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Journal ArticleDOI: 10.1007/S10571-021-01064-9

The Roles of Serotonin in Neuropsychiatric Disorders.

02 Mar 2021-Cellular and Molecular Neurobiology (Springer US)-pp 1-22
Abstract: The serotonergic system extends throughout the central nervous system (CNS) and the gastrointestinal (GI) tract. In the CNS, serotonin (5-HT, 5-hydroxytryptamine) modulates a broad spectrum of functions, including mood, cognition, anxiety, learning, memory, reward processing, and sleep. These processes are mediated through 5-HT binding to 5-HT receptors (5-HTRs), are classified into seven distinct groups. Deficits in the serotonergic system can result in various pathological conditions, particularly depression, schizophrenia, mood disorders, and autism. In this review, we outlined the complexity of serotonergic modulation of physiologic and pathologic processes. Moreover, we provided experimental and clinical evidence of 5-HT's involvement in neuropsychiatric disorders and discussed the molecular mechanisms that underlie these illnesses and contribute to the new therapies.

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Topics: Serotonergic (62%), Mood disorders (57%), Serotonin pathway (54%) ... read more
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5 results found


Open accessJournal ArticleDOI: 10.3390/MOLECULES26102838
11 May 2021-Molecules
Abstract: Statins are among the most widely used drug classes in the world. Apart from their basic mechanism of action, which is lowering cholesterol levels, many pleiotropic effects have been described so far, such as anti-inflammatory and antiatherosclerotic effects. A growing number of scientific reports have proven that these drugs have a beneficial effect on the functioning of the nervous system. The first reports proving that lipid-lowering therapy can influence the development of neurological and psychiatric diseases appeared in the 1990s. Despite numerous studies about the mechanisms by which statins may affect the functioning of the central nervous system (CNS), there are still no clear data explaining this effect. Most studies have focused on the metabolic effects of this group of drugs, however authors have also described the pleiotropic effects of statins, pointing to their probable impact on the neurotransmitter system and neuroprotective effects. The aim of this paper was to review the literature describing the impacts of statins on dopamine, serotonin, acetylcholine, and glutamate neurotransmission, as well as their neuroprotective role. This paper focuses on the mechanisms by which statins affect neurotransmission, as well as on their impacts on neurological and psychiatric diseases such as Parkinson’s disease (PD), Alzheimer’s disease (AD), vascular dementia (VD), stroke, and depression. The pleiotropic effects of statin usage could potentially open floodgates for research in these treatment domains, catching the attention of researchers and clinicians across the globe.

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1 Citations


Journal ArticleDOI: 10.1016/J.PHARMTHERA.2021.107937
Abstract: Biased agonism (or “functional selectivity”) at G-protein-coupled receptors has attracted rapidly increasing interest as a means to improve discovery of more efficacious and safer pharmacotherapeutics. However, most studies are limited to in vitro tests of cellular signaling and few biased agonists have progressed to in vivo testing. As concerns 5-HT1A receptors, which exert a major control of serotonergic signaling in diverse CNS regions, study of biased agonism has previously been limited by the poor target selectivity and/or partial agonism of classically available ligands. However, a new generation of highly selective, efficacious and druggable agonists has advanced the study of biased agonism at this receptor and created new therapeutic opportunities. These novel agonists show differential properties for G-protein signaling, cellular signaling (particularly pERK), electrophysiological effects, neurotransmitter release, neuroimaging by PET and pharmacoMRI, and behavioral tests of mood, motor activity and side effects. Overall, NLX-101 (a.k.a. F15599) exhibits preferential activation of cortical and brain stem 5-HT1A receptors, whereas NLX-112 (a.k.a. befiradol or F13640) shows prominent activation of 5-HT1A autoreceptors in Raphe nuclei and in regions associated with motor control. Accordingly, NLX-101 is potently active in rodent models of depression and respiratory control, whereas NLX-112 shows promising activity in models of Parkinson's disease across several species – rat, marmoset and macaque. Moreover, NLX-112 has also been labeled with 18F to produce the first agonist PET radiopharmaceutical (known as [18F]-F13640) for investigation of the active state of 5-HT1A receptors in rodent, primate and human. The structure-functional activity relationships of biased agonists have been investigated by receptor modeling and novel compounds have been identified which exhibit increased affinity at 5-HT1A receptors and new profiles of cellular signaling bias, notably for β-arrestin recruitment versus pERK. Taken together, the data suggest that 5-HT1A receptor biased agonists constitute potentially superior pharmacological agents for treatment of CNS disorders involving serotonergic mechanisms.

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Topics: Functional selectivity (56%), Agonist (53%), Receptor (53%) ... read more

1 Citations


Open accessJournal ArticleDOI: 10.1007/S12035-021-02525-4
Abstract: This study aims to identify neuropsychiatric manifestations in neurological Wilson disease (NWD), and their correlation with MRI changes and glutamate excitotoxicity. Forty-three consecutive patients with NWD from a tertiary care teaching hospital were evaluated prospectively who fulfilled the inclusion criteria. The neuropsychiatric evaluation was done using Neuropsychiatric Inventory (NPI) battery that assesses 12 domains including delusion, hallucination, agitation/aggression, dysphoria/depression, anxiety, euphoria, apathy, disinhibition, irritability, aberrant motor activity, appetite change, and abnormal nighttime behavior. Cranial MRI was done using a 3 T machine, and locations of signal changes were noted including the total number of MRI lesions. Serum glutamate level was measured by a fluorescence microplate reader. Abnormal NPI in various domains and total NPI scores were correlated with MRI lesions, serum and urinary copper, and glutamate level. The median age of the patients was 16 years. Forty-one (48.8%) patients had cognitive impairment and 37 (86%) had movement disorder. Neurobehavioral abnormality was detected in all—commonest being agitation (90.7%) followed by appetite change (81.4%), elation (74.4%), irritability (69.8%), anxiety (67.4%), depression (65.1%), apathy (44.2%), night time abnormal behavior (32.6%), aberrant motor behavior (20.9%), delusions (16.3%), and hallucination (18.6%). The thalamic lesion was associated with depression, globus pallidus with depression and anxiety, caudate with anxiety and agitation, brainstem with irritability, and frontal cortex with apathy. Serum glutamate level was higher in NWD. NPI sum score correlated with MRI load and glutamate level. Varying severity of neurobehavioral abnormalities are common in the patients with NWD and correlate with the location of MRI lesion and glutamate level.

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Journal ArticleDOI: 10.1016/J.NEUROPHARM.2021.108782
Antonio Leo1, Carmen De Caro1, P. Mainardi, Martina Tallarico1  +7 moreInstitutions (3)
15 Oct 2021-Neuropharmacology
Abstract: The Microbiota-Gut-Brain axis (MGBA) is a bidirectional communication pathway between gut bacteria and the central nervous system (CNS) (including the intestine) that exerts a profound influence on neural development, neuroinflammation, activation of stress response and neurotransmission, in addition to modulating complex behaviours, such as sociability and anxiety. Several MGBA modulating approaches are possible, such as probiotic administration. A reasonable pharmacological approach would also be the contemporarily administration of both prebiotics and postbiotics. To test this hypothesis, we probed the effects of α-lactalbumin (ALAC; a prebiotic in the dose range of 125–500 mg/kg) and sodium butyrate (NaB; a postbiotic in the dose range of 30–300 mg/kg) alone and in combination. We used two animal behavioural models of idiopathic autism, (BTBR mice) and anxiety/depression (chronic unexpected mild stress - CUMS mice) respectively, using several standard behavioural paradigms such as Three-chamber social interaction test, Marble burying assay, depression-, anxiety- and memory-tests. In BTBR autistic mice, we found that both ALAC and NaB improve animal sociability, and memory in the passive avoidance (PA); drug combination was more effective in almost all tests also reducing immobility time in the forced swimming test (FST), which was not affected by single drug administration. Similarly, in the CUMS mice, single drug administration was effective in improving: 1) depressive-like behaviour in the FST and sucrose preference test; 2) memory and learning in the PA, novel object recognition and Morris water maze tests. Drug combination was again more effective than single drug administration in most cases; however, in the CUMS model, neither single drug or combination was effective in the elevated plus maze test for anxiety. Our results suggest that in both models, ALAC and NaB combination is more effective in improving some pathological aspects of animal behaviour than single administration and that the prebiotic/postbiotic approach should be considered a reasonable approach for the manipulation of the MGBA to improve efficacy.

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211 results found


Journal ArticleDOI: 10.1016/J.BIOPSYCH.2006.02.013
Ronald S. Duman1, Lisa M. Monteggia2Institutions (2)
Abstract: There is a growing body of evidence demonstrating that stress decreases the expression of brain-derived neurotrophic factor (BDNF) in limbic structures that control mood and that antidepressant treatment reverses or blocks the effects of stress. Decreased levels of BDNF, as well as other neruotrophic factors, could contribute to the atrophy of certain limbic structures, including the hippocampus and prefrontal cortex that has been observed in depressed subjects. Conversely, the neurotrophic actions of antidepressants could reverse neuronal atrophy and cell loss and thereby contribute to the therapeutic actions of these treatments. This review provides a critical examination of the neurotrophic hypothesis of depression that has evolved from this work, including analysis of preclinical cellular (adult neurogenesis) and behavioral models of depression and antidepressant actions, as well as clinical neuroimaging and postmortem studies. Although there are some limitations, the results of these studies are consistent with the hypothesis that decreased expression of BDNF and possibly other growth factors contributes to depression and that upregulation of BDNF plays a role in the actions of antidepressant treatment.

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Topics: Brain-derived neurotrophic factor (61%), Neurotrophic factors (59%), Mood disorders (51%) ... read more

2,775 Citations


Open accessJournal ArticleDOI: 10.1038/S41467-018-07771-0
Abstract: The assay for transposase-accessible chromatin using sequencing (ATAC-seq) is widely used to identify regulatory regions throughout the genome. However, very few studies have been performed at the single cell level (scATAC-seq) due to technical challenges. Here we developed a simple and robust plate-based scATAC-seq method, combining upfront bulk Tn5 tagging with single-nuclei sorting. We demonstrate that our method works robustly across various systems, including fresh and cryopreserved cells from primary tissues. By profiling over 3000 splenocytes, we identify distinct immune cell types and reveal cell type-specific regulatory regions and related transcription factors. ATAC-seq is widely used to identify regulatory regions in the genome. Here the authors develop a simple and robust plate-based single-cell ATAC-seq method that works in fresh and cryopreserved cells.

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1,207 Citations


Open accessJournal ArticleDOI: 10.1016/J.NEURON.2012.03.017
07 Jun 2012-Neuron
Abstract: Recent studies indicate that dopamine neurons in the ventral tegmental area (VTA) and substantia nigra pars compacta (SNc) convey distinct signals. To explore this difference, we comprehensively identified each area's monosynaptic inputs using the rabies virus. We show that dopamine neurons in both areas integrate inputs from a more diverse collection of areas than previously thought, including autonomic, motor, and somatosensory areas. SNc and VTA dopamine neurons receive contrasting excitatory inputs: the former from the somatosensory/motor cortex and subthalamic nucleus, which may explain their short-latency responses to salient events; and the latter from the lateral hypothalamus, which may explain their involvement in value coding. We demonstrate that neurons in the striatum that project directly to dopamine neurons form patches in both the dorsal and ventral striatum, whereas those projecting to GABAergic neurons are distributed in the matrix compartment. Neuron-type-specific connectivity lays a foundation for studying how dopamine neurons compute outputs.

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Topics: Medium spiny neuron (63%), Ventral tegmental area (62%), Rostromedial tegmental nucleus (60%) ... read more

896 Citations


Open accessJournal ArticleDOI: 10.1016/J.BRAINRESREV.2008.12.009
Mary M. Heinricher1, Isaura Tavares2, Isaura Tavares3, J L Leith  +1 moreInstitutions (4)
Abstract: The dorsal horn of the spinal cord is the location of the first synapse in pain pathways, and as such, offers a very powerful target for regulation of nociceptive transmission by both local segmental and supraspinal mechanisms. Descending control of spinal nociception originates from many brain regions and plays a critical role in determining the experience of both acute and chronic pain. The earlier concept of descending control as an “analgesia system” is now being replaced with a more nuanced model in which pain input is prioritized relative to other competing behavioral needs and homeostatic demands. Descending control arises from a number of supraspinal sites, including the midline periaqueductal gray-rostral ventromedial medulla (PAG-RVM) system, and the more lateral and caudal dorsal reticular nucleus (DRt) and ventrolateral medulla (VLM). Inhibitory control from the PAG-RVM system preferentially suppresses nociceptive inputs mediated by C-fibers, preserving sensory-discriminative information conveyed by more rapidly conducting A-fibers. Analysis of the circuitry within the RVM reveals that the neural basis for bidirectional control from the midline system is two populations of neurons, ON-cells and OFF-cells, that are differentially recruited by higher structures important in fear, illness and psychological stress to enhance or inhibit pain. Dynamic shifts in the balance between pain inhibiting and facilitating outflows from the brainstem play a role in setting the gain of nociceptive processing as dictated by behavioral priorities, but are also likely to contribute to pathological pain states.

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Topics: Rostral ventromedial medulla (62%), Periaqueductal gray (56%), Chronic pain (55%) ... read more

721 Citations


Open accessJournal ArticleDOI: 10.1038/S41598-018-25980-X
16 May 2018-Scientific Reports
Abstract: We identify the physical mechanism through which newly developed quaternary ammonium salt (QAS) deposit control additives (DCAs) affect the rheological properties of cavitating turbulent flows, resulting in an increase in the volumetric efficiency of clean injectors fuelled with diesel or biodiesel fuels. Quaternary ammonium surfactants with appropriate counterions can be very effective in reducing the turbulent drag in aqueous solutions, however, less is known about the effect of such surfactants in oil-based solvents or in cavitating flow conditions. Small-angle neutron scattering (SANS) investigations show that in traditional DCA fuel compositions only reverse spherical micelles form, whereas reverse cylindrical micelles are detected by blending the fuel with the QAS additive. Moreover, experiments utilising X-ray micro computed tomography (micro-CT) in nozzle replicas, quantify that in cavitation regions the liquid fraction is increased in the presence of the QAS additive. Furthermore, high-flux X-ray phase contrast imaging (XPCI) measurements identify a flow stabilization effect in the region of vortex cavitation by the QAS additive. The effect of the formation of cylindrical micelles is reproduced with computational fluid dynamics (CFD) simulations by including viscoelastic characteristics for the flow. It is demonstrated that viscoelasticity can reduce turbulence and suppress cavitation, and subsequently increase the injector’s volumetric efficiency.

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Topics: Cavitation (51%)

697 Citations