Naphyrone, also known as NRG-1, is a novel psychoactive substance (NPS), a cathinone with stimulatory properties available on the grey/illicit drug market for almost a decade. It is structurally related to infamously known powerful stimulants with the pyrovalerone structure, such as alpha-pyrrolidinovalerophenone (α-PVP) or methylenedioxypyrovalerone (MDPV) that are labeled as a cheap replacement for cocaine and other stimulants. Despite the known addictive potential of α-PVP and MDPV, there are no studies directly evaluating naphyrone's addictive potential e.g., in conditioned place preference (CPP) test or using self-administration. Therefore, our study was designed to evaluate the addictive potential in a CPP test in male Wistar rats and compare its effect to another powerful stimulant with a high addictive potential - methamphetamine. Naphyrone increased time spent in the drug-paired compartment with 5 and 20 mg/kg s.c. being significant and 10 mg/kg s.c. reaching the threshold (p = 0.07); the effect was comparable to that of methamphetamine 1.5 mg/kg s.c. The lowest dose, naphyrone 1 mg/kg s.c., had no effect on CPP. Interestingly, no dose response effect was detected. Based on these data, we are able to conclude that naphyrone has an addictive potential and may possess a significant risk to users.

• MeSH
• alkaloidy farmakologie   MeSH
• chování zvířat účinky léků   MeSH
• klasické podmiňování účinky léků   MeSH
• krysa rodu rattus MeSH
• methamfetamin aplikace a dávkování   farmakologie   MeSH
• modely nemocí na zvířatech MeSH
• pentanony aplikace a dávkování   farmakologie   MeSH
• poruchy spojené s užíváním psychoaktivních látek * MeSH
• potkani Wistar MeSH
• pyrrolidiny aplikace a dávkování   farmakologie   MeSH
• stimulanty centrálního nervového systému aplikace a dávkování   farmakologie   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

Schizophrenia is severe neuropsychiatric disease, which is commonly accompanied not only by positive or negative symptoms, but also by cognitive impairment. To study neuronal mechanisms underlying cognitive distortions and mechanisms underlying schizophrenia, animal pharmacological models of cognitive symptoms are commonly used. Between various cognitive impairments in schizophrenia patients, disturbed time perception has often been reported. Here, we examined temporal and spatial cognition in a modified Carousel maze task in the animal model of schizophrenia induced by non-competitive NMDA-receptor antagonists MK-801. Male Long-Evans rats (n = 18) first learned to avoid the aversive sector on a rotating arena in both dark and light intervals. We verified that during dark, rats used temporal cues, while during light they relied predominantly on spatial cues. We demonstrated that the timing strategy depends on the stable rotation speed of the arena and on the repositioning clues such as aversive stimuli. During testing (both in light and dark intervals), half of the rats received MK-801 and the control half received saline solution. We observed dose-dependent disruptions of both temporal and spatial cognition. Namely, both doses of MK-801 (0.1 and 0.12 mg/kg) significantly impaired timing strategy in the dark and increased locomotor activity. MK-801 dose 0.1 mg/kg, but not 0.12, also impaired spatial avoidance strategy in light. We found that the timing strategy is more sensitive to NMDA antagonist MK-801 than the spatial strategy. To conclude, a modified version of the Carousel maze is a useful and sensitive tool for detecting timing impairments in the MK-801 induced rodent model of schizophrenia.

• MeSH
• antagonisté excitačních aminokyselin aplikace a dávkování   farmakologie   MeSH
• bludiště - učení účinky léků   MeSH
• chování zvířat účinky léků   MeSH
• dizocilpinmaleát aplikace a dávkování   farmakologie   MeSH
• kognitivní dysfunkce chemicky indukované   patofyziologie   MeSH
• krysa rodu rattus MeSH
• modely nemocí na zvířatech MeSH
• potkani Long-Evans MeSH
• schizofrenie chemicky indukované   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

BACKGROUND AND PURPOSE: Deschloroketamine (DCK), a structural analogue of ketamine, has recently emerged on the illicit drug market as a recreational drug with a modestly long duration of action. Despite it being widely used by recreational users, no systematic research on its effects has been performed to date. EXPERIMENTAL APPROACH: Pharmacokinetics, acute effects, and addictive potential in a series of behavioural tests in Wistar rats were performed following subcutaneous (s.c.) administration of DCK (5, 10, and 30 mg·kg-1 ) and its enantiomers S-DCK (10 mg·kg-1 ) and R-DCK (10 mg·kg-1 ). Additionally, activity at human N-methyl-d-aspartate (NMDA) receptors was also evaluated. KEY RESULTS: DCK rapidly crossed the blood brain barrier, with maximum brain levels achieved at 30 min and remaining high at 2 h after administration. Its antagonist activity at NMDA receptors is comparable to that of ketamine with S-DCK being more potent. DCK had stimulatory effects on locomotion, induced place preference, and robustly disrupted PPI. Locomotor stimulant effects tended to disappear more quickly than disruptive effects on PPI. S-DCK had more pronounced stimulatory properties than its R-enantiomer. However, the potency in disrupting PPI was comparable in both enantiomers. CONCLUSION AND IMPLICATIONS: DCK showed similar behavioural and addictive profiles and pharmacodynamics to ketamine, with S-DCK being in general more active. It has a slightly slower pharmacokinetic profile than ketamine, which is consistent with its reported longer duration of action. These findings have implications and significance for understanding the risks associated with illicit use of DCK.

• MeSH
• chování zvířat * účinky léků   MeSH
• ketamin * aplikace a dávkování   škodlivé účinky   analogy a deriváty   farmakokinetika   farmakologie   MeSH
• krysa rodu rattus MeSH
• lokomoce * účinky léků   MeSH
• potkani Wistar MeSH
• receptory N-methyl-D-aspartátu metabolismus   MeSH
• zakázané drogy * škodlivé účinky   farmakokinetika   farmakologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Hyaluronan (HA) is a core constituent of perineuronal nets (PNNs) that surround subpopulations of neurones. The PNNs control synaptic stabilization in both the developing and adult central nervous system, and disruption of PNNs has shown to reactivate neuroplasticity. We investigated the possibility of memory prolongation by attenuating PNN formation using 4-methylumbelliferone (4-MU), an inhibitor of HA synthesis. Adult C57BL/6 mice were fed with chow containing 5% (w/w) 4-MU for 6 months, at a dose ~6.7 mg/g/day. The oral administration of 4-MU reduced the glycosaminoglycan level in the brain to 72% and the spinal cord to 50% when compared to the controls. Spontaneous object recognition test (SOR) performed at 2, 3, 6 and 7 months showed a significant increase in SOR score in the 6-months treatment group 24 h after object presentation. The effect however did not persist in the washout group (1-month post treatment). Immunohistochemistry confirmed a reduction of PNNs, with shorter and less arborization of aggrecan staining around dendrites in hippocampus after 6 months of 4-MU treatment. Histopathological examination revealed mild atrophy in articular cartilage but it did not affect the motor performance as demonstrated in rotarod test. In conclusion, systemic oral administration of 4-MU for 6 months reduced PNN formation around neurons and enhanced memory retention in mice. However, the memory enhancement was not sustained despite the reduction of PNNs, possibly due to the lack of memory enhancement training during the washout period. Our results suggest that 4-MU treatment might offer a strategy for PNN modulation in memory enhancement.

• MeSH
• agrekany účinky léků   MeSH
• aplikace orální MeSH
• centrální nervový systém účinky léků   MeSH
• chování zvířat účinky léků   MeSH
• extracelulární matrix účinky léků   MeSH
• hymekromon aplikace a dávkování   farmakologie   MeSH
• kyselina hyaluronová metabolismus   MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• neuroplasticita účinky léků   MeSH
• oligodendroglie účinky léků   MeSH
• rozpoznávání (psychologie) účinky léků   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Methamphetamine (MA), as massively abused psychoactive stimulant, has been associated with many neurological diseases. It has various potent and neurotoxic properties. There are many mechanisms of action that contribute to its neurotoxic and degenerative effects, including excessive neurotransmitter (NEU) release, blockage of NEU uptake transporters, degeneration of NEU receptors, process of oxidative stress etc. MA intoxication is caused by blood-brain barrier disruption resulted from MA-induced oxidation stress. In our laboratory we constantly work on animal research of MA. Our current interest is to investigate processes of MA-induced alteration in neurotransmission, especially during development of laboratory rat. This review will describe current understanding in role of NEUs, which are affected by MA-induced neurotoxicity caused by altering the action of NEUs in the central nervous system (CNS). It also briefly brings information about NEUs development in critical periods of development.

• MeSH
• centrální nervový systém účinky léků   růst a vývoj   metabolismus   MeSH
• chování zvířat účinky léků   MeSH
• krysa rodu rattus MeSH
• lidé MeSH
• methamfetamin toxicita   MeSH
• nervový přenos účinky léků   MeSH
• neurogeneze účinky léků   MeSH
• neurotoxické syndromy etiologie   metabolismus   patologie   MeSH
• neurotransmiterové látky toxicita   MeSH
• stimulanty centrálního nervového systému toxicita   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Methamphetamine (MA) is one of the most abused psychostimulants in the Czech Republic and worldwide. Previous studies have demonstrated the adverse effects of maternal drug abuse. However, the father's contribution as a parent and donor of the half genetic information is unclear. The present study aimed to examine the effect of paternal MA exposure on behavioral development and locomotor activity in rat offspring. MA was administrated subcutaneously for 30 days at a dose of 5 mg/kg to adult male rats. The impact of paternal MA exposure on rat pups was investigated using behavioral tests during development and locomotor activity tests in adulthood. Prior to testing, adult offspring were exposed to an acute challenge dose of MA (1 mg/kg) to examine the possible sensitizing effect of the paternal treatment. Our results found no significant differences in behavioral development or locomotor activity in adulthood of offspring linked to paternal MA application. These results differ from the effects induced by maternal MA application. Further, our results demonstrated a significant increase in locomotor activity on the Laboras test after acute MA application. When comparing sex differences, females showed more activity than males in adulthood, whereas males were more active during development.

• MeSH
• chování zvířat účinky léků   MeSH
• krysa rodu rattus MeSH
• lokomoce účinky léků   MeSH
• methamfetamin toxicita   MeSH
• metoda rotující tyčky MeSH
• otec - expozice noxám * MeSH
• pohlavní dimorfismus MeSH
• polohový reflex účinky léků   MeSH
• potkani Wistar MeSH
• senzorimotorický kortex účinky léků   růst a vývoj   MeSH
• sexuální faktory MeSH
• stimulanty centrálního nervového systému toxicita   MeSH
• věkové faktory MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• srovnávací studie MeSH

Perinatal exposure to Δ9-tetrahydrocannabinol (THC) affects brain development and might increase the incidence of psychopathology later in life, which seems to be related to a dysregulation of endocannabinoid and/or dopaminergic systems. We here evaluated the transcriptional regulation of the genes encoding for the cannabinoid CB1 receptor (Cnr1) and the dopamine D2 receptor (Drd2) in perinatal THC-(pTHC) exposed male rats, focusing on the role of DNA methylation analyzed by pyrosequencing. Simultaneously, the molecular and behavioral abnormalities at two different time points (i.e., neonatal age and adulthood) and the potential preventive effect of peripubertal treatment with cannabidiol, a non-euphoric component of Cannabis, were assessed. The DRD2 methylation was also evaluated in a cohort of subjects with schizophrenia. We observed an increase in both Cnr1 and Drd2 mRNA levels selectively in the prefrontal cortex of adult pTHC-exposed rats with a consistent reduction in DNA methylation at the Drd2 regulatory region, paralleled by social withdrawal and cognitive impairment which were reversed by cannabidiol treatment. These adult abnormalities were preceded at neonatal age by delayed appearance of neonatal reflexes, higher Drd2 mRNA and lower 2-arachidonoylglycerol (2-AG) brain levels, which persisted till adulthood. Alterations of the epigenetic mark for DRD2 were also found in subjects with schizophrenia. Overall, reported data add further evidence to the dopamine-cannabinoid interaction in terms of DRD2 and CNR1 dysregulation which could be implicated in the pathogenesis of schizophrenia spectrum disorders, suggesting that cannabidiol treatment may normalize pTHC-induced psychopathology by modulating the altered dopaminergic activity.

• MeSH
• chování zvířat účinky léků   MeSH
• lidé MeSH
• maternofetální výměna látek MeSH
• messenger RNA metabolismus   MeSH
• metylace DNA účinky léků   MeSH
• potkani Sprague-Dawley MeSH
• prefrontální mozková kůra účinky léků   metabolismus   MeSH
• receptor kanabinoidní CB1 genetika   MeSH
• receptory dopaminu D2 genetika   MeSH
• regulace genové exprese účinky léků   MeSH
• schizofrenie genetika   MeSH
• těhotenství MeSH
• tetrahydrokanabinol farmakologie   MeSH
• zpožděný efekt prenatální expozice * MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Evidence from clinical and preclinical studies implicates dysfunction of N-methyl-D-aspartate receptors (NMDARs) in schizophrenia progression and symptoms. We investigated the antipsychotic effect of two neuroactive steroids in an animal model of schizophrenia induced by systemic application of MK-801. The neuroactive steroids differ in their mechanism of action at NMDARs. MS-249 is positive, while PA-Glu is a negative allosteric NMDAR modulator. We hypothesized that the positive NMDA receptor modulator would attenuate deficits caused by MK-801 co-application more effectively than PA-Glu. The rats were tested in a battery of tests assessing spontaneous locomotion, anxiety and cognition. Contrary to our expectations, PA-Glu exhibited a superior antipsychotic effect to MS-249. The performance of MS-249-treated rats in cognitive tests differed depending on the level of stress the rats were exposed to during test sessions. In particular, with the increasing severity of stress exposure, the performance of animals worsened. Our results demonstrate that enhancement of NMDAR function may result in unspecific behavioral responses. Positive NMDAR modulation can influence other neurobiological processes besides memory formation, such as anxiety and response to stress.

• MeSH
• antipsychotika farmakologie   MeSH
• bicyklické sloučeniny heterocyklické metabolismus   MeSH
• chování zvířat účinky léků   MeSH
• dizocilpinmaleát farmakologie   MeSH
• HEK293 buňky MeSH
• lidé MeSH
• modely nemocí na zvířatech MeSH
• potkani Long-Evans MeSH
• potkani Wistar MeSH
• pregnenolon metabolismus   farmakologie   MeSH
• receptory N-methyl-D-aspartátu antagonisté a inhibitory   metabolismus   MeSH
• schizofrenie farmakoterapie   metabolismus   MeSH
• steroidy farmakologie   MeSH
• test vyvýšeného křížového bludiště MeSH
• úleková reakce účinky léků   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Chronic sensitization to serotonin 1A and 7 receptors agonist 8-OH-DPAT induces compulsive checking and perseverative behavior. As such, it has been used to model obsessive-compulsive disorder (OCD)-like behavior in mice and rats. In this study, we tested spatial learning in the 8-OH-DPAT model of OCD and the effect of co-administration of memantine and riluzole-glutamate-modulating agents that have been shown to be effective in several clinical trials. Rats were tested in the active place avoidance task in the Carousel maze, where they learned to avoid the visually imperceptible shock sector. All rats were subcutaneously injected with 8-OH-DPAT (0.25 mg/kg) or saline (control group) during habituation. During acquisition, they were pretreated with riluzole (1 mg/kg), memantine (1 mg/kg), or saline solution 30 min before each session and injected with 8-OH-DPAT ("OH" groups) or saline ("saline" groups) right before the experiment. We found that repeated application of 8-OH-DPAT during both habituation and acquisition significantly increased locomotion, but it impaired the ability to avoid the shock sector. However, the application of 8-OH-DPAT in habituation had no impact on the learning process if discontinued in acquisition. Similarly, memantine and riluzole did not affect the measured parameters in the "saline" groups, but in the "OH" groups, they significantly increased locomotion. In addition, riluzole increased the number of entrances and decreased the maximum time avoided of the shock sector. We conclude that monotherapy with glutamate-modulating agents does not reduce but exacerbates cognitive symptoms in the animal model of OCD.

• MeSH
• 8-hydroxy-2-(di-N-propylamino)tetralin škodlivé účinky   farmakologie   MeSH
• chování zvířat účinky léků   MeSH
• krysa rodu rattus MeSH
• memantin farmakologie   MeSH
• modely nemocí na zvířatech MeSH
• obsedantně kompulzivní porucha * chemicky indukované   farmakoterapie   patofyziologie   MeSH
• paměť účinky léků   MeSH
• potkani Long-Evans MeSH
• prostorové učení účinky léků   MeSH
• riluzol farmakologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Schizophrenia is a debilitating mental disorder characterized by positive, negative and cognitive symptoms. Whereas positive symptoms are satisfactorily addressed by current antipsychotic treatment, negative and cognitive symptomatic treatment remains largely ineffective. This review investigates the treatment efficacy regarding cognitive symptoms and evaluates the contribution of different monoamine receptor systems involved in schizophrenia pathophysiology to cognition. In the review, we included preclinical studies assessing the effect of different treatments on cognition in pre-pulse inhibition and two spatial cognitive tests. While pre-pulse inhibition investigates pre-attentive processes operating outside of conscious awareness, the spatial tasks require continuous attention and active engagement in task solving for a successful outcome. The schizophrenia-like phenotype was attained by acute or subchronic administration of non-competitive NMDA receptor antagonist MK-801.

• MeSH
• antipsychotika farmakologie   terapeutické užití   MeSH
• chování zvířat účinky léků   MeSH
• modely nemocí na zvířatech * MeSH
• nervový přenos účinky léků   MeSH
• schizofrenie farmakoterapie   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH