Showing papers on "Serotonin published in 2023"

Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors

Abstract: Decreased dendritic spine density in the cortex is a hallmark of several neuropsychiatric diseases, and the ability to promote cortical neuron growth has been hypothesized to underlie the rapid and sustained therapeutic effects of psychedelics. Activation of 5-hydroxytryptamine (serotonin) 2A receptors (5-HT2ARs) is essential for psychedelic-induced cortical plasticity, but it is currently unclear why some 5-HT2AR agonists promote neuroplasticity, whereas others do not. We used molecular and genetic tools to demonstrate that intracellular 5-HT2ARs mediate the plasticity-promoting properties of psychedelics; these results explain why serotonin does not engage similar plasticity mechanisms. This work emphasizes the role of location bias in 5-HT2AR signaling, identifies intracellular 5-HT2ARs as a therapeutic target, and raises the intriguing possibility that serotonin might not be the endogenous ligand for intracellular 5-HT2ARs in the cortex. Description The mechanism underlying psychedelic action Psychedelic compounds promote cortical structural and functional neuroplasticity through the activation of serotonin 2A receptors. However, the mechanisms by which receptor activation leads to changes in neuronal growth are still poorly defined. Vargas et al. found that activation of intracellular serotonin 2A receptors is responsible for the plasticity-promoting and antidepressant-like properties of psychedelic compounds, but serotonin may not be the natural ligand for those intracellular receptors (see the Perspective by Hess and Gould). —PRS Membrane-permeable psychedelics promote cortical neuron growth by activating intracellular serotonin 2A receptors.

Cardiac Roles of Serotonin (5-HT) and 5-HT-Receptors in Health and Disease

Abstract: Serotonin acts solely via 5-HT4-receptors to control human cardiac contractile function. The effects of serotonin via 5-HT4-receptors lead to positive inotropic and chronotropic effects, as well as arrhythmias, in the human heart. In addition, 5-HT4-receptors may play a role in sepsis, ischaemia, and reperfusion. These presumptive effects of 5-HT4-receptors are the focus of the present review. We also discuss the formation and inactivation of serotonin in the body, namely, in the heart. We identify cardiovascular diseases where serotonin might play a causative or additional role. We address the mechanisms which 5-HT4-receptors can use for cardiac signal transduction and their possible roles in cardiac diseases. We define areas where further research in this regard should be directed in the future, and identify animal models that might be generated to this end. Finally, we discuss in what regard 5-HT4-receptor agonists or antagonists might be useful drugs that could enter clinical practice. Serotonin has been the target of many studies for decades; thus, we found it timely to summarise our current knowledge here.

Pharmacologic Activity of Substituted Tryptamines at 5-Hydroxytryptamine (5-HT)2A Receptor (5-HT2AR), 5-HT2CR, 5-HT1AR, and Serotonin Transporter

Abstract: Novel psychoactive substances, including synthetic substituted tryptamines, represent a potential public health threat. Additionally, some substituted tryptamines are being studied under medical guidance as potential treatments of psychiatric disorders. Characterizing the basic pharmacology of substituted tryptamines will aid in understanding differences in potential for harm or therapeutic use. Using human embryonic kidney cells stably expressing 5-hydroxytryptamine (5-HT)1A, 5-HT2A, and 5-HT2C receptors (5-HT1AR, 5-HT2AR, and 5HT2CR, respectively) or the serotonin transporter (SERT), we measured affinities, potencies and efficacies of 21 substituted tryptamines. With the exception of two 4-acetoxy compounds, substituted tryptamines exhibited affinities and potencies less than one micromolar at the 5-HT2AR, the primary target for psychedelic effects. In comparison, half or more exhibited low affinities/potencies at 5-HT2CR, 5-HT1AR, and SERT. Sorting by the ratio of 5-HT2A to 5-HT2C, 5-HT1A, or SERT affinity revealed chemical determinants of selectivity. We found that although 4-substituted compounds exhibited affinities that ranged across a factor of 100, they largely exhibited high selectivity for 5-HT2ARs versus 5-HT1ARs and 5-HT2CRs. 5-substituted compounds exhibited high affinities for 5-HT1ARs, low affinities for 5-HT2CRs, and a range of affinities for 5-HT2ARs, resulting in selectivity for 5-HT2ARs versus 5-HT2CRs but not versus 5-HT1ARs. Additionally, a number of psychedelics bound to SERT, with non–ring-substituted tryptamines most consistently exhibiting binding. Interestingly, substituted tryptamines and known psychedelic standards exhibited a broad range of efficacies, which were lower as a class at 5-HT2ARs compared with 5-HT2CRs and 5-HT1ARs. Conversely, coupling efficiency/amplification ratio was highest at 5-HT2ARs in comparison with 5-HT2CRs and 5-HT1ARs. SIGNIFICANCE STATEMENT Synthetic substituted tryptamines represent both potential public health threats and potential treatments of psychiatric disorders. The substituted tryptamines tested differed in affinities, potencies, and efficacies at 5-hydroxytryptamine (5-HT)2A, 5-HT2C, and 5HT1A receptors and the serotonin transporter (SERT). Several compounds were highly selective for and coupled very efficiently downstream of 5-HT2A versus 5-HT1A and 5-HT2C receptors, and some bound SERT. This basic pharmacology of substituted tryptamines helps us understand the pharmacologic basis of their potential for harm and as therapeutic agents.

A Preliminary Study on the Interplay between the Serum Levels of Neurotransmitters and Thyroid Hormones for the Evaluation of the Behavioral Phenotype of Dogs

Abstract: Simple Summary The domestic dog (Canis familiaris) represents an ideal model to study the effects of the selection process on motivation in companion animals. The dog’s temperament is related to breed and is controlled by neurotransmitter levels. Measuring these hormonal mediators can confirm or contradict the behavioral standards of the animal breed. The current study showed that in dog breeds classified with different behavioral standards, neurotransmitter values could reveal abnormal behaviors that cannot be assessed with simple ethograms. Abstract A total of 112 dogs (49 males and 63 females) belonging to different breeds (i.e., Boxer, Cirneco dell’Etna, Fonni’s Dog, Labrador, Crossbreed, German Shepherd, Pit Bull, Shar-Pei, Yorkshire) were analyzed to compare the serum concentration of serotonin, dopamine, norepinephrine, prolactin, beta-endorphins, thyroxine (T4), triiodothyronine (T3), thyroid-stimulating hormone (TSH), and assess whether these parameters can be correlated with the behavioral phenotype of the investigated breeds. T4 was above or below the threshold in 61% and 14% of dogs, respectively; T3, in contrast, 41% of dogs showed values below the limit, while 26% above it. TSH was within the reference range in 58% of dogs; 94% of the dogs had prolactin in the reference range and only five animals showed values above the limit. For beta-endorphins, 49% of dogs had values above the limit, while 46% had values within the reference range. Serotonin and dopamine values below physiological limits were found in 62% and 70% of dogs, respectively. Finally, 61% of the dogs showed norepinephrine values within the reference range. The study confirmed that the assessment of the serum values of hormones and neurotransmitters in dogs could be useful to better understand the behavioral phenotype of the animal and could be useful for breeders and trainers for the selection of the most suitable subjects for specific tasks.

Serotonin sensing by microglia conditions the proper development of neuronal circuits and of social and adaptive skills

Abstract: The proper maturation of emotional and sensory circuits requires fine-tuning of serotonin (5-HT) level during early postnatal development. Consistently, dysfunctions of the serotonergic system have been associated with neurodevelopmental psychiatric diseases, including autism spectrum disorders (ASD). However, the mechanisms underlying the developmental effects of 5-HT remain partially unknown, one obstacle being the action of 5-HT on different cell types. Here, we focused on microglia, which play a role in brain wiring refinement, and we investigated whether the control of these cells by 5-HT is relevant for neurodevelopment and spontaneous behaviors in mice. Since the main 5-HT sensor in microglia is the 5-HT2B receptor subtype, we prevented 5-HT signaling specifically in microglia by conditional invalidation of the Htr2b gene in these cells. We observed that abrogating the serotonergic control of microglia during early postnatal development affects the phagolysosomal compartment of these cells and their proximity to dendritic spines and perturbs neuronal circuits maturation. Furthermore, this early ablation of microglial 5-HT2B receptors leads to adult hyperactivity in a novel environment and behavioral defects in sociability and flexibility. Importantly, we show that these behavioral alterations result from a developmental effect, since they are not observed when microglial Htr2b invalidation is induced later, at P30 onward. Thus, a primary alteration of 5-HT sensing in microglia, during a critical time window between birth and P30, is sufficient to impair social and flexibility skills. This link between 5-HT and microglia may explain the association between serotonergic dysfunctions and behavioral traits like impaired sociability and inadaptability to novelty, which are prominent in psychiatric disorders such as ASD.

Exploring the Role of Serotonin as an Immune Modulatory Component in Cardiovascular Diseases

Abstract: Serotonin, also known as 5-hydroxytryptamine (5-HT) is a well-known neurotransmitter in the central nervous system (CNS), but also plays a significant role in peripheral tissues. There is a growing body of evidence suggesting that serotonin influences immune cell responses and contributes to the development of pathological injury in cardiovascular diseases, such as atherosclerosis, as well as other diseases which occur as a result of immune hyperactivity. In particular, high levels of serotonin are able to activate a multitude of 5-HT receptors found on the surface of immune cells, thereby influencing the process of atherosclerotic plaque formation in arteries. In this review, we will discuss the differences between serotonin production in the CNS and the periphery, and will give a brief outline of the function of serotonin in the periphery. In this context, we will particularly focus on the effects of serotonin on immune cells related to atherosclerosis and identify caveats that are important for future research.

Hybrid molecules combining GABA-A and serotonin 5-HT6 receptors activity designed to tackle neuroinflammation associated with depression

Abstract: There is clear evidence that the presence of inflammatory factors and impaired GABA-ergic neurotransmission in depressed patients is associated with poor clinical outcome. We designed hybrid molecules, bearing the GABA molecule assembled with chemical fragments that interact with the serotonin 5-HT6 receptor. Such a combination aimed to curb neuroinflammation, remodel GABA-ergic signaling, and provide antidepressant-like activity. The most promising hybrid 3B exerted nanomolar affinity for 5-HT6 receptors and exerted agonistic properties on GABA-A receptors. Developability studies conferred that 3B exerted favorable drug-like properties and optimal brain penetration. In in vivo studies, 3B exerted robust antidepressant-like activity and proved to be highly effective in reducing levels of oxidative stress markers and the pro-inflammatory cytokine IL-6. The inetersting pharmacological profile of 3B makes it a promising candidate for further development for depression associated with neuroinflammation.

A leaky umbrella has little value: evidence clearly indicates the serotonin system is implicated in depression.

Abstract: A recent “umbrella” review examined various biomarkers relating to the serotonin system, and concluded there was no consistent evidence implicating serotonin in the pathophysiology of depression. We present reasons for why this conclusion is overstated, including methodological weaknesses in the review process, selective reporting of data, over-simplification, and errors in the interpretation of neuropsychopharmacological findings. We use the examples of tryptophan depletion and serotonergic molecular imaging, the two research areas most relevant to the investigation of serotonin, to illustrate this.

Memory and anxiety-like behavior of rats in the plus-maze discriminative avoidance task: Role of serotonergic transmission in the basolateral amygdala.

Abstract: Optimal levels of anxiety are critical to memory consolidation, but maladaptive anxiety can disrupt memory acquisition. Serotonergic activity within the amygdala influences both anxiety-like behavior and aversive memory consolidation. To evaluate the effects of serotoninergic manipulations within the basolateral amygdala (BLA) on anxiety-like behavior and aversive memory in rats tested in the plus-maze discriminative avoidance task (PMDAT). The PMDAT investigates aversive memory and anxiety-like behavior simultaneously in rodents. Three-month-old male Wistar rats received bilateral infusions (1 μL per side) of saline, 8-OH-DPAT (5-HT1 agonist; 10 nmol), WAY100135 (5-HT1 antagonist; 0.9 nmol), ketanserine (5-HT 2 antagonist; 10 nmol), or fluoxetine (serotonin reuptake inhibitor; 1.6 nmol) into the BLA and were submitted to PMDAT training session 15 min later. In the test, 24 hr later, animals were re-exposed to the apparatus without the infusion of drugs, and aversive memory was evaluated. (a) 8-OH-DPAT did not affect memory or anxiety, but impaired avoidance behavior toward the aversive arm during training; (b) fluoxetine, WAY100135 and ketanserin impaired memory formation; (c) ketanserin decreased anxiety-like behavior; and (d) none of the treatments induced motor changes. The results showed that an increase in serotonin (5-HT) availability or the blockade of 5HT1A and 5HT2A BLA receptors impaired aversive memory formation. However, only 5HT2A receptor antagonism induced anxiolytic effects. Thus, both memory and anxiety-like behavior can be modified by changes in serotonergic transmission in the basolateral amygdala, but the effects on both phenomena seem to be mediated by different mechanisms related to serotonergic transmission. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Social stress-induced serotonin dysfunction activates spexin in male Nile tilapia (Oreochromis Niloticus)

Abstract: Significance Spexin (SPX) is a novel neuropeptide involved in multiple biological roles. We recently reported that SPX1a gene expression is up-regulated in the midbrain area during social defeat stress in male Nile tilapia. We identified a strong relationship between serotonin and SPX1a gene expression in vitro and in vivo study during social stress. Our findings suggest that the serotoninergic system is an upstream regulator of SPX during chronic social defeat that reacts to stress-related physiological functions. The novel findings in this study unveil a potential 5-HT-SPX-related antidepressant pathway that will be important to understand the role of SPX in social stress-associated anxiety and psychiatric/behavioral disorders.

A mechanism of uncompetitive inhibition of the serotonin transporter

Abstract: The serotonin transporter (SERT/SLC6A4) is arguably the most extensively studied solute carrier (SLC). During its eponymous action – that is, the retrieval of serotonin from the extracellular space – SERT undergoes a conformational cycle. Typical inhibitors (antidepressant drugs and cocaine), partial and full substrates (amphetamines and their derivatives), and atypical inhibitors (ibogaine analogues) bind preferentially to different states in this cycle. This results in competitive or non-competitive transport inhibition. Here, we explored the action of N -formyl-1,3-bis (3,4-methylenedioxyphenyl)-prop-2-yl-amine (ECSI#6) on SERT: inhibition of serotonin uptake by ECSI#6 was enhanced with increasing serotonin concentration. Conversely, the K M for serotonin was lowered by augmenting ECSI#6. ECSI#6 bound with low affinity to the outward-facing state of SERT but with increased affinity to a potassium-bound state. Electrophysiological recordings showed that ECSI#6 preferentially interacted with the inward-facing state. Kinetic modeling recapitulated the experimental data and verified that uncompetitive inhibition arose from preferential binding of ECSI#6 to the K + -bound, inward-facing conformation of SERT. This binding mode predicted a pharmacochaperoning action of ECSI#6, which was confirmed by examining its effect on the folding-deficient mutant SERT-PG 601,602 AA: preincubation of HEK293 cells with ECSI#6 restored export of SERT-PG 601,602 AA from the endoplasmic reticulum and substrate transport. Similarly, in transgenic flies, the administration of ECSI#6 promoted the delivery of SERT-PG 601,602 AA to the presynaptic specialization of serotonergic neurons. To the best of our knowledge, ECSI#6 is the first example of an uncompetitive SLC inhibitor. Pharmacochaperones endowed with the binding mode of ECSI#6 are attractive, because they can rescue misfolded transporters at concentrations, which cause modest transport inhibition.

Identification of a serotonin N-acetyltransferase from Staphylococcus pseudintermedius ED99

Abstract: Serotonin N-acetyltransferase (SNAT) catalyzes the biosynthesis of N-acetylserotonin (NAS) and N-acetyltryptamine (NAT), two pleiotropic molecules with neurotransmitter functions. Here, we report the identification of a SNAT protein in the genus Staphylococcus. The SNAT gene identified in Staphylococcus pseudintermedius ED99, namely SPSE_0802, encodes a 140 residues-long cytoplasmic protein. The recombinant protein SPSE_0802 was expressed in E. coli BL21 and found to acetylate serotonin (SER) and tryptamine (TRY) as well as other trace amines in vitro. The production of the neuromodulators NAS and NAT was detected in the cultures of different members of the genus Staphylococcus and the role of SPSE_0802 in this production was confirmed in an ED99 SPSE_0802 deletion mutant. A search for SNAT homologues showed that the enzyme is widely distributed across the genus which correlated with the SNAT activity detected in 22 out of the 40 Staphylococcus strains tested. The N-acetylated products of SNAT are precursors for melatonin synthesis and are known to act as neurotransmitters and activate melatonin receptors, among others, inducing various responses in the human body. The identification of SNAT in staphylococci could contribute to a better understanding of the interaction between those human colonizers and the host peripheral nervous system.

Neurexins in serotonergic neurons regulate neuronal survival, serotonin transmission, and complex mouse behaviors

Abstract: Extensive serotonin (5-hydroxytryptamine, 5-HT) innervation throughout the brain corroborates 5-HT’s modulatory role in numerous cognitive activities. Volume transmission is the major mode for 5-HT transmission but mechanisms underlying 5-HT signaling are still largely unknown. Abnormal brain 5-HT levels and function have been implicated in autism spectrum disorder (ASD). Neurexin ( Nrxn ) genes encode presynaptic cell adhesion molecules important for the regulation of synaptic neurotransmitter release, notably glutamatergic and GABAergic transmission. Mutations in Nrxn genes are associated with neurodevelopmental disorders including ASD. However, the role of Nrxn genes in the 5-HT system is poorly understood. Here, we generated a mouse model with all three Nrxn genes disrupted specifically in 5-HT neurons to study how Nrxns affect 5-HT transmission. Loss of Nrxns in 5-HT neurons reduced the number of serotonin neurons in the early postnatal stage, impaired 5-HT release, and decreased 5-HT release sites and serotonin transporter expression. Furthermore, 5-HT neuron-specific Nrxn knockout reduced sociability and increased depressive-like behavior. Our results highlight functional roles for Nrxns in 5-HT neurotransmission, 5-HT neuron survival, and the execution of complex behaviors.

Short- and Long-Term Effects of Cocaine on Enteric Neuronal Functions

Abstract: Cocaine is one of the most consumed illegal drugs among (young) adults in the European Union and it exerts various acute and chronic negative effects on psychical and physical health. The central mechanism through which cocaine initially leads to improved performance, followed by addictive behavior, has already been intensively studied and includes effects on the homeostasis of the neurotransmitters dopamine, partly mediated via nicotinic acetylcholine receptors, and serotonin. However, effects on the peripheral nervous system, including the enteric nervous system, are much less understood, though a correlation between cocaine consumption and gastrointestinal symptoms has been reported. The aim of the present study was to gain more information on the effects of cocaine on enteric neuronal functions and the underlying mechanisms. For this purpose, functional experiments using an organ bath, Ussing chamber and neuroimaging techniques were conducted on gastrointestinal tissues from guinea pigs. Key results obtained are that cocaine (1) exhibits a stimulating, non-neuronal effect on gastric antrum motility, (2) acutely (but not chronically) diminishes responses of primary cultured enteric neurons to nicotinic and serotonergic stimulation and (3) reversibly attenuates neuronal-mediated intestinal mucosal secretion. It can be concluded that cocaine, among its central effects, also alters enteric neuronal functions, providing potential explanations for the coexistence of cocaine abuse and gastrointestinal complaints.

A portable electrochemical sensing platform for serotonin detection based on surface-modified carbon fiber microelectrodes.

Abstract: Serotonin (5-HT) is one of the key neurotransmitters in the human body, regulating numerous physiological functions. A disruption in 5-HT homeostasis could result in serious health problems, including neurodegenerative disorders, depression, and 5-HT syndrome. Detection of 5-HT concentrations in biological fluids, such as urine, is a potential solution for early diagnosis of these diseases. In this study, we developed a novel, simple, and low-cost electrochemical sensing platform consisting of a portable workstation with customized electrodes for 5-HT detection in artificial biological fluids. Nafion/carbon nanotubes (CNTs) and electrochemically modified carbon fiber microelectrodes (Nafion-CNT/EC CFMEs) displayed improved 5-HT sensitivity and selectivity. Together with a customized Ag/AgCl reference electrode and Pt counter electrode, the portable 5-HT sensing platform had a sensitivity of 0.074 μA μM-1 and a limit of detection (LOD) of 140 nM. This system was also assessed to measure 5-HT spiked in artificial urine samples, showing nearly full recovery rates. These satisfactory results demonstrated that the portable system exhibits outstanding performance and confirmed the feasibility of 5-HT detection, which can be used to provide point-of-care analysis in actual biological samples.

Dissecting the Functional Organization of the C. elegans Serotonergic System at Whole-Brain Scale

Abstract: Serotonin controls many aspects of animal behavior and cognition. But how serotonin acts on its diverse receptor types in neurons across the brain to modulate global activity and behavior is unknown. Here, we examine how serotonin release from a feeding-responsive neuron in C. elegans alters brain-wide activity to induce foraging behaviors, like slow locomotion and increased feeding. A comprehensive genetic analysis identifies three core serotonin receptors that collectively induce slow locomotion upon serotonin release and three others that interact with them to further modulate this behavior. The core receptors have different functional roles: some induce behavioral responses to sudden increases in serotonin release, whereas others induce responses to persistent release. Whole-brain calcium imaging reveals widespread serotonin-associated brain dynamics, impacting different behavioral networks in different ways. We map out all sites of serotonin receptor expression in the connectome, which, together with synaptic connectivity, helps predict serotonin-associated brain-wide activity changes. These results provide a global view of how serotonin acts at defined sites across a connectome to modulate brain-wide activity and behavior.

Fluoxetine-induced Hypotension: A Case Report

Abstract: Fluoxetine is a Selective Serotonin Reuptake Inhibitor (SSRI) that exerts its anti-depressive effect by blocking the presynaptic reuptake of the neurotransmitter serotonin, 5-hydroxytryptamine (5-HT). Although fluoxetine is usually considered safe for most patients, in the present case report, we describe a young patient with Mixed Anxiety and Depression Disorder (MADD) treated with fluoxetine 10 mg/day, who developed hypotension when the dosage was titrated up to 20 mg/day. After discontinuing the use of fluoxetine, the symptoms of hypotension improved. A temporal association and dose-dependent relationship between the hypotension and the use of fluoxetine was observed. To the best of our knowledge, this is the first case report that precisely associates regular doses of fluoxetine with the presence of hypotension. Because boosting central serotonergic function lowers blood pressure, it is suggested that a significant effect of fluoxetine on the vasomotor center may be responsible for the reduction of blood pressure. Thus, physicians should be aware of the possible risk of hypotension induced by fluoxetine and recommend patients discontinue the drug immediately if complications have occurred.

Tryptophan Hydroxylase-2-Mediated Serotonin Biosynthesis Suppresses Cell Reprogramming into Pluripotent State

Abstract: The monoamine neurotransmitter serotonin (5-hydroxytryptamine, 5-HT) has important functions both in the neural system and during embryonic development in mammals. In this study, we set out to investigate whether and how endogenous serotonin affects reprogramming to pluripotency. As serotonin is synthesized from tryptophan by the rate limiting enzymes tryptophan hydroxylase-1 and -2 (TPH1 and TPH2), we have assessed the reprogramming of TPH1- and/or TPH2-deficient mouse embryonic fibroblasts (MEFs) to induced pluripotent stem cells (iPSCs). The reprogramming of the double mutant MEFs showed a dramatic increase in the efficiency of iPSC generation. In contrast, ectopic expression of TPH2 alone or in conjunction with TPH1 reverted the rate of reprogramming of the double mutant MEFs to the wild-type level and besides, TPH2 overexpression significantly suppressed reprogramming of wild-type MEFs. Our data thus suggest a negative role of serotonin biosynthesis in the reprogramming of somatic cells to a pluripotent state.