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Acta Pharmacologica Sinica Sep 2022Major depressive disorder is a global mental illness associated with severe mortality and disability. The dopaminergic system is involved in both the etiology and...
Major depressive disorder is a global mental illness associated with severe mortality and disability. The dopaminergic system is involved in both the etiology and therapeutics of depression. Distinct functions of dopamine D and D receptor subtypes have attracted considerable research interest, and their roles in the pathogenesis of depression and interaction with antidepressants need to be comprehensively elucidated. Herein, we investigated the antidepressant effects of a candidate antidepressant from a cinnamamide derivative, M2, and examined underlying neural mechanisms. We observed that a single dose of M2 (30 mg/kg, ip) produced rapid antidepressant-like effects in mice subjected to the forced swim and tail suspension tests. Using whole-cell recordings in mouse coronal brain slices, we found that application of M2 (10-150 μM) concentration-dependently increased the frequency of spontaneous excitatory postsynaptic currents (sEPSCs) of the pyramidal neurons in the medial prefrontal cortex (mPFC). Furthermore, M2-induced enhancement of sEPSC frequency was abolished by sulpiride (10 µM), a dopamine D2 receptor antagonist, but not by the dopamine receptor D antagonist, SCH23390 (10 μM). In addition, M2 administration significantly increased expression levels of synaptogenesis-related proteins, including p-mTOR and p-TrkB, in the mPFC at 30 min, and increased postsynaptic protein PSD-95 at 24 h. Our results demonstrated that M2 produces rapid antidepressant actions through a novel mechanism via dopamine D receptor-mediated enhancement of mPFC neurotransmission.
Topics: Animals; Antidepressive Agents; Cinnamates; Depressive Disorder, Major; Dopamine; Dopamine Antagonists; Mice; Prefrontal Cortex; Receptors, Dopamine D1; Receptors, Dopamine D2
PubMed: 35079131
DOI: 10.1038/s41401-021-00854-7 -
Scientific Reports Jan 2020Dopamine is a neurotransmitter of great physiological relevance. Disorders in dopaminergic signal transduction are associated with psychiatric and neurological...
Dopamine is a neurotransmitter of great physiological relevance. Disorders in dopaminergic signal transduction are associated with psychiatric and neurological pathologies such as Parkinson's disease, schizophrenia and substance abuse. Therefore, a detailed understanding of dopaminergic neurotransmission may provide access to novel therapeutic strategies for the treatment of these diseases. Caged compounds with photoremovable groups represent molecular tools to investigate a biological target with high spatiotemporal resolution. Based on the crystal structure of the D receptor in complex with eticlopride, we have developed caged D/D receptor ligands by rational design. We initially found that eticlopride, a widely used D/D receptor antagonist, was photolabile and therefore is not suitable for caging. Subtle structural modification of the pharmacophore led us to the photostable antagonist dechloroeticlopride, which was chemically transformed into caged ligands. Among those, the 2-nitrobenzyl derivative 4 (MG307) showed excellent photochemical stability, pharmacological behavior and decaging properties when interacting with dopamine receptor-expressing cells.
Topics: Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Drug Design; Drug Development; Drug Stability; Humans; Ligands; Molecular Conformation; Parkinson Disease; Photochemical Processes; Receptors, Dopamine D2; Receptors, Dopamine D3
PubMed: 31965029
DOI: 10.1038/s41598-020-57770-9 -
Psychopharmacology Jun 2024Evidence on the effect of dopamine D1-like and D2-like receptor antagonists on licking microstructure and the forced swimming response led us to suggest that (i)... (Review)
Review
RATIONALE
Evidence on the effect of dopamine D1-like and D2-like receptor antagonists on licking microstructure and the forced swimming response led us to suggest that (i) dopamine on D1-like receptors plays a role in activating reward-directed responses and (ii) the level of response activation is reboosted based on a process of evaluation of response efficacy requiring dopamine on D2-like receptors. A main piece of evidence in support of this hypothesis is the observation that the dopamine D2-like receptor antagonist raclopride induces a within-session decrement of burst number occurring after the contact with the reward. The few published studies with a detailed analysis of the time-course of this measure were conducted in our laboratory.
OBJECTIVES
The aim of this review is to recapitulate and discuss the evidence in support of the analysis of the within-session burst number as a behavioural substrate for the study of the mechanisms governing ingestion, behavioural activation and the related evaluation processes, and its relevance in the analysis of drug effects on ingestion.
CONCLUSIONS
The evidence gathered so far suggests that the analysis of the within-session time-course of burst number provides an important behavioural substrate for the study of the mechanisms governing ingestion, behavioural activation and the related evaluation processes, and might provide decisive evidence in the analysis of the effects of drugs on ingestion. However, further evidence from independent sources is necessary to validate the use and the proposed interpretation of this measure.
Topics: Dopamine; Animals; Humans; Receptors, Dopamine D1; Receptors, Dopamine D2; Time Factors; Dopamine Antagonists; Reward; Eating; Drinking Behavior; Dopamine D2 Receptor Antagonists
PubMed: 38702473
DOI: 10.1007/s00213-024-06600-1 -
Neurochemistry International Feb 2019The catecholamine neurotransmitter dopamine (DA) exerts powerful modulatory control of physiology and behavior across phylogeny. Perturbations of DA signaling in humans...
The catecholamine neurotransmitter dopamine (DA) exerts powerful modulatory control of physiology and behavior across phylogeny. Perturbations of DA signaling in humans are associated with multiple neurodegenerative and behavioral disorders, including Parkinson's disease, attention-deficit/hyperactivity disorder, addiction and schizophrenia. In the nematode C. elegans, DA signaling regulates mating behavior, learning, food seeking and locomotion. Previously, we demonstrated that loss of function mutations in the dat-1 gene that encodes the presynaptic DA transporter (DAT-1) results in a rapid cessation of movement when animals are placed in water, termed Swimming Induced Paralysis (Swip). Loss of function mutations in genes that support DA biosynthesis, DA vesicular packaging and DA action at the extrasynaptic D2-type DA receptor DOP-3 suppress Swip in dat-1 animals, consistent with paralysis as arising from excessive DA signaling. Although animals grown on the vesicular monoamine transporter antagonist reserpine diminish Swip, the drug must be applied chronically, can impact the signaling of multiple biogenic amines, and has been reported to have penetrant, off-target actions. Here, we demonstrate that the antipsychotic drug azaperone potently and rapidly suppresses Swip behavior in either dat-1 mutants, as well as in wildtype animals treated with the DAT-1 antagonist nisoxetine, with genetic experiments consistent with DOP-3 antagonism as the mechanism of Swip suppression. Reversal of Swip in previously paralyzed dat-1 animals by azaperone application demonstrates an otherwise functionally-intact swimming circuit in these mutants. Finally, whereas azaperone suppresses DA-dependent Swip, the drug fails to attenuate the DA-independent paralysis induced by βPEA, aldicarb or genetic disruption of γ-aminobutyric acid (GABA) signaling. We discuss our findings with respect to the use of azaperone as a potent and selective tool in the identification and analysis of presynaptic mechanisms that regulate DA signaling.
Topics: Animals; Animals, Genetically Modified; Antipsychotic Agents; Azaperone; Caenorhabditis elegans; Caenorhabditis elegans Proteins; Dopamine; Dopamine Antagonists; Dopamine Plasma Membrane Transport Proteins; Fluoxetine; Reserpine; Signal Transduction
PubMed: 29800604
DOI: 10.1016/j.neuint.2018.05.013 -
Journal of Physiology and Pharmacology... Dec 2020Chronic epigastric pain syndrome (CEPS) is an important diagnostic problem, especially in patients without macroscopic and microscopic changes in gastric mucosa. The... (Comparative Study)
Comparative Study Randomized Controlled Trial
Chronic epigastric pain syndrome (CEPS) is an important diagnostic problem, especially in patients without macroscopic and microscopic changes in gastric mucosa. The cause of this ailment is unclear. The aim of this study was the assessment of coexistence between symptoms of this syndrome and secretion level of dopamine (DA), as well as the efficacy of peripheral and central D2 receptors antagonist. Sixty depressive patients with CEPS occurring independently of the diet and with no Helicobacter pylori infection and 30 healthy subjects were enrolled in this study. Plasma DA and urinary homovanilic acid (HVA) concentration were measured by ELISA, and the mRNA expression of dopa decarboxylase (DDC) in gastric mucosa was evaluated by RT-PCR in 30 patients with CEPS and 30 controls. Severity of epigastric pain before and after 12 weeks 2 x 50 mg itopride or sulpiride treatment was evaluated using the modified 10-point Visual Analogue Scale. Higher average levels of plasma DA and urinary HVA levels in CEPS patients than controls 129.5 ± 22.0 versus 109.1 ± 18.4 pg/ml (p < 0.001) and 6.82 ± 1.55 versus 5.39 ± 1.04 mg/24 h, respectively were obtained. Moreover, the expression of DDC in gastric mucosa of CEPS patients was higher than in healthy subjects (p < 0.01). Sulpiride subsided epigastric pain in 73.3%, but itopride reduced it only in 6.6% of CEPS patients. We concluded that altered dopamine signalling may affect locally-and-centrally mediated chronic epigastric pain.
Topics: Abdominal Pain; Adult; Benzamides; Benzyl Compounds; Case-Control Studies; Chronic Pain; Depression; Dopamine; Dopamine Antagonists; Female; Gastric Mucosa; Homovanillic Acid; Humans; Male; Middle Aged; Pain Measurement; Signal Transduction; Sulpiride
PubMed: 33727428
DOI: 10.26402/jpp.2020.6.05 -
Drug Design, Development and Therapy 2021Depressive episodes, the most frequent episodes in bipolar disorder, contribute in large part to poor functional outcomes. Very few treatments, however, have been... (Review)
Review
Depressive episodes, the most frequent episodes in bipolar disorder, contribute in large part to poor functional outcomes. Very few treatments, however, have been approved by the Food and Drug Administration for the treatment of bipolar depression. Cariprazine, a broad-spectrum dopamine antagonist/partial agonist with dopamine D3/D2 (preferring D3) and serotonin 5-HT1A receptor partial agonist properties, was recently approved. A review of the literature suggests that it is an effective and well-tolerated treatment for bipolar depression.
Topics: Adult; Antipsychotic Agents; Bipolar Disorder; Depression; Dopamine Antagonists; Drug Partial Agonism; Humans; Piperazines
PubMed: 34012253
DOI: 10.2147/DDDT.S240860 -
Proteins May 2015Human dopamine receptor D4 (DRD4), a member of G-protein coupled receptor (GPCR) family, plays a central role in cell signaling and trafficking. Dysfunctional activity...
Human dopamine receptor D4 (DRD4), a member of G-protein coupled receptor (GPCR) family, plays a central role in cell signaling and trafficking. Dysfunctional activity of DRD4 can lead to several psychiatric conditions and, therefore, represents target for many neurological disorders. However, lack of atomic structure impairs our understanding of the mechanism regulating its activity. Here, we report the modeled structure of DRD4 alone and in complex with dopamine and spiperone, its natural agonist and antagonist, respectively. To assess the conformational dynamics induced upon ligand binding, all-atom explicit solvent molecular dynamics simulations in membrane environment were performed. Comprehensive analyses of simulations reveal that agonist binding triggers a series of conformational changes in the transmembrane region, including rearrangement of residues, characteristic of transmission and tyrosine toggle molecular switches. Further, the trajectories indicate that a loop region in the intracellular region--ICL3, is significantly dynamic in nature, mainly due to the side-chain movements of conserved proline residues involved in SH3 binding domains. Interestingly, in dopamine-bound receptor simulation, ICL3 represents an open conformation ideal for G protein binding. The structural and dynamical information presented here suggest a mode of activation of DRD4, upon ligand binding. Our study will help in further understanding of receptor activation, as acquiring structural information is crucial for the design of highly selective DRD4 ligands.
Topics: Binding Sites; Dopamine; Dopamine Agonists; Dopamine Antagonists; Humans; Hydrogen Bonding; Molecular Docking Simulation; Molecular Dynamics Simulation; Protein Binding; Protein Structure, Secondary; Protein Structure, Tertiary; Receptors, Dopamine D4; Spiperone
PubMed: 25371112
DOI: 10.1002/prot.24716 -
The Journal of Neuroscience : the... Nov 2017Nucleus accumbens (NAc) shell shows unique dopamine (DA) signals and plays a unique role in DA-dependent behaviors such as reward-motivated learning and the response to...
Nucleus accumbens (NAc) shell shows unique dopamine (DA) signals and plays a unique role in DA-dependent behaviors such as reward-motivated learning and the response to drugs of abuse. A disynaptic mechanism for DA release was reported and shown to require synchronized firing of cholinergic interneurons (CINs) and activation of nicotinic acetylcholine (ACh) receptors (nAChRs) in DA neuron (DAN) axons. The properties of this disynaptic mechanism of DA transmission are not well understood in the NAc shell. In this study, fast-scan cyclic voltammetry was used to examine the modulation of DA transmission evoked by CINs firing in the shell of mice and compared with other striatal regions. We found that DA signals in the shell displayed significant degree of summation in response to train stimulation of CINs, contrary to core and dorsal striatum. The summation was amplified by a D2-like receptor antagonist and experiments with mice with targeted deletion of D2 receptors to DANs or CINs revealed that D2 receptors in CINs mediate a fast inhibition observed within 100 ms of the first pulse, whereas D2 autoreceptors in DAN terminals are engaged in a slower inhibition that peaks at ∼500 ms. ACh also contributes to the use-dependent inhibition of DA release through muscarinic receptors only in the shell, where higher activity of acetylcholinesterase minimizes nAChR desensitization and promotes summation. These findings show that DA signals are modulated differentially by endogenous DA and ACh in the shell, which may underlie the unique features of shell DA signals The present study reports that dopamine (DA) release evoked by activation of cholinergic interneurons displays a high degree of summation in the shell and shows unique modulation by endogenous DA and acetylcholine. Desensitization of nicotinic receptors, which is a prevailing mechanism for use-dependent inhibition in the nucleus accumbens core and dorsal striatum, is also minimal in the shell in part due to elevated acetylcholinesterase activity. This distinctive modulation of DA transmission in the shell may have functional implications in the acquisition of reward-motivated behaviors and reward seeking.
Topics: Animals; Cholinergic Antagonists; Dopamine; Dopamine Antagonists; Dose-Response Relationship, Drug; Male; Mice; Mice, 129 Strain; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Nucleus Accumbens; Organ Culture Techniques; Receptors, Dopamine; Receptors, Nicotinic
PubMed: 29030431
DOI: 10.1523/JNEUROSCI.0596-17.2017 -
Psychopharmacology Bulletin Mar 2024This is a comprehensive review of the literature regarding the use of Solriamfetol for excessive daytime sleepiness. It covers the background and current therapeutic... (Review)
Review
PURPOSE OF REVIEW
This is a comprehensive review of the literature regarding the use of Solriamfetol for excessive daytime sleepiness. It covers the background and current therapeutic approaches to treating excessive daytime sleepiness, the management of common comorbidities, and the existing evidence investigating the use of Solriamfetol for this purpose.
RECENT FINDINGS
Excessive daytime sleepiness leads to worse quality of life, a medical sequela and significant economic cost. There are multiple phenotypes of excessive daytime sleepiness depending on the comorbidity making treatment challenging. Due to the complexity of etiology there is not a cure for this ailment. Solriamfetol is a norepinephrine/dopamine dual reuptake antagonist that can be used to manage daytime sleepiness. Solriamfetol was first approved by the FDA in 2018 for use in excessive daytime sleepiness associated with obstructive sleep apnea and narcolepsy. Ongoing literature has proved this drug to be a safe and effective alternative pharmacotherapy.
SUMMARY
Recent epidemiological data estimate up to one-third of the general adult population suffers from excessive daytime sleepiness. There is no cure to daytime somnolence and current pharmacotherapeutic regimens have worrisome side effect profiles. Solriamfetol is a new class of drug that offers a safe and effective alternative option for clinical providers treating excessive daytime sleepiness.
Topics: Adult; Humans; Quality of Life; Carbamates; Phenylalanine; Dopamine Antagonists; Disorders of Excessive Somnolence
PubMed: 38449471
DOI: No ID Found -
Neurodegenerative Disease Management Apr 2019Tardive dyskinesia (TD) is a bothersome and - at times, disabling - movement disorder associated with exposure to dopamine receptor antagonist medications. On 11 April...
Tardive dyskinesia (TD) is a bothersome and - at times, disabling - movement disorder associated with exposure to dopamine receptor antagonist medications. On 11 April 2017, valbenazine became the first US FDA-approved medication indicated for the treatment of TD. Valbenazine is a vesicular monoamine transporter 2 (VMAT2) inhibitor that decreases the abnormal movements of TD. The FDA considered valbenazine a breakthrough therapy in 2014 given its underlying mechanism and its importance in addressing an unmet need, as there were no available FDA-approved medications indicated for TD. The advantages of valbenazine include once-daily dosing and a rapid onset of effect within 2 weeks of treatment initiation.
Topics: Adrenergic Uptake Inhibitors; Dopamine Antagonists; Humans; Tardive Dyskinesia; Tetrabenazine; Valine; Vesicular Monoamine Transport Proteins
PubMed: 30724115
DOI: 10.2217/nmt-2019-0001