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Antipsychotic dopamine glutamate

Andrea de Bartolomeis, Felice Iasevoli, Federica Marmo, Elisabetta Filomena Buonaguro, Livia Avvisati, Gianmarco Latte, Carmine Tomasetti
Caffeine and nicotine are widely used by schizophrenia patients and may worsen psychosis and affect antipsychotic therapies. However, they have also been accounted as augmentation strategies in treatment-resistant schizophrenia. Despite both substances are known to modulate dopamine and glutamate transmission, little is known about the molecular changes induced by these compounds in association to antipsychotics, mostly at the level of the postsynaptic density (PSD), a site of dopamine-glutamate interplay. Here we investigated whether caffeine and nicotine, alone or combined with haloperidol, elicited significant changes in the levels of both transcripts and proteins of the PSD members Homer1 and Arc, which have been implicated in synaptic plasticity, schizophrenia pathophysiology, and antipsychotics molecular action...
February 20, 2018: European Neuropsychopharmacology: the Journal of the European College of Neuropsychopharmacology
Kazunori Suzuki, Akina Harada, Hirobumi Suzuki, Clizia Capuani, Annarosa Ugolini, Mauro Corsi, Haruhide Kimura
Activation of indirect pathway medium spiny neurons (MSNs) via promotion of cAMP production is the principal mechanism of action of current antipsychotics with dopamine D2 receptor antagonism. TAK-063 [1-[2-fluoro-4-(1H-pyrazol-1-yl)phenyl]-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one] is a novel phosphodiesterase 10A inhibitor that activates both direct and indirect pathway MSNs through increasing both cAMP and cGMP levels by inhibition of their degradation. The activation of indirect pathway MSNs through the distinct mechanism of action of these drugs raises the possibility of augmented pharmacological effects by combination therapy...
February 2018: Pharmacology Research & Perspectives
Ana Paula Chiapinotto Ceretta, Catiuscia Molz de Freitas, Larissa Finger Schaffer, Jeane Binotto Reinheimer, Mariana Maikéli Dotto, Elizete de Moraes Reis, Rahisa Scussel, Ricardo Andrez Machado-de-Ávila, Roselei Fachinetto
Tardive dyskinesia (TD) is a common adverse effect observed in patients with long-term use of typical antipsychotic medications. A vacuous chewing movement (VCM) model induced by haloperidol has been used to study these abnormalities in experimental animals. The cause of TD and its treatment remain unknown, but several lines of evidence suggest that dopamine receptor supersensitivity and gamma-aminobutyric acid (GABA) insufficiency play important roles in the development of TD. This study investigated the effects of treatment with the GABA-mimetic drug gabapentin on the development of haloperidol-induced VCMs...
January 25, 2018: Pharmacology, Biochemistry, and Behavior
Gretchen L Snyder, Kimberly E Vanover
Schizophrenia is a pervasive neuropsychiatric disorder affecting over 1% of the world's population. Dopamine system dysfunction is strongly implicated in the etiology of schizophrenia. Data support the long-standing concept of schizophrenia as a disease characterized by hyperactivity within midbrain (striatal D2) dopamine systems. In addition, there is now considerable evidence that glutamate neurotransmission, mediated through NMDA-type receptors, is deficient in patients with schizophrenia and that hypoactivity in cortical dopamine and glutamate pathways is a key feature of this serious mental disorder...
2017: Advances in Neurobiology
Adam Włodarczyk, Joanna Szarmach, Wiesław Jerzy Cubała, Mariusz Stanisław Wiglusz
Antipsychotics are a key intervention strategy in pharmacotherapy of schizophrenia. However, benzodiazepines are often prescribed to control sleep disturbances, anxiety or behavioural disinhibition. There is clinical evidence for the beneficial effect of the combined treatment of antipsychotics and benzodiazepines resulting in more favorable treatment outcome in schizophrenia with regard to positive and negative symptoms. This clinical phenomenon seems to be associated with the GABA-ergic activit ythat is believed to be disrupted in the schizophrenia and direct benzodiazepines effect on GABA-A receptors...
September 2017: Psychiatria Danubina
Haitao Wang, Mohd Farhan, Jiangping Xu, Philip Lazarovici, Wenhua Zheng
Schizophrenia is one of the most devastating heterogeneous psychiatric disorders. The dopamine hypothesis is the longest standing pathoetiologic theory of schizophrenia based on neurochemical evidences of elevated brain striatal dopamine synthesis capacity and increased dopamine release in response to stress. Dopamine and cyclic AMP-regulated phosphoprotein of relative molecular mass 32,000 (DARPP-32) is a cytosolic protein highly enriched in the medium spiny neurons of the neostriatum, considered as the most important integrator between the cortical input and the basal ganglia, and associated with motor control...
August 8, 2017: Oncotarget
Hagar Tadmor, Idit Golani, Ravid Doron, Ilana Kremer, Alon Shamir
Schizophrenia is a severe syndrome that affects about 1% of the world population. Since the mid-1950s, antipsychotics have been used to treat schizophrenia with preference for treating positive symptoms; however, their tolerance level is low, there are numerous side effects, and only some patients respond to the treatment. Antipsychotic medications that are more effective, better tolerated, and with fewer adverse effects are urgently needed. Given the accumulating evidence of the role filled by the ErbB signaling network in the biology of the dopamine, GABA, and glutamate systems, and in the etiology of schizophrenia, we hypothesized that the ErbB network is a candidate for development of a novel agent through which various symptoms of schizophrenia and other psychiatric disorders might be treated...
August 14, 2017: Progress in Neuro-psychopharmacology & Biological Psychiatry
Catherine Lévesque, Giovanni Hernandez, Souha Mahmoudi, Frédéric Calon, Fabrizio Gasparini, Baltazar Gomez-Mancilla, Pierre J Blanchet, Daniel Lévesque
Tardive dyskinesia (TD) is a potentially disabling condition encompassing all delayed, persistent, and often irreversible abnormal involuntary movements arising in a fraction of subjects during long-term exposure to centrally acting dopamine receptor-blocking agents such as antipsychotic drugs and metoclopramide. However, the pathogenesis of TD has proved complex and remains elusive. To investigate the mechanism underlying the development of TD, we have chronically exposed 17 Cebus apella monkeys to typical (11) or atypical (6) antipsychotic drugs...
October 11, 2017: Neuroscience
Yurie Matsumoto, Minae Niwa, Akihiro Mouri, Yukihiro Noda, Takeshi Fukushima, Norio Ozaki, Toshitaka Nabeshima
BACKGROUND: Stress during the adolescent period influences postnatal maturation and behavioral patterns in adulthood. Adolescent stress-induced molecular and functional changes in neurons are the key clinical features of psychiatric disorders including schizophrenia. OBJECTIVE: In the present study, we exposed genetically vulnerable mice to isolation stress to examine the molecular changes in the glutamatergic system involving N-methyl-d-aspartate (NMDA) receptors via dopaminergic disturbance in the prefrontal cortex (PFc)...
October 2017: Psychopharmacology
Haitao Wang, Mohd Farhan, Jiangping Xu, Philip Lazarovici, Wenhua Zheng
Schizophrenia is one of the most devastating heterogeneous psychiatric disorders. The dopamine hypothesis is the longest standing pathoetiologic theory of schizophrenia based on neurochemical evidences of elevated brain striatal dopamine synthesis capacity and increased dopamine release in response to stress. Dopamine and cyclic AMP-regulated phosphoprotein of relative molecular mass 32,000 (DARPP-32) is a cytosolic protein highly enriched in the medium spiny neurons of the neostriatum, considered as the most important integrator between the cortical input and the basal ganglia, and associated with motor control...
April 21, 2017: Oncotarget
Yong-Ku Kim, Joonho Choi, Seon-Cheol Park
Despite the substantial burden of illness in schizophrenia, there has been a discrepancy between the beneficial effects of an increased use of antipsychotic medications and achieving limited recovery or remission. Because the focus of the most common antipsychotic medications is on dopamine, which is associated with positive symptoms, there is an unmet need for patients with negative symptoms. Since cognitive and negative symptoms rather than positive symptoms are more closely associated with psychosocial impairments in patients with schizophrenia, the non-dopaminergic systems including glutamate and γ-aminobutyric acid (GABA) of the prefrontal cortex should be of concern as well...
March 30, 2017: International Journal of Molecular Sciences
Ramin Ekhteiari Salmas, Philip Seeman, Busecan Aksoydan, Ismail Erol, Isik Kantarcioglu, Matthias Stein, Mine Yurtsever, Serdar Durdagi
Dopamine receptor D2 (D2R) plays an important role in the human central nervous system and is a focal target of antipsychotic agents. The D2(High)R and D2(Low)R dimeric models previously developed by our group are used to investigate the prediction of binding affinity of the LY404,039 ligand and its binding mechanism within the catalytic domain. The computational data obtained using molecular dynamics simulations fit well with the experimental results. The calculated binding affinities of LY404,039 using MM/PBSA for the D2(High)R and D2(Low)R targets were -12...
March 22, 2017: ACS Chemical Neuroscience
Elisabetta Filomena Buonaguro, Felice Iasevoli, Federica Marmo, Anna Eramo, Gianmarco Latte, Camilla Avagliano, Carmine Tomasetti, Andrea de Bartolomeis
OBJECTIVES: The postsynaptic density (PSD) represents a site of dopamine-glutamate integration. Despite multiple evidence of PSD involvement in antipsychotic-induced synaptic changes, there are no direct head-to-head comparisons of the effects at the PSD of antipsychotics with different receptor profile and at different doses after chronic administration. METHODS: Molecular imaging of gene expression was used to investigate whether chronic treatment with first and second generation antipsychotics (haloperidol, asenapine and olanzapine) may induce changes in the expression levels of PSD transcripts involved in schizophrenia pathophysiology, i...
February 22, 2017: Progress in Neuro-psychopharmacology & Biological Psychiatry
Sabine Janssen, Bastiaan R Bloem, Bart P van de Warrenburg
A wide variety of drugs can cause myoclonus. To illustrate this, we first discuss two personally observed cases, one presenting with generalized, but facial-predominant, myoclonus that was induced by amantadine; and the other presenting with propriospinal myoclonus triggered by an antibiotic. We then review the literature on drugs that may cause myoclonus, extracting the corresponding clinical phenotype and suggested underlying pathophysiology. The most frequently reported classes of drugs causing myoclonus include opiates, antidepressants, antipsychotics, and antibiotics...
August 2017: Journal of Neurology
Danish Mahmood
Histamine H3 receptors are present as autoreceptors on histaminergic neurons and as heteroreceptors on nonhistaminergic neurones. They control the release and synthesis of histamine and several other key neurotransmitters in the brain. H3 antagonism may be a novel approach to develop a new class of antipsychotic medications given the gathering evidence reporting therapeutic efficacy in several central nervous system disorders. Several medications such as cariprazine, lurasidone, LY214002, bexarotene, rasagiline, raloxifene, BL-1020 and ITI-070 are being developed to treat the negative symptoms and cognitive impairments of schizophrenia...
October 2016: International Journal of Health Sciences
Nao Chuhma, Susana Mingote, Abigail Kalmbach, Leora Yetnikoff, Stephen Rayport
Brain imaging has revealed alterations in dopamine uptake, release, and receptor levels in patients with schizophrenia that have been resolved on the scale of striatal subregions. However, the underlying synaptic mechanisms are on a finer scale. Dopamine neuron synaptic actions vary across the striatum, involving variations not only in dopamine release but also in dopamine neuron connectivity, cotransmission, modulation, and activity. Optogenetic studies have revealed that dopamine neurons release dopamine in a synaptic signal mode, and that the neurons also release glutamate and gamma-aminobutyric acid as cotransmitters, with striking regional variation...
January 1, 2017: Biological Psychiatry
Diane Grillault Laroche, Adeline Gaillard
The prevalence of OCS and OCD is higher in schizophrenic patients than in the general population. These disorders are sometimes induced by AAPs. There is higher frequency of OCS and greater severity in patients treated with antipsychotics with predominant anti-serotoninergic profiles opposed to those with predominant dopaminergic blockade. Induced OCS may be due to complex neuromodulation involving many serotonin, dopamine and glutamate receptors and several subtypes. Concerning connectivity, AAPs differentially influence the BOLD signal, depending on the intensity of D2 receptor blockade...
December 30, 2016: Psychiatry Research
Nadja P Maric, Milica J Jovicic, Marina Mihaljevic, Cedo Miljevic
Preclinical Research After the identification of the schizophrenia as an illness over a century ago, treatment of affected individuals included unspecific, mostly very robust methods including deep insulin coma and lobectomy/leucotomy. The first relatively specific treatment of schizophrenia started about 60 years ago with the antipsychotic chlorpromazine. All currently approved antipsychotic drugs block dopamine receptors, indicating that manipulation of dopaminergic function is fundamental to a therapeutic response in psychosis...
November 2016: Drug Development Research
Kirsten E Schoonover, Lesley A McCollum, Rosalinda C Roberts
The substantia nigra (SN) provides the largest dopaminergic input to the brain, projects to the striatum (the primary locus of action for antipsychotic medication), and receives GABAergic and glutamatergic inputs. This study used western blot analysis to compare protein levels of tyrosine hydroxylase (TH), glutamate decarboxylase (GAD67), and vesicular glutamate transporters (vGLUT1 and vGLUT2) in postmortem human SN in schizophrenia subjects (n=13) and matched controls (n=12). As a preliminary analysis, the schizophrenia group was subdivided by (1) treatment status: off medication (n=4) or on medication (n=9); or (2) treatment response: treatment resistant (n=5) or treatment responsive (n=4)...
January 2017: Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology
Nora Wa van de Kerkhof, Durk Fekkes, Frank Mma van der Heijden, Witte Jg Hoogendijk, Gerald Stöber, Jos Im Egger, Willem Ma Verhoeven
Cycloid psychoses (CP) differ from schizophrenia regarding symptom profile, course, and prognosis and over many decades they were thought to be a separate entity within the psychosis spectrum. As to schizophrenia, research into the pathophysiology has focused on dopamine, brain-derived neurotrophic factor, and glutamate signaling in which, concerning the latter, the N-methyl-d-aspartate receptor plays a crucial role. The present study aims to determine whether CP can biochemically be delineated from schizophrenia...
2016: Neuropsychiatric Disease and Treatment
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