Cannabidiol (CBD), a non-psychotomimetic constituent of Cannabis sativa, has been recently approved for epileptic syndromes often associated with Autism spectrum disorder (ASD). However, the putative efficacy and mechanism of action of CBD in patients suffering from ASD and related comorbidities remain debated, especially because of the complex pharmacology of CBD. We used pharmacological, immunohistochemical and biochemical approaches to investigate the effects and mechanisms of action of CBD in the recently validated Fmr1-Δexon 8 rat model of ASD, that is also a model of Fragile X Syndrome (FXS), the leading monogenic cause of autism. CBD rescued the cognitive deficits displayed by juvenile Fmr1-Δexon 8 animals, without inducing tolerance after repeated administration. Blockade of CA1 hippocampal GPR55 receptors prevented the beneficial effect of both CBD and the fatty acid amide hydrolase (FAAH) inhibitor URB597 in the short-term recognition memory deficits displayed by Fmr1-Δexon 8 rats. Thus, CBD may exert its beneficial effects through CA1 hippocampal GPR55 receptors. Docking analysis further confirmed that the mechanism of action of CBD might involve competition for brain fatty acid binding proteins (FABPs) that deliver anandamide and related bioactive lipids to their catabolic enzyme FAAH. These findings demonstrate that CBD reduced cognitive deficits in a rat model of FXS and provide initial mechanistic insights into its therapeutic potential in neurodevelopmental disorders.
- MeSH
- hipokampální oblast CA1 účinky léků metabolismus MeSH
- hipokampus * účinky léků metabolismus MeSH
- kanabidiol * farmakologie terapeutické užití MeSH
- krysa rodu rattus MeSH
- modely nemocí na zvířatech * MeSH
- paměť účinky léků MeSH
- protein FMRP metabolismus genetika MeSH
- receptory kanabinoidní * metabolismus MeSH
- receptory spřažené s G-proteiny metabolismus MeSH
- rozpoznávání (psychologie) * účinky léků MeSH
- simulace molekulového dockingu MeSH
- syndrom fragilního X * farmakoterapie metabolismus MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví 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
In agreement with the neurodevelopmental hypothesis of schizophrenia, prenatal exposure of rats to the antimitotic agent methylazoxymethanol acetate (MAM) at gestational day 17 produced long-lasting behavioral alterations such as social withdrawal and cognitive impairment in the social interaction test and in the novel object recognition test, respectively. At the molecular level, an increased cannabinoid receptor type-1 (CB1) mRNA and protein expression, which might be due to reduction in DNA methylation at the gene promoter in the prefrontal cortex (PFC), coincided with deficits in the social interaction test and in the novel object recognition test in MAM rats. Both the schizophrenia-like phenotype and altered transcriptional regulation of CB1 receptors were reversed by peripubertal treatment (from PND 19 to PND 39) with the non-psychotropic phytocannabinoid cannabidiol (30 mg/kg/day), or, in part, by treatment with the cannabinoid CB1 receptor antagonist/inverse agonist AM251 (0.5 mg/kg/day), but not with haloperidol (0.6 mg/kg/day). These results suggest that early treatment with cannabidiol may prevent both the appearance of schizophrenia-like deficits as well as CB1 alterations in the PFC at adulthood, supporting that peripubertal cannabidiol treatment might be protective against MAM insult.
- MeSH
- endokanabinoidy metabolismus MeSH
- ethanolaminy metabolismus MeSH
- glyceridy metabolismus MeSH
- hipokampus metabolismus MeSH
- interpersonální vztahy MeSH
- kanabidiol farmakologie MeSH
- krysa rodu rattus MeSH
- kyseliny arachidonové metabolismus MeSH
- kyseliny olejové metabolismus MeSH
- kyseliny palmitové metabolismus MeSH
- messenger RNA metabolismus MeSH
- methylazoxymethanolacetát farmakologie MeSH
- modely nemocí na zvířatech MeSH
- piperidiny farmakologie MeSH
- pohybová aktivita účinky léků MeSH
- polynenasycené alkamidy metabolismus MeSH
- prefrontální mozková kůra metabolismus MeSH
- puberta MeSH
- pyrazoly farmakologie MeSH
- receptor kanabinoidní CB1 metabolismus MeSH
- rozpoznávání (psychologie) účinky léků MeSH
- schizofrenie chemicky indukované farmakoterapie metabolismus MeSH
- těhotenství MeSH
- zpožděný efekt prenatální expozice farmakoterapie metabolismus MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- těhotenství MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
In the present study, the effect of the medial septal (MS) lesions on exploratory activity in the open field and the spatial and object recognition memory has been investigated. This experiment compares three types of MS lesions: electrolytic lesions that destroy cells and fibers of passage, neurotoxic - ibotenic acid lesions that spare fibers of passage but predominantly affect the septal noncholinergic neurons, and immunotoxin - 192 IgG-saporin infusions that only eliminate cholinergic neurons. The main results are: the MS electrolytic lesioned rats were impaired in habituating to the environment in the repeated spatial environment, but rats with immuno- or neurotoxic lesions of the MS did not differ from control ones; the MS electrolytic and ibotenic acid lesioned rats showed an increase in their exploratory activity to the objects and were impaired in habituating to the objects in the repeated spatial environment; rats with immunolesions of the MS did not differ from control rats; electrolytic lesions of the MS disrupt spatial recognition memory; rats with immuno- or neurotoxic lesions of the MS were normal in detecting spatial novelty; all of the MS-lesioned and control rats clearly reacted to the object novelty by exploring the new object more than familiar ones. Results observed across lesion techniques indicate that: (i) the deficits after nonselective damage of MS are limited to a subset of cognitive processes dependent on the hippocampus, (ii) MS is substantial for spatial, but not for object recognition memory - the object recognition memory can be supported outside the septohippocampal system; (iii) the selective loss of septohippocampal cholinergic or noncholinergic projections does not disrupt the function of the hippocampus to a sufficient extent to impair spatial recognition memory; (iv) there is dissociation between the two major components (cholinergic and noncholinergic) of the septohippocampal pathway in exploratory behavior assessed in the open field - the memory exhibited by decrements in exploration of repeated object presentations is affected by either electrolytic or ibotenic lesions, but not saporin.
- MeSH
- bludiště - učení účinky léků fyziologie MeSH
- hipokampus účinky léků patologie fyziologie MeSH
- imunotoxiny toxicita MeSH
- krysa rodu rattus MeSH
- neurotoxiny toxicita MeSH
- pátrací chování účinky léků fyziologie MeSH
- potkani Wistar MeSH
- rozpoznávání (psychologie) účinky léků fyziologie MeSH
- septální jádra účinky léků patologie fyziologie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
The use of methamphetamine (MA) among pregnant women is an increasing world-wide health problem. Prenatal MA exposure may cause changes in foetus but the exact effects have remained unclear. The aim of this study is to present the effect of prenatal MA exposure on recognition memory in adult rats. Adult female Wistar rats were injected daily with D-methamphetamine HCl (MA; 5 mg/kg, s.c.) during the entire gestation period. Control females were treated with saline in the same regime. Adult male offspring was administrated acutely by MA (1 mg/kg i.p.) or saline 30 minutes before beginning of an experiment. For testing recognition memory two tasks were chosen: Novel Object Recognition Test (NORT) and Object Location Test (OLT). Our results demonstrate that prenatally MA-exposed animals were worse in NORT independently on an acute administration of MA in adulthood. Prenatally MA-exposed rats did not deteriorate in OLT, but after acute administration of MA in adulthood, there was significant worsening compared to appropriate control. Prenatally saline-exposed offspring did not deteriorate in any test even after acute administration of MA. Our data suggest that prenatal MA exposure in rats cause impairment in recognition memory in adult offspring, but not in spatial memory. In addition, acute administration of MA to controls did not deteriorate either recognition or spatial memory.
- MeSH
- chování zvířat účinky léků MeSH
- krysa rodu rattus MeSH
- methamfetamin toxicita MeSH
- modely nemocí na zvířatech MeSH
- novorozená zvířata MeSH
- paměť účinky léků MeSH
- potkani Wistar MeSH
- rozpoznávání (psychologie) účinky léků MeSH
- stimulanty centrálního nervového systému toxicita MeSH
- těhotenství u zvířat * MeSH
- těhotenství MeSH
- zpožděný efekt prenatální expozice chemicky indukované psychologie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- těhotenství MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Rat hippocampus plays a crucial role in many spatial tasks, including recognition of position of objects, which can be approached and explored. Whether hippocampus is also necessary for recognizing positions of objects located in an inaccessible part of the environment remains unclear. To address this question, we conditioned rats to press a lever when an object displayed on a distant computer screen was in a particular position ("reward position") and not to press the lever when the object was in other positions ("nonreward positions"). After the rats had reached an asymptotic performance, the role of the dorsal hippocampus was assessed by blocking its activity with muscimol. The rats without functional dorsal hippocampus did not discriminate the reward position from the nonreward positions. Then the same rats were trained to discriminate light and dark conditions. The hippocampal inactivation did not disrupt the ability to discriminate these two conditions. It indicated that the inactivation itself had no major effect on the operant behavior and its control by visual stimuli. We conclude that rats use dorsal hippocampus for recognizing positions of objects located in an inaccessible part of the environment.
- MeSH
- chování zvířat fyziologie MeSH
- diskriminace (psychologie) účinky léků fyziologie MeSH
- hipokampus účinky léků fyziologie MeSH
- krysa rodu rattus MeSH
- muscimol farmakologie MeSH
- operantní podmiňování MeSH
- potkani Long-Evans MeSH
- receptory GABA-A - antagonisté farmakologie MeSH
- rozpoznávání (psychologie) účinky léků fyziologie MeSH
- vnímání prostoru účinky léků fyziologie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Prazosin, an alpha(1)-adrenoceptor antagonist, is well known for its depressant effect on motivation and motor activity, while it has no effect on retention of spatial behavior in several tasks, e.g. in the Morris water maze and radial arm maze. The role of alpha(1)-adrenoceptors in operant tasks with stimulus-controlled behavior has not yet been tested. The present study investigated the effect of prazosin on the modulation of overall motor activity and on cognitive performance in a spatial operant task called object-position recognition task, where operant behavior (lever pressing) was controlled by spatial stimuli displayed on a computer screen. This task has been previously showed to be hippocampal-dependent. Pre-test injection of prazosin at the dose of 3 mg/kg decreased the responding rate, while it did not affect the recognition of object's position. In conclusion, we validated the new cognitive test with a drug with known pharmacological effects on behavior and confirmed the depressant effect of prazosin on motor activity and no effect on retrieval of spatial memory in the hippocampal-dependent operant task.
- MeSH
- alfa-1-adrenergní receptory - antagonisté farmakologie MeSH
- alfa-1-adrenergní receptory účinky léků metabolismus MeSH
- chování zvířat účinky léků MeSH
- hipokampus účinky léků metabolismus MeSH
- kognice účinky léků MeSH
- krysa rodu rattus MeSH
- operantní podmiňování účinky léků MeSH
- pohybová aktivita účinky léků MeSH
- potkani Long-Evans MeSH
- prazosin farmakologie MeSH
- rozpoznávání (psychologie) účinky léků MeSH
- vnímání prostoru 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
- MeSH
- analýza rozptylu MeSH
- časové faktory MeSH
- chování zvířat účinky léků MeSH
- finanční podpora výzkumu jako téma MeSH
- krysa rodu rattus MeSH
- lékové interakce MeSH
- náhodné rozdělení MeSH
- neparametrická statistika MeSH
- nootropní látky aplikace a dávkování terapeutické užití MeSH
- poruchy paměti chemicky indukované prevence a kontrola MeSH
- potkani Wistar MeSH
- pyrrolidiny aplikace a dávkování terapeutické užití MeSH
- rozpoznávání (psychologie) účinky léků MeSH
- rozvrh dávkování léků MeSH
- sociální izolace MeSH
- trimethylcínové sloučeniny MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- srovnávací studie MeSH
- MeSH
- chování zvířat účinky léků MeSH
- čich účinky záření MeSH
- finanční podpora výzkumu jako téma MeSH
- glutamát sodný toxicita MeSH
- krysa rodu rattus MeSH
- novorozená zvířata fyziologie MeSH
- pohybová aktivita účinky léků MeSH
- potkani Wistar MeSH
- rozpoznávání (psychologie) účinky léků MeSH
- sociální chování MeSH
- těhotenství MeSH
- tělesná hmotnost účinky léků MeSH
- úzkost psychologie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- těhotenství MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- srovnávací studie MeSH