N-acetyl-L-aspartyl-L-glutamát (NAAG) je agonistou metabotropních glutamátových receptorů skupiny II. Cílem naší studie bylo zjistit, jestli neonatální (12. postnatální den) intacerebroventrikulární (i.c.v.) infuze NAAG, která vede k excitotoxickému poškození neuronů, neovlivní psychóze podobné chování způsobené podáním dizocilpinu (MK-801) v časné dospělosti (50. postnatální den). Chování potkanů bylo charakterizováno v testu otevřeného pole („open field test“). Dále byl sledován vliv neonatálně infundovaného NAAG na deficit ve zpracování senzorických informací (měřeno jako prepulzní inhibice – PPI – akustické úlekové reakce) způsobený i.p. injekcí MK-801. Pozorování svědčí pro významnou změnu chování potkana po podání MK-801, a to jak v testu otevřeného pole, tak i v PPI úlekové reakce. Samotné neonatální poškození mozku způsobené NAAG nemělo výrazný vliv ani na adaptivní chování ani na velikost PPI potkana v jeho časné dospělosti. Toto neonatální poškození mozku však snížilo deficit PPI u mladých dospělých zvířat způsobený i.p. injekcí MK-801, ale nemělo významný vliv na chování takto ovlivněných zvířat v testu otevřeného pole. Mechanizmus tohoto „protektivního“ účinku neonatální mozkové léze způsobené NAAG na zpracování senzorimotorických informací je diskutován.

N-acetyl-L-aspartyl-L-glutamate (NAAG) acts as an agonist of metabotropic glutamate receptors group II (mGluR II). The goal of the study was to investigate if intracerebroventricular (i.c.v.) infusion of NAAG (on postnatal day 12), leading to an neonatal (excitotoxic) brain lesion, can influence the psychosis-like behavior induced by dizocilpine (MK-801) in young adult rats (on postnatal day 50). Rat behavior was assessed by an open field test. Furthermore, the effect of neonatal brain damage on deficits in prepulse inhibition (PPI) of the acoustic startle response was investigated after the injection of MK-801. Obtained data revealed important changes in the rat behavior induced by injected MK-801 both in the open field test and in PPI. The neonatal NAAG-induced brain damage did not significantly change the adaptive behavior of young adults in the open field test and senzorimotor gating ascertained as PPI of acoustic startle. However, the neonatal infusion of NAAG decreased the deficits in PPI induced by administered MK-801 in early adulthood but did not alter significantly adaptive behavior in the open field test. Possible mechanisms of the „protective“ action of neonatal brain lesion induced by NAAG on the sensorimotor information processing will be discussed.

• MeSH
• chování MeSH
• dizocilpinmaleát aplikace a dávkování   farmakologie   MeSH
• finanční podpora výzkumu jako téma MeSH
• krysa rodu rattus MeSH
• modely u zvířat MeSH
• mozek patologie   účinky léků   MeSH
• receptory metabotropního glutamátu agonisté   aplikace a dávkování   fyziologie   MeSH
• receptory N-methyl-D-aspartátu fyziologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• zvířata MeSH
• Publikační typ
• přehledy MeSH
• srovnávací studie MeSH

N-Methyl-D-aspartátový (NMDA) receptor patří do skupiny glutamátových receptorů, které se dále dělí na ionotropní a metabotropní. V CNS má vliv na synaptickou plasticitu a rozvoj neuronálních synapsí. Ionotropní NMDA receptory jsou aktivovány glutamátem, díky čemuž proudí pozitivně nabité ionty skrz membránu po svém koncentračním gradientu. Nicméně nadměrné hladiny glutamátu působí excitotoxicky díky vysokým intracelulárním hladinám Ca2+ a mohou vést k buněčné smrti neuronů pozorované např. u neurodegenerativních onemocnění. Antagonisté NMDA receptorů, mezi které patří například dizocilpin, ovlivňují prostupnost NMDA receptoru a zamezují tak vstupu iontů Ca2+ do buňky. Dizocilpin působí jako nekompetitivní antagonista NMDA receptoru, má antikonvulzivní a anestetické účinky. Jeho terapeutické použití u lidí není vhodné z důvodu výskytu četných vedlejších účinků, experimentálně je však využíván jako farmakologicky indukovaný animální model schizofrenie.

N-Methyl-D-aspartate (NMDA) receptor belongs to the group of glutamate receptors, which are further divided into ionotropic and metabotropic. It affects synaptic plasticity and the development of neuronal synapsis in CNS. Ionotropic NMDA receptors are activated by glutamate, thereby flowing positively charged ions through the membrane along its concentration gradient. However, glutamate overload leads to excitotoxicity, due to high levels of Ca2+, which leads to cell death assocciated with neurodegenerative diseases. NMDA antagonists like dizocilpine reduce intracellular concentration of Ca2+ by modulating permeability of NMDA receptor channel. Dizocilpine act as a non-competitive NMDA receptor antagonist with anticonvulsant and anesthetic properties. Its therapeutic use in humans is limited due its numerous side effects, but it is experimentally used as an animal model of schizophrenia.

• MeSH
• agonisté excitačních aminokyselin terapeutické užití   MeSH
• antipsychotika terapeutické užití   MeSH
• dizocilpinmaleát * terapeutické užití   MeSH
• farmakologické jevy MeSH
• krysa rodu rattus MeSH
• modely u zvířat MeSH
• morčata MeSH
• N-methylaspartát terapeutické užití   MeSH
• schizofrenie farmakoterapie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• morčata MeSH
• zvířata MeSH
• Publikační typ
• práce podpořená grantem MeSH
• přehledy MeSH

The discoordination hypothesis of schizophrenia posits discoordination of neural activity as the central mechanism that underlies some psychotic symptoms (including 'hallmark' cognitive symptoms) of schizophrenia. To test this proposition, we studied the activity of hippocampal neurons in urethane anesthetized Long Evans rats after 0.15mg/kg dizocilpine (MK-801), an N-Methyl-d-aspartate (NMDA) glutamate receptor antagonist, which can cause psychotic symptoms in humans and cognitive control impairments in animals. We observed that MK-801 altered the temporal coordination, but not rate, of neuronal firing. Coactivation between neurons increased, driven primarily by increased coincident firing of cell pairs that did not originally fire together before MK-801 injection. Increased pairwise coactivation manifested as disorganized discharge on the level of neuronal ensembles, which in turn could lead to disorganization in information processing. Disorganization of neuronal activity after a psychotomimetic dose of MK-801 supports the discoordination hypothesis of psychosis.

• MeSH
• akční potenciály účinky léků   fyziologie   MeSH
• dizocilpinmaleát farmakologie   MeSH
• hipokampus účinky léků   patofyziologie   MeSH
• mikroelektrody MeSH
• neurony účinky léků   fyziologie   MeSH
• potkani Long-Evans MeSH
• psychotropní léky farmakologie   MeSH
• theta rytmus EEG účinky léků   fyziologie   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

• MeSH
• dizocilpinmaleát aplikace a dávkování   MeSH
• epilepsie parciální MeSH
• krysa rodu rattus MeSH
• mozková kůra patofyziologie   MeSH
• novorozenec MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• novorozenec MeSH
• zvířata MeSH

Spatial working memory or short-term place memory is impaired in schizophrenia. The efficiency of antipsychotic drugs, particularly of typical antipsychotics, on cognitive deficit in schizophrenia remains disputable. Inhibition of serotonin (5-HT) 2A/2C receptors is important for cognitive improvement in schizophrenic patients treated with antipsychotics. The aim of the present work was to establish the effect of the 5-HT2A/2C receptor antagonist ritanserin (2.5 or 5 mg/kg), the dopamine D2 antagonist haloperidol (0.1 or 1 mg/kg), and the atypical antipsychotic risperidone (0.1 mg/kg or 1 mg/kg), which is an antagonist of both 5-HT2A/2C and D2 receptors, on cognitive deficit induced by subchronic administration of dizocilpine (MK-801, 0.1 mg/kg). We used the active allothetic place avoidance (AAPA) task, requiring the rat to differentiate between relevant and irrelevant stimuli, in a way similar to disruption of information processing disturbed in schizophrenic patients. Our results show that treatment with 5-HT2A/2C receptor antagonists, regardless of their effect on D2 receptors, blocked the cognitive impairment produced by MK-801. Haloperidol did not sufficiently reduce the deficit in AAPA induced by MK-801. Interestingly, administration of risperidone and haloperidol alone, but not ritanserin, impaired the AAPA performance in intact rats. Ritanserin and risperidone actually improve cognition independently of their effect on locomotor activity in an animal model of schizophrenia-like behavior. This finding is in accordance with the assumption that some antipsychotics are primarily effective against cognitive dysfunction in schizophrenia.

• MeSH
• časové faktory MeSH
• chování zvířat účinky léků   MeSH
• dizocilpinmaleát farmakologie   MeSH
• financování organizované MeSH
• haloperidol farmakologie   MeSH
• krysa rodu rattus MeSH
• potkani Wistar MeSH
• risperidon farmakologie   MeSH
• ritanserin farmakologie   MeSH
• učení vyhýbat se účinky léků   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH

• MeSH
• chování zvířat účinky léků   MeSH
• dizocilpinmaleát farmakologie   MeSH
• ischemie patologie   MeSH
• králíci MeSH
• mícha krevní zásobení   patologie   účinky léků   MeSH
• stříbro MeSH
• zvířata MeSH
• Check Tag
• králíci MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• zvířata MeSH

N-methyl-D-aspartate receptors (NMDARs) play a significant role in developing several central nervous system (CNS) disorders. Currently, memantine, used for treating Alzheimer's disease, and ketamine, known for its anesthetic and antidepressant properties, are two clinically used NMDAR open-channel blockers. However, despite extensive research into NMDAR modulators, many have shown either harmful side effects or inadequate effectiveness. For instance, dizocilpine (MK-801) is recognized for its powerful psychomimetic effects due to its high-affinity and nearly irreversible inhibition of the GluN1/GluN2 NMDAR subtypes. Unlike ketamine, memantine and MK-801 also act through a unique, low-affinity "membrane-to-channel inhibition" (MCI). We aimed to develop an open-channel blocker based on MK-801 with distinct inhibitory characteristics from memantine and MK-801. Our novel compound, K2060, demonstrated effective voltage-dependent inhibition in the micromolar range at key NMDAR subtypes, GluN1/GluN2A and GluN1/GluN2B, even in the presence of Mg2+. K2060 showed reversible inhibitory dynamics and a partially trapping open-channel blocking mechanism with a significantly stronger MCI than memantine. Using hippocampal slices, 30 μM K2060 inhibited excitatory postsynaptic currents in CA1 hippocampal neurons by ∼51 %, outperforming 30 μM memantine (∼21 % inhibition). K2060 exhibited No Observed Adverse Effect Level (NOAEL) of 15 mg/kg upon intraperitoneal administration in mice. Administering K2060 at a 10 mg/kg dosage resulted in brain concentrations of approximately 2 μM, with peak concentrations (Tmax) achieved within 15 minutes. Finally, applying K2060 with trimedoxime and atropine in mice exposed to tabun improved treatment outcomes. These results underscore K2060's potential as a therapeutic agent for CNS disorders linked to NMDAR dysfunction.

• MeSH
• antagonisté excitačních aminokyselin farmakologie   MeSH
• dizocilpinmaleát * farmakologie   MeSH
• excitační postsynaptické potenciály účinky léků   MeSH
• hipokampus účinky léků   metabolismus   MeSH
• lidé MeSH
• memantin farmakologie   MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• neurony účinky léků   metabolismus   MeSH
• receptory N-methyl-D-aspartátu * antagonisté a inhibitory   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

RATIONALE: Augmentation therapy with serotonin-1A receptor (5-HT1A) partial agonists has been suggested to ameliorate psychotic symptoms in patients with schizophrenia. OBJECTIVE AND METHODS: The objective of the present study was to examine the effect of repeated administration of tandospirone (0.05 and 5 mg/kg) on locomotor activity in a novel environment and on sensorimotor gating in rats treated with the N-methyl-D-aspartate receptor antagonist MK-801, which has been used in animal models of schizophrenia. Furthermore, we sought to determine whether the effect of tandospirone on these behavioural measures is blocked by WAY 100635 (0.3 mg/kg), a 5-HT1A receptor antagonist, and whether there is an interaction between haloperidol (0.1 mg/kg; a dopamine-D2 receptor antagonist) and tandospirone. RESULTS: Tandospirone at 5 mg/kg, but not 0.05 mg/kg, decreased locomotor activity in saline or MK-801-treated rats, which were not affected by co-treatment with WAY 100635. Haloperidol decreased locomotion both in saline and MK-801-treated animals, and this effect was not evident in the latter group receiving the higher dose of tandospirone. Tandospirone (5 mg/kg)-induced disruption of sensorimotor gating in saline or MK-801-treated animals was reversed by WAY-100635, but not by haloperidol. CONCLUSIONS: These findings suggest that behavioural changes induced by tandospirone are not fully blocked by 5-HT1A antagonists and that tandospirone (5 mg/kg) potentiates the effect of MK-801. Overall, these findings point to an interaction between NMDA and 5-HT(1A) receptors. Part of the effect of tandospirone on locomotor activity may be mediated by the actions of its active metabolites on other neurotransmitter systems.

• MeSH
• agonisté serotoninových receptorů aplikace a dávkování   farmakologie   MeSH
• antagonisté excitačních aminokyselin toxicita   MeSH
• antipsychotika farmakologie   MeSH
• dizocilpinmaleát toxicita   MeSH
• haloperidol farmakologie   MeSH
• isoindoly aplikace a dávkování   farmakologie   MeSH
• krysa rodu rattus MeSH
• modely nemocí na zvířatech MeSH
• piperaziny aplikace a dávkování   farmakologie   MeSH
• pohybová aktivita účinky léků   MeSH
• potkani Wistar MeSH
• pyrimidiny aplikace a dávkování   farmakologie   MeSH
• receptor serotoninový 5-HT1A účinky léků   metabolismus   MeSH
• schizofrenie farmakoterapie   patofyziologie   MeSH
• senzorický gating účinky léků   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• srovnávací studie MeSH

Schizophrenia is a devastating disorder affecting 1 % of the world's population. An important role in the study of this disease is played by animal models. Since there is evidence that acute psychotic episodes can have consequences on later cognitive functioning, the present study has investigated the effects of a single systemic application of higher doses of (+)MK-801 (3 mg/kg and 5 mg/kg) to adult male Long-Evans rats from the Institute's breeding colony on delayed testing in the active place avoidance task with reversal on the Carousel (a rotating arena). Besides significant mortality due to the injections, a disruption of procedural functions in active place avoidance, after the dose 5 mg/kg was observed. It was concluded that Long-Evans rats from our breeding colony do not represent a suitable biomodel for studying the effects of single high-dose NMDA antagonists.

• MeSH
• antagonisté excitačních aminokyselin aplikace a dávkování   toxicita   MeSH
• dizocilpinmaleát aplikace a dávkování   toxicita   MeSH
• kognitivní poruchy chemicky indukované   psychologie   MeSH
• krysa rodu rattus MeSH
• potkani Long-Evans MeSH
• psychomotorický výkon účinky léků   MeSH
• reverzní učení účinky léků   MeSH
• toxické psychózy psychologie   MeSH
• učení vyhýbat se účinky léků   MeSH
• úniková reakce účinky léků   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

The prevention of engram interference, pattern separation, flexibility, cognitive coordination and spatial navigation are usually studied separately at the behavioral level. Impairment in executive functions is often observed in patients suffering from schizophrenia. We have designed a protocol for assessing these functions all together as behavioral separation. This protocol is based on alternated or sequential training in two tasks testing different hippocampal functions (the Morris water maze and active place avoidance), and alternated or sequential training in two similar environments of the active place avoidance task. In Experiment 1, we tested, in adult rats, whether the performance in two different spatial tasks was affected by their order in sequential learning, or by their day-to-day alternation. In Experiment 2, rats learned to solve the active place avoidance task in two environments either alternately or sequentially. We found that rats are able to acquire both tasks and to discriminate both similar contexts without obvious problems regardless of the order or the alternation. We used two groups of rats, controls and a rat model of psychosis induced by a subchronic intraperitoneal application of 0.08mg/kg of dizocilpine (MK-801), a non-competitive antagonist of NMDA receptors. Dizocilpine had no selective effect on parallel/sequential learning of tasks/contexts. However, it caused hyperlocomotion and a significant deficit in learning in the active place avoidance task regardless of the task alternation. Cognitive coordination tested by this task is probably more sensitive to dizocilpine than spatial orientation because no hyperactivity or learning impairment was observed in the Morris water maze.

• MeSH
• analýza rozptylu MeSH
• antagonisté excitačních aminokyselin toxicita   MeSH
• bludiště - učení účinky léků   MeSH
• dizocilpinmaleát toxicita   MeSH
• krysa rodu rattus MeSH
• lokomoce účinky léků   MeSH
• modely nemocí na zvířatech MeSH
• poruchy učení chemicky indukované   patofyziologie   MeSH
• potkani Long-Evans MeSH
• reakční čas účinky léků   MeSH
• učení vyhýbat se účinky léků   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH