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Ketamine schizophrenia

Sara de la Salle, Joelle Choueiry, Dhrasti Shah, Hayley Bowers, Judy McIntosh, Vadim Ilivitsky, Verner Knott
N-methyl-D-aspartate (NMDA) receptor antagonists administered to healthy humans results in schizophrenia-like symptoms, which preclinical research suggests are due to glutamatergically altered brain oscillations. Here, we examined resting-state electroencephalographic activity in 21 healthy volunteers assessed in a placebo-controlled, double-blind, randomized study involving administration of either a saline infusion or a sub-anesthetic dose of ketamine, an NMDA receptor antagonist. Frequency-specific current source density (CSD) was assessed at sensor-level and source-level using eLORETA within regions of interest of a triple network model of schizophrenia (this model posits a dysfunctional switching between large-scale Default Mode and Central Executive networks by the monitor-controlling Salience Network)...
2016: Frontiers in Pharmacology
Agnieszka Potasiewicz, Małgorzata Hołuj, Tomasz Kos, Piotr Popik, Hugo R Arias, Agnieszka Nikiforuk
The cognitive impairments and negative symptoms experienced by schizophrenia patients still await effective treatment. Alpha7 nicotinic acetylcholine receptors (α7 nAChRs) have gain considerable attention in this regard. It has been recently proposed that positive allosteric modulators (PAMs) of α7 nAChRs may represent an alternative strategy to that based on orthosteric agonists. The aim of the present study is to evaluate the efficacy of PAM-2 (3-furan-2-yl-N-p-tolyl-acrylamide) against cognitive deficits and negative-like symptoms in a rat model of schizophrenia based on administration of ketamine, a NMDAR antagonist...
October 4, 2016: Neuropharmacology
Elizabeth Finbarrs-Bello, Emmanuel Nebeuwa Obikili, Esom Emmanuel Anayochukwu, Anyanwu Emeka Godson
AIM: This study evaluated the curative potential of Crinum giganteum in the treatment of schizophrenia using an NMDA-receptor antagonist-induced schizophrenic Wistar rat model. METHODS: Twenty-five adult Wistar rats of both sexes of average weights 180 g were divided into two groups: control and schizophrenic rat models. The controls received 0.1 ml of 0. 9% saline, while schizophrenia was induced in models using 25 mg/kg of ketamine hydrochloride (i.p.) for 7 days...
September 15, 2016: Open Access Macedonian Journal of Medical Sciences
Tatiane da Silva Araújo, Adriano Jose Maia Chaves Filho, Aline Santos Monte, Ana Isabelle de Góis Queiroz, Rafaela Carneiro Cordeiro, Michel de Jesus Souza Machado, Ricardo de Freitas Lima, David Freitas de Lucena, Michael Maes, Danielle Macêdo
Immune dysregulation observed in schizophrenia alters tryptophan metabolism. Tryptophan metabolism is triggered by indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO). Tryptophan is converted to quinolinic acid, a potent neurotoxin, and to kynurenic acid, an NMDA antagonist. 1-Methyl-D-tryptophan (MDT) inhibits IDO. Melatonin is metabolized by IDO while inhibiting TDO. We evaluated the reversal of ketamine-induced schizophrenia-like behavioral and neurochemical alterations in mice by the administration of MDT (20 or 40 mg/kg, i...
September 21, 2016: Journal of Psychiatric Research
Naomi S Kort, Judith M Ford, Brian J Roach, Handan Gunduz-Bruce, John H Krystal, Judith Jaeger, Robert M G Reinhart, Daniel H Mathalon
BACKGROUND: Recent theoretical models of schizophrenia posit that dysfunction of the neural mechanisms subserving predictive coding contributes to symptoms and cognitive deficits, and this dysfunction is further posited to result from N-methyl-D-aspartate glutamate receptor (NMDAR) hypofunction. Previously, by examining auditory cortical responses to self-generated speech sounds, we demonstrated that predictive coding during vocalization is disrupted in schizophrenia. To test the hypothesized contribution of NMDAR hypofunction to this disruption, we examined the effects of the NMDAR antagonist, ketamine, on predictive coding during vocalization in healthy volunteers and compared them with the effects of schizophrenia...
July 1, 2016: Biological Psychiatry
Daiki Yamanaka, Takashi Kawano, Hiroki Tateiwa, Hideki Iwata, Fabricio M Locatelli, Masataka Yokoyama
BACKGROUND: Anti-N-methyl-d-aspartate receptor (NMDA-R) encephalitis is a recently identified but increasingly recognized autoimmune paraneoplastic disease. Because these patients present complex neuropsychiatric symptoms due to NMDA-R dysfunction, the optimal methods of sedation/anesthesia remain controversial. Here, we present animal experiment data, along with a related case report, implying the safe and effective use of dexmedetomidine in patients with anti-NMDA-R encephalitis. FINDINGS: (1) Animal experiment: in order to investigate whether dexmedetomidine may interfere with NMDA-R activity, an NMDA antagonist (MK-801) model in rats was used to simulate anti-NMDA-R encephalitis...
2016: SpringerPlus
A Fodor, B Klausz, B Toth, D Zelena
OBJECTIVE: A disturbance of sensorimotor gating measured by prepulse inhibition of acoustic startle (PPI) is one of the best tests of the schizophrenia-like behavior. Vasopressin was implicated in the development of schizophrenia; therefore, the naturally occurring vasopressin-deficient Brattleboro rat has been suggested to be a reliable non-pharmacological animal model. However, previous studies focusing on PPI deficit did not use proper control and despite clear gender differences in the development of the disorder, the effect of gender has been mostly neglected...
January 2016: Endocrine Regulations
Linda J Bristow, Amy E Easton, Yu-Wen Li, Digavalli V Sivarao, Regina Lidge, Kelli M Jones, Debra Post-Munson, Christopher Daly, Nicholas J Lodge, Lizbeth Gallagher, Thaddeus Molski, Richard Pieschl, Ping Chen, Adam Hendricson, Ryan Westphal, James Cook, Christiana Iwuagwu, Daniel Morgan, Yulia Benitex, Dalton King, John E Macor, Robert Zaczek, Richard Olson
The development of alpha7 nicotinic acetylcholine receptor agonists is considered a promising approach for the treatment of cognitive symptoms in schizophrenia patients. In the present studies we characterized the novel agent, (2R)-N-(6-(1H-imidazol-1-yl)-4-pyrimidinyl)-4'H-spiro[4-azabicyclo[2.2.2]octane-2,5'-[1,3]oxazol]-2'-amine (BMS-933043), in vitro and in rodent models of schizophrenia-like deficits in cognition and sensory processing. BMS-933043 showed potent binding affinity to native rat (Ki = 3.3 nM) and recombinant human alpha7 nicotinic acetylcholine receptors (Ki = 8...
2016: PloS One
Elisabetta F Buonaguro, Carmine Tomasetti, Paolo Chiodini, Federica Marmo, Gianmarco Latte, Rodolfo Rossi, Livia Avvisati, Felice Iasevoli, Andrea de Bartolomeis
In this study, we investigated whether minocycline, a second-generation tetracycline proposed as an add-on to antipsychotics in treatment-resistant schizophrenia (TRS), may affect the expression of Homer and Arc postsynaptic density (PSD) transcripts, implicated in synaptic regulation. Minocycline was administered alone or with haloperidol in rats exposed or not to ketamine, mimicking acute glutamatergic psychosis or naturalistic conditions, respectively. Arc expression was significantly reduced by minocycline compared with controls...
July 21, 2016: Journal of Psychopharmacology
Alexandra I Zugno, Lara Canever, Alexandra S Heylmann, Patrícia G Wessler, Amanda Steckert, Gustavo A Mastella, Mariana B de Oliveira, Louyse S Damázio, Felipe D Pacheco, Octacílio P Calixto, Flávio P Pereira, Tamires P Macan, Thayara H Pedro, Patrícia F Schuck, João Quevedo, Josiane Budni
Recent studies have shown benefits for the supplementation of folic acid in schizophrenic patients. The aim of this study was to evaluate the effects of folic acid addition on adult rats, over a period of 7 or 14 days. It also sets out to verify any potential protective action using an animal model of schizophrenia induced by ketamine, in behavioral and biochemical parameters. This study used two protocols (acute and chronic) for the administration of ketamine at a dose of 25 mg/kg (i.p.). The folic acid was given by oral route in doses of 5, 10 and 50 mg/kg, once daily, for 7 and/or 14 days in order to compare the protective effects of folic acid...
October 2016: Journal of Psychiatric Research
Jen-Cheng Lin, Mei-Yi Lee, Ming-Huan Chan, Yi-Chyan Chen, Hwei-Hsien Chen
Ketamine is emerging as a new hope against depression, but ketamine-associated psychotomimetic effects limit its clinical use. An adjunct therapy along with ketamine to alleviate its adverse effects and even potentiate the antidepressant effects might be an alternative strategy. Betaine, a methyl derivative of glycine and a dietary supplement, has been shown to have antidepressant-like effects and to act like a partial agonist at the glycine site of N-methyl-D-aspartate receptors (NMDARs). Accordingly, betaine might have potential to be an adjunct to ketamine treatment for depression...
September 2016: Psychopharmacology
M Steffens, B Becker, C Neumann, A M Kasparbauer, I Meyhöfer, B Weber, M A Mehta, R Hurlemann, U Ettinger
The uncompetitive NMDA receptor antagonist ketamine has been proposed to model symptoms of psychosis. Smooth pursuit eye movements (SPEM) are an established biomarker of schizophrenia. SPEM performance has been shown to be impaired in the schizophrenia spectrum and during ketamine administration in healthy volunteers. However, the neural mechanisms mediating SPEM impairments during ketamine administration are unknown. In a counter-balanced, placebo-controlled, double-blind, within-subjects design, 27 healthy participants received intravenous racemic ketamine (100 ng/mL target plasma concentration) on one of two assessment days and placebo (intravenous saline) on the other...
June 25, 2016: Human Brain Mapping
David A Cox, Michael G Gottschalk, Hendrik Wesseling, Agnes Ernst, Jason D Cooper, Sabine Bahn
Pharmacological and genetic rodent models of schizophrenia play an important role in the drug discovery pipeline, but quantifying the molecular similarity of such models with the underlying human pathophysiology has proved difficult. We developed a novel systems biology methodology for the direct comparison of anterior prefrontal cortex tissue from four established glutamatergic rodent models and schizophrenia patients, enabling the evaluation of which model displays the greatest similarity to schizophrenia across different pathophysiological characteristics of the disease...
June 19, 2016: Schizophrenia Research
Paul M Anderson, Nigel C Jones, Terence J O'Brien, Didier Pinault
The non-competitive N-methyl d-aspartate glutamate receptor (NMDAR) antagonist ketamine elicits a brain state resembling high-risk states for developing psychosis and early stages of schizophrenia characterized by sensory and cognitive deficits and aberrant ongoing gamma (30-80 Hz) oscillations in cortical and subcortical structures, including the thalamus. The underlying mechanisms are unknown. The goal of the present study was to determine whether a ketamine-induced psychotic-relevant state disturbs the functional state of the corticothalamic (CT) pathway...
June 3, 2016: Cerebral Cortex
Benneth Ben-Azu, Adegbuyi Oladele Aderibigbe, Abayomi Mayowa Ajayi, Ezekiel Oluwagbenga Iwalewa
CONTEXT: Schizophrenia is a heterogenous neurological disorder, which has been hypothetically linked to oxidative imbalance and associated behavioral perturbations. Preliminary evidence from animal models predictive of human psychosis suggests that Terminalia ivorensis A. Chev. (Combretaceae) has antipsychotic-like activity in mice. OBJECTIVE: This study investigates the neuroprotective property of the ethanol stem bark extracts of T. ivorensis (EETI) in reversal treatment of ketamine-induced schizophrenia-like behaviors and oxidative alteration in adult male Swiss albino mice...
June 2, 2016: Pharmaceutical Biology
Zhen Qi, Gina P Yu, Felix Tretter, Oliver Pogarell, Anthony A Grace, Eberhard O Voit
BACKGROUND: The life of schizophrenia patients is severely affected by deficits in working memory. In various brain regions, the reciprocal interactions between excitatory glutamatergic neurons and inhibitory GABAergic neurons are crucial. Other neurotransmitters, in particular dopamine, serotonin, acetylcholine, and norepinephrine, modulate the local balance between glutamate and GABA and therefore regulate the function of brain regions. Persistent alterations in the balances between the neurotransmitters can result in working memory deficits...
November 2016: Biochimica et Biophysica Acta
Tiphaine Pouvreau, Emmanuelle Tagliabue, Yusuf Usun, Séverine Eybrard, Francisca Meyer, Alain Louilot
Striatal dopaminergic dysregulation in schizophrenia could result from a prefronto-striatal dysconnectivity, of neurodevelopmental origin, involving N-methyl-d-aspartate (NMDA) receptors. The dorsomedian shell part of the nucleus accumbens is a striatal subregion of particular interest inasmuch as it has been described as the common target region for antipsychotics. Moreover, NMDA receptors located on the dopaminergic endings have been reported in the shell. The present study examines in adult rats the effects of early functional inactivation of the left prefrontal cortex on behavioral and dopaminergic responses in the dorsomedian shell part of the nucleus accumbens following administration of two noncompetitive NMDA receptor antagonists, ketamine, and dizocilpine (MK-801)...
July 20, 2016: ACS Chemical Neuroscience
Anastasios Lafioniatis, Martha A Orfanidou, Evangelia S Papadopoulou, Nikolaos Pitsikas
Several lines evidence indicate that the non-competitive N-methyl-d-aspartate (NMDA) receptor antagonist ketamine and the mixed dopamine (DA) D1/D2 receptor agonist apomorphine induce schizophrenia-like symptoms in rodents, including memory impairments and social withdrawal. Nitric oxide (NO) has been proposed to act as an intracellular messenger in the brain and its overproduction is associated with schizophrenia. The current study was designed to investigate the ability of the inducible NO synthase (iNOS) inhibitor aminoguanidine (AG) to counteract schizophrenia-like behavioural deficits produced by ketamine and apomorphine in rats...
August 1, 2016: Behavioural Brain Research
M R Hudson, G Rind, T J O'Brien, N C Jones
Recent heuristic models of schizophrenia propose that abnormalities in the gamma frequency cerebral oscillations may be closely tied to the pathophysiology of the disorder, with hypofunction of N-methyl-d-aspartate receptors (NMDAr) implicated as having a crucial role. Prepulse inhibition (PPI) is a behavioural measure of sensorimotor gating that is disrupted in schizophrenia. We tested the ability for antipsychotic drugs with diverse pharmacological actions to (1) ameliorate NMDAr antagonist-induced disruptions to gamma oscillations and (2) attenuate NMDAr antagonist-induced disruptions to PPI...
2016: Translational Psychiatry
Danish Mahmood, Mohd Akhtar, Kausar Jahan, Dipanjan Goswami
BACKGROUND: Animal models based on N-methyl-d-aspartate receptor blockade have been extensively used for schizophrenia. Ketamine and MK-801 produce behaviors related to schizophrenia and exacerbated symptoms in patients with schizophrenia, which led to the use of PCP (phencyclidine)- and MK-801 (dizocilpine)-treated animals as models for schizophrenia. METHODS: The study investigated the effect of subchronic dosing (once daily, 7 days) of histamine H3 receptor (H3R) antagonists, ciproxifan (CPX) (3 mg/kg, i...
September 1, 2016: Journal of Basic and Clinical Physiology and Pharmacology
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