuated by pretreatment with the selective 5-HT2A receptor antagonist M100907. Moreover, carvedilol did not induce the head-twitch response in mice, suggesting a lack of psychedelic effects. However, carvedilol did not activate canonical 5-HT2A receptor signaling pathways and antagonized serotonin-mediated signaling. It also reduced the head-twitch response induced by 2,5-Dimethoxy-4-iodoamphetamine, suggesting potential in vivo antagonism, allosteric modulation, or functional bias. These data suggest that carvedilol has functionally relevant interactions with 5-HT2A receptors, providing a novel mechanism of action for a clinically used compound. However, our findings do not clearly delineate the precise mechanism of action of carvedilol at 5-HT2A receptors, and additional experiments are needed to elucidate the role of 5-HT2A receptors in the behavioral and clinical effects of carvedilol.

Serotonin 2A receptors are a stress response system: implications for post-traumatic stress disorder

Serotonin, one of the first neurotransmitters to be identified, is an evolutionarily old molecule that is highly conserved across the animal kingdom, and widely used throughout the brain. Despite this, ascribing a specific set of functions to brain serotonin and its receptors has been difficult and controversial. The 2A subtype of serotonin receptors (5-HT2A receptor) is the major excitatory serotonin receptor in the brain and has been linked to the effects of drugs that produce profound sensory and cognitive changes. Numerous studies have shown that this receptor is upregulated by a broad variety of stressors, and have related 5-HT2A receptor function to associative learning. This review proposes that stress, particularly stress related to danger and existential threats, increases the expression and function of 5-HT2A receptors. It is argued that this is a neurobiological adaptation to promote learning and avoidance of danger in the future. Upregulation of 5-HT2A receptors during stressful events forms associations that tune the brain to environmental cues that signal danger. It is speculated that life-threatening situations may activate this system and contribute to the symptoms associated with post-traumatic stress disorder (PTSD). 3,4-Methylenedioxymethamphetamine, which activates 5-HT2A receptors, has been successful in the treatment of PTSD and has recently achieved status as a breakthrough therapy. An argument is presented that 3,4-methylenedioxymethamphetamine may paradoxically act through these same 5-HT2A receptors to ameliorate the symptoms of PTSD. The central thematic contention is that a key role of serotonin may be to function as a stress detection and response system.

Revised Pharmacophore Model for 5-HT2A Receptor Antagonists Derived from the Atypical Antipsychotic Agent Risperidone.

Pharmacophore models for 5-HT2A receptor antagonists consist of two aromatic/hydrophobic regions at a given distance from a basic amine. We have previously shown that both aromatic/hydrophobic moieties are unnecessary for binding or antagonist action. Here, we deconstructed the 5-HT2A receptor antagonist/serotonin-dopamine antipsychotic agent risperidone into smaller structural segments that were tested for 5-HT2A receptor affinity and function. We show, again, that the entire risperidone structure is unnecessary for retention of affinity or antagonist action. Replacement of the 6-fluoro-3-(4-piperidinyl)-1,2-benz[ d]isoxazole moiety by isosteric tryptamines resulted in retention of affinity and antagonist action. Additionally, 3-(4-piperidinyl)-1,2-benz[ d]isoxazole (10), which represents less than half the structural features of risperidone, retains both affinity and antagonist actions. 5-HT2A receptor homology modeling/docking studies suggest that 10 binds in a manner similar to risperidone and that there is a large cavity to accept various N4-substituted analogues of 10 such as risperidone and related agents. Alterations of this "extended" moiety improve receptor binding and functional potency. We propose a new risperidone-based pharmacophore for 5-HT2A receptor antagonist action.

Acute stress effect on hypothalamus BDNF expression, monoamines levels and adrenal catecholamines in mouse lines differed by 5-HT1A receptor function

Homicide is a leading cause of death across the U.S., and it disproportionally affects Blacks in urban areas. This study fills a gap in the literature by examining homicide mortality and Black–White homicide disparities in the 30 biggest U.S. cities and for the entire U.S. across 2 time periods (2008–2012 and 2013–2017).Using data from the National Vital Statistics System for 2008–2017, this study calculated age-adjusted homicide mortality rates (per 100,000) for the total, White, and Black populations in the 30 biggest cities, and the U.S. Black-to-White rate ratios were calculated to examine homicide mortality across the time periods. Data were analyzed in 2020.A total of 26 cities were included in the final analysis. Results show that U.S. homicides increased slightly but significantly across the time periods (p<0.05). A total of 6 cities saw significant increases in homicides and 5 saw significant decreases. Homicide mortality rates were 1.8 times to >20 times greater for Blacks than for Whites, and these disparities persisted across the time periods for most cities. Only 2 of 26 cities had mortality rates and racial inequities in rates that were lower than the national average.Homicide mortality increased slightly across the U.S. and most cities from 2008 to 2017. The majority of cities faced high homicide mortality rates and large inequities. Black–White disparities in homicide remain substantial at the national and city levels. These findings can inform city leaders in their efforts to address the homicide, violence, and racial inequities associated with them through the implementation of policies and programs.

Reduced cortical serotonin 5-HT2A receptor binding and glutamate activity in high compulsive drinker rats

Serotonin2A receptors and glutamate signaling have been implicated in the pathophysiology and treatment of compulsive spectrum disorders. Schedule-Induced Polydipsia (SIP), characterized by excessive drinking under intermittent food reinforcement schedules, is a valid model for studying the compulsive phenotype in rats. We explored the expression, function, and neurochemistry of 5-HT2A receptors in the frontal cortex (FC) of rats with individual differences to compulsivity. Rats were selected for high (HD) versus low (LD) drinking on SIP. First, we measured 5-HT2A, 5-HT1A, and mGlu2/3 receptors and serotonin transporter binding in different brain regions. Second, we assessed the effect of microinfusion into the medial prefrontal cortex (mPFC) of the 5-HT2A/C receptor agonist DOI, the mGlu2/3 agonist LY379268, and the combination of DOI with the 5-HT2A receptor antagonist M100907 and the 5-HT2C receptor antagonist SB242084. Finally, we measured the serotonin and glutamate efflux in mPFC in basal condition and after DOI local application. The compulsive HD rats showed a specific reduction of 5-HT2A receptor binding in FC compared to LD rats. The highest dose of DOI reduced compulsive drinking in HD rats on SIP, whereas LY379268 did not induce any significant effect. The 5-HT2A receptor antagonist M100907 reversed the DOI induced reduction on compulsive drinking in HD rats while blocking the 5-HT2C receptor did not affect SIP. Compulsive HD rats showed increased serotonin and decreased glutamate efflux in basal conditions that were modified by the DOI application. These findings indicate that reduced 5-HT2A receptor binding and glutamate neurochemical mechanisms may underlie compulsive behavior vulnerability.

Cav1.2 L-type calcium channels regulate stress coping behavior via serotonin neurons

Human genetic variation in the gene CACNA1C, which codes for the alpha-1c subunit of Cav1.2 L-type calcium channels (LTCCs), has been broadly associated with enhanced risk for neuropsychiatric disorders including major depression, bipolar and schizophrenia. Little is known about the specific neural circuits through which CACNA1C and Cav1.2 LTCCs impact disease etiology. However, serotonin (5-HT) neurotransmission has been consistently implicated in these neuropsychiatric disorders and Cav1.2 LTCCs may influence 5-HT neuron activity during relevant behavioral states such as stress. We utilized a temporally controlled and 5-HT neuron specific Cacna1c knockout mouse model to assess stress-coping behavior using the forced swim test and dorsal raphe (DR) 5-HT neuron Fos activation. Furthermore, we assessed 5-HT1A receptor function and feedback inhibition of the DR following administration of the 5-HT1A antagonist WAY-100635. We find that 5-HT neuron Cacna1c knockout disrupts active-coping behavior in the forced swim test and that this behavioral effect is rescued by blocking 5-HT1A receptors. Moreover, Cacna1c knockout mice display enhanced Fos expression in caudal DR 5-HT neurons and an enhanced response to a 5-HT1A receptor antagonist in rostral DR 5-HT neurons, indicating that loss of Cacna1c disrupts both 5-HT neuron activation and 5-HT1A dependent feedback inhibition across the caudal to rostral DR. Collectively, these results reveal an important role for 5-HT neuron Cav1.2 LTCCs in stress-coping behavior and 5-HT1A receptor function. This suggests that alterations in CACNA1C function or expression could influence the development or treatment of neuropsychiatric disorder through serotonergic mechanisms.

The putative lithium-mimetic ebselen reduces impulsivity in rodent models.

Deficits in impulse control feature in many psychiatric conditions including bipolar disorder, suicidality and addictions. Lithium lowers impulsivity in clinical populations and decreases pathological gambling in experimental medicine studies, but suffers from adverse effects, poor compliance and a low therapeutic index. Recently we identified that the neuroprotective agent ebselen, which is reportedly safe in humans, inhibited inositol monophosphatase (IMPase), a candidate lithium mechanism. Ebselen also reduced 5-HT receptor (5-HT2A) function which predicts impulsivity lowering properties. Here we investigated the effect of ebselen in rat models of impulsive behaviour. Ebselen was tested in two models of impulsivity with human analogues: the five-choice serial reaction time task (5-CSRTT) and rodent gambling task (rGT). The main outcome measures were premature responses (5-CSRTT and rGT) and choice behaviour (rGT), which model motor impulsivity and choice impulsivity, respectively. At doses that decreased 5-HT2A receptor function (DOI-induced wet dog shakes), ebselen decreased premature responding in the 5-CSRTT both in the absence and presence of cocaine. The 5-HT2A receptor antagonist MDL 100,907 also reduced premature responding in the 5-CSRTT although not in the presence of cocaine. In the rGT ebselen showed a tendency to reduce premature responding but had no effect on choice behaviour. These findings suggest that ebselen preferentially reduces motor impulsivity over choice impulsivity, and that inhibition of 5-HT2A receptor function is a contributing mechanism. Collectively, these data support the repurposing of ebselen as an anti-impulsive treatment and fast-tracking to clinical trials in patient groups characterised by poor impulse control.