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Current Neuropharmacology 2018Antipsychotic-induced metabolic side effects are major concerns in psychopharmacology and clinical psychiatry. Their pathogenetic mechanisms are still not elucidated. (Review)
Review
BACKGROUND
Antipsychotic-induced metabolic side effects are major concerns in psychopharmacology and clinical psychiatry. Their pathogenetic mechanisms are still not elucidated.
METHODS
Herein, we review the impact of neurotransmitters on metabolic regulation, providing insights into antipsychotic-induced metabolic side effects.
RESULTS
Antipsychotic drugs seem to interfere with feeding behaviors and energy balance, processes that control metabolic regulation. Reward and energy balance centers in central nervous system constitute the central level of metabolic regulation. The peripheral level consists of skeletal muscles, the liver, the pancreas, the adipose tissue and neuroendocrine connections. Neurotransmitter receptors have crucial roles in metabolic regulation and they are also targets of antipsychotic drugs. Interaction of antipsychotics with neurotransmitters could have both protective and harmful effects on metabolism.
CONCLUSION
Emerging evidence suggests that antipsychotics have different liabilities to induce obesity, diabetes and dyslipidemia. However this diversity cannot be explained merely by drugs'pharmacodynamic profiles, highlighting the need for further research.
Topics: Animals; Antipsychotic Agents; Humans; Metabolic Diseases; Receptors, Neurotransmitter
PubMed: 28676017
DOI: 10.2174/1570159X15666170630163616 -
Pharmacological Reviews Oct 2021Many physiologic effects of l-glutamate, the major excitatory neurotransmitter in the mammalian central nervous system, are mediated via signaling by ionotropic... (Review)
Review
Many physiologic effects of l-glutamate, the major excitatory neurotransmitter in the mammalian central nervous system, are mediated via signaling by ionotropic glutamate receptors (iGluRs). These ligand-gated ion channels are critical to brain function and are centrally implicated in numerous psychiatric and neurologic disorders. There are different classes of iGluRs with a variety of receptor subtypes in each class that play distinct roles in neuronal functions. The diversity in iGluR subtypes, with their unique functional properties and physiologic roles, has motivated a large number of studies. Our understanding of receptor subtypes has advanced considerably since the first iGluR subunit gene was cloned in 1989, and the research focus has expanded to encompass facets of biology that have been recently discovered and to exploit experimental paradigms made possible by technological advances. Here, we review insights from more than 3 decades of iGluR studies with an emphasis on the progress that has occurred in the past decade. We cover structure, function, pharmacology, roles in neurophysiology, and therapeutic implications for all classes of receptors assembled from the subunits encoded by the 18 ionotropic glutamate receptor genes. SIGNIFICANCE STATEMENT: Glutamate receptors play important roles in virtually all aspects of brain function and are either involved in mediating some clinical features of neurological disease or represent a therapeutic target for treatment. Therefore, understanding the structure, function, and pharmacology of this class of receptors will advance our understanding of many aspects of brain function at molecular, cellular, and system levels and provide new opportunities to treat patients.
Topics: Animals; Central Nervous System; Glutamic Acid; Humans; Neurotransmitter Agents; Receptors, Glutamate; Receptors, Ionotropic Glutamate
PubMed: 34753794
DOI: 10.1124/pharmrev.120.000131 -
Molecules (Basel, Switzerland) Jul 2020The γ-aminobutyric acid (GABA) type B receptor (GABA-R) belongs to class C of the G-protein coupled receptors (GPCRs). Together with the GABA receptor, the receptor... (Review)
Review
The γ-aminobutyric acid (GABA) type B receptor (GABA-R) belongs to class C of the G-protein coupled receptors (GPCRs). Together with the GABA receptor, the receptor mediates the neurotransmission of GABA, the main inhibitory neurotransmitter in the central nervous system (CNS). In recent decades, the receptor has been extensively studied with the intention being to understand pathophysiological roles, structural mechanisms and develop drugs. The dysfunction of the receptor is linked to a broad variety of disorders, including anxiety, depression, alcohol addiction, memory and cancer. Despite extensive efforts, few compounds are known to target the receptor, and only the agonist baclofen is approved for clinical use. The receptor is a mandatory heterodimer of the GABA and GABA subunits, and each subunit is composed of an extracellular Venus Flytrap domain (VFT) and a transmembrane domain of seven α-helices (7TM domain). In this review, we briefly present the existing knowledge about the receptor structure, activation and compounds targeting the receptor, emphasizing the role of the receptor in previous and future drug design and discovery efforts.
Topics: Baclofen; Binding Sites; Drug Development; GABA-B Receptor Antagonists; Humans; Ligands; Models, Molecular; Protein Conformation, alpha-Helical; Receptors, GABA-B
PubMed: 32646032
DOI: 10.3390/molecules25133093 -
Neuron Feb 2016To understand brain function, it is essential that we discover how cellular signaling specifies normal and pathological brain function. In this regard, chemogenetic... (Review)
Review
To understand brain function, it is essential that we discover how cellular signaling specifies normal and pathological brain function. In this regard, chemogenetic technologies represent valuable platforms for manipulating neuronal and non-neuronal signal transduction in a cell-type-specific fashion in freely moving animals. Designer Receptors Exclusively Activated by Designer Drugs (DREADD)-based chemogenetic tools are now commonly used by neuroscientists to identify the circuitry and cellular signals that specify behavior, perceptions, emotions, innate drives, and motor functions in species ranging from flies to nonhuman primates. Here I provide a primer on DREADDs highlighting key technical and conceptual considerations and identify challenges for chemogenetics going forward.
Topics: Animals; Drug Design; Humans; Ligands; Molecular Targeted Therapy; Receptors, Neurotransmitter; Signal Transduction; Translational Research, Biomedical
PubMed: 26889809
DOI: 10.1016/j.neuron.2016.01.040 -
Translational Psychiatry Sep 2022Social isolation and discrimination are growing public health concerns associated with poor physical and mental health. They are risk factors for increased morbidity and... (Review)
Review
Social isolation and discrimination are growing public health concerns associated with poor physical and mental health. They are risk factors for increased morbidity and mortality and reduced quality of life. Despite their detrimental effects on health, there is a lack of knowledge regarding translation across the domains of experimental research, clinical studies, and real-life applications. Here, we review and synthesize evidence from basic research in animals and humans to clinical translation and interventions. Animal models indicate that social separation stress, particularly in early life, activates the hypothalamic-pituitary-adrenal axis and interacts with monoaminergic, glutamatergic, and GABAergic neurotransmitter systems, inducing long-lasting reductions in serotonin turnover and alterations in dopamine receptor sensitivity. These findings are of particular importance for human social isolation stress, as effects of social isolation stress on the same neurotransmitter systems have been implicated in addictive, psychotic, and affective disorders. Children may be particularly vulnerable due to lasting effects of social isolation and discrimination stress on the developing brain. The effects of social isolation and loneliness are pronounced in the context of social exclusion due to discrimination and racism, during widespread infectious disease related containment strategies such as quarantine, and in older persons due to sociodemographic changes. This highlights the importance of new strategies for social inclusion and outreach, including gender, culture, and socially sensitive telemedicine and digital interventions for mental health care.
Topics: Aged; Animals; Child; Humans; Hypothalamo-Hypophyseal System; Mental Health; Neurotransmitter Agents; Pituitary-Adrenal System; Quality of Life; Receptors, Dopamine; Serotonin; Social Isolation
PubMed: 36130935
DOI: 10.1038/s41398-022-02178-4 -
Nature Jul 2018Fast inhibitory neurotransmission in the brain is principally mediated by the neurotransmitter GABA (γ-aminobutyric acid) and its synaptic target, the type A GABA...
Fast inhibitory neurotransmission in the brain is principally mediated by the neurotransmitter GABA (γ-aminobutyric acid) and its synaptic target, the type A GABA receptor (GABA receptor). Dysfunction of this receptor results in neurological disorders and mental illnesses including epilepsy, anxiety and insomnia. The GABA receptor is also a prolific target for therapeutic, illicit and recreational drugs, including benzodiazepines, barbiturates, anaesthetics and ethanol. Here we present high-resolution cryo-electron microscopy structures of the human α1β2γ2 GABA receptor, the predominant isoform in the adult brain, in complex with GABA and the benzodiazepine site antagonist flumazenil, the first-line clinical treatment for benzodiazepine overdose. The receptor architecture reveals unique heteromeric interactions for this important class of inhibitory neurotransmitter receptor. This work provides a template for understanding receptor modulation by GABA and benzodiazepines, and will assist rational approaches to therapeutic targeting of this receptor for neurological disorders and mental illness.
Topics: Benzodiazepines; Bicuculline; Binding, Competitive; Brain Chemistry; Cell Membrane; Cryoelectron Microscopy; Flumazenil; GABA Modulators; Glycosylation; HEK293 Cells; Humans; Immunoglobulin Fab Fragments; Ligands; Models, Molecular; Receptors, GABA-A; gamma-Aminobutyric Acid
PubMed: 29950725
DOI: 10.1038/s41586-018-0255-3 -
Neuron Jun 2018Glutamate serves as both the mammalian brain's primary excitatory neurotransmitter and as a key neuromodulator to control synapse and circuit function over a wide range... (Review)
Review
Glutamate serves as both the mammalian brain's primary excitatory neurotransmitter and as a key neuromodulator to control synapse and circuit function over a wide range of spatial and temporal scales. This functional diversity is decoded by two receptor families: ionotropic glutamate receptors (iGluRs) and metabotropic glutamate receptors (mGluRs). The challenges posed by the complexity and physiological importance of each of these subtypes has limited our appreciation and understanding of how these receptors work in concert. In this review, by comparing both receptor families with a focus on their crosstalk, we argue for a more holistic understanding of neural glutamate signaling.
Topics: Animals; Brain; Central Nervous System; Glutamic Acid; Humans; Neuronal Plasticity; Neurotransmitter Agents; Optogenetics; Receptors, Ionotropic Glutamate; Receptors, Metabotropic Glutamate; Synaptic Transmission
PubMed: 29953871
DOI: 10.1016/j.neuron.2018.05.018 -
Cell Feb 2021Ligand-gated ion channels mediate signal transduction at chemical synapses and transition between resting, open, and desensitized states in response to neurotransmitter...
Ligand-gated ion channels mediate signal transduction at chemical synapses and transition between resting, open, and desensitized states in response to neurotransmitter binding. Neurotransmitters that produce maximum open channel probabilities (Po) are full agonists, whereas those that yield lower than maximum Po are partial agonists. Cys-loop receptors are an important class of neurotransmitter receptors, yet a structure-based understanding of the mechanism of partial agonist action has proven elusive. Here, we study the glycine receptor with the full agonist glycine and the partial agonists taurine and γ-amino butyric acid (GABA). We use electrophysiology to show how partial agonists populate agonist-bound, closed channel states and cryo-EM reconstructions to illuminate the structures of intermediate, pre-open states, providing insights into previously unseen conformational states along the receptor reaction pathway. We further correlate agonist-induced conformational changes to Po across members of the receptor family, providing a hypothetical mechanism for partial and full agonist action at Cys-loop receptors.
Topics: Animals; Binding Sites; Cell Line; Cryoelectron Microscopy; Glycine; HEK293 Cells; Humans; Imaging, Three-Dimensional; Ion Channel Gating; Maleates; Models, Molecular; Mutant Proteins; Mutation; Neurotransmitter Agents; Protein Domains; Receptors, Glycine; Styrene; Zebrafish; gamma-Aminobutyric Acid
PubMed: 33567265
DOI: 10.1016/j.cell.2021.01.026 -
Nature Sep 2017Type 2 innate lymphoid cells (ILC2s) both contribute to mucosal homeostasis and initiate pathologic inflammation in allergic asthma. However, the signals that direct...
Type 2 innate lymphoid cells (ILC2s) both contribute to mucosal homeostasis and initiate pathologic inflammation in allergic asthma. However, the signals that direct ILC2s to promote homeostasis versus inflammation are unclear. To identify such molecular cues, we profiled mouse lung-resident ILCs using single-cell RNA sequencing at steady state and after in vivo stimulation with the alarmin cytokines IL-25 and IL-33. ILC2s were transcriptionally heterogeneous after activation, with subpopulations distinguished by expression of proliferative, homeostatic and effector genes. The neuropeptide receptor Nmur1 was preferentially expressed by ILC2s at steady state and after IL-25 stimulation. Neuromedin U (NMU), the ligand of NMUR1, activated ILC2s in vitro, and in vivo co-administration of NMU with IL-25 strongly amplified allergic inflammation. Loss of NMU-NMUR1 signalling reduced ILC2 frequency and effector function, and altered transcriptional programs following allergen challenge in vivo. Thus, NMUR1 signalling promotes inflammatory ILC2 responses, highlighting the importance of neuro-immune crosstalk in allergic inflammation at mucosal surfaces.
Topics: Animals; Female; Gene Expression Regulation; Hypersensitivity; Immunity, Innate; Inflammation; Interleukin-17; Interleukin-33; Ligands; Lung; Lymphocytes; Male; Mice; Mice, Inbred C57BL; Neuropeptides; Receptors, Neurotransmitter; Respiratory Mucosa; Signal Transduction; Transcription, Genetic
PubMed: 28902842
DOI: 10.1038/nature24029 -
Revista Da Associacao Medica Brasileira... Aug 2015alcohol is a psychotropic depressant of the central nervous system (CNS) that promotes simultaneous changes in several neuronal pathways, exerting a profound... (Review)
Review
INTRODUCTION
alcohol is a psychotropic depressant of the central nervous system (CNS) that promotes simultaneous changes in several neuronal pathways, exerting a profound neurological impact that leads to various behavioral and biological alterations.
OBJECTIVES
to describe the effects of alcohol on the CNS, identifying the signaling pathways that are modified and the biological effects resulting from its consumption.
METHODS
a literature review was conducted and articles published in different languages over the last 15 years were retrieved.
RESULTS
the studies reviewed describe the direct effect of alcohol on several neurotransmitter receptors (gamma-aminobutyric acid [GABA], glutamate, endocannabinoids AEA and 2-AG, among others), the indirect effect of alcohol on the limbic and opioid systems, and the effect on calcium and potassium channels and on proteins regulated by GABA in the hippocampus.
DISCUSSION AND CONCLUSION
the multiple actions of alcohol on the CNS result in a general effect of psychomotor depression, difficulties in information storage and logical reasoning and motor incoordination, in addition to stimulating the reward system, a fact that may explain the development of addiction. Knowledge on the neuronal signaling pathways that are altered by alcohol allows the identification of effectors which could reduce its central action, thus, offering new therapeutic perspectives for the rehabilitation of alcohol addicts.
Topics: Alcohol-Induced Disorders, Nervous System; Alcoholism; Central Nervous System; Central Nervous System Depressants; Ethanol; Humans; Receptors, Neurotransmitter
PubMed: 26466222
DOI: 10.1590/1806-9282.61.04.381