INTRODUCTION: Psilocybin is one of the most extensively studied psychedelic drugs with a broad therapeutic potential. Despite the fact that its psychoactivity is mainly attributed to the agonism at 5-HT2A receptors, it has high binding affinity also to 5-HT2C and 5-HT1A receptors and indirectly modulates the dopaminergic system. Psilocybin and its active metabolite psilocin, as well as other serotonergic psychedelics, induce broadband desynchronization and disconnection in EEG in humans as well as in animals. The contribution of serotonergic and dopaminergic mechanisms underlying these changes is not clear. The present study thus aims to elucidate the pharmacological mechanisms underlying psilocin-induced broadband desynchronization and disconnection in an animal model. METHODS: Selective antagonists of serotonin receptors (5-HT1A WAY100635, 5-HT2A MDL100907, 5-HT2C SB242084) and antipsychotics haloperidol, a D2 antagonist, and clozapine, a mixed D2 and 5-HT receptor antagonist, were used in order to clarify the underlying pharmacology. RESULTS: Psilocin-induced broadband decrease in the mean absolute EEG power was normalized by all antagonists and antipsychotics used within the frequency range 1-25 Hz; however, decreases in 25-40 Hz were influenced only by clozapine. Psilocin-induced decrease in global functional connectivity and, specifically, fronto-temporal disconnection were reversed by the 5-HT2A antagonist while other drugs had no effect. DISCUSSION: These findings suggest the involvement of all three serotonergic receptors studied as well as the role of dopaminergic mechanisms in power spectra/current density with only the 5-HT2A receptor being effective in both studied metrics. This opens an important discussion on the role of other than 5-HT2A-dependent mechanisms underlying the neurobiology of psychedelics.

• Publikační typ
• časopisecké články MeSH

Serotonergic psychedelics are recently gaining a lot of attention as a potential treatment of several neuropsychiatric disorders. Broadband desynchronization of EEG activity and disconnection in humans have been repeatedly shown; however, translational data from animals are completely lacking. Therefore, the main aim of our study was to assess the effects of tryptamine and phenethylamine psychedelics (psilocin 4 mg/kg, LSD 0.2 mg/kg, mescaline 100 mg/kg, and DOB 5 mg/kg) on EEG in freely moving rats. A system consisting of 14 cortical EEG electrodes, co-registration of behavioral activity of animals with subsequent analysis only in segments corresponding to behavioral inactivity (resting-state-like EEG) was used in order to reach a high level of translational validity. Analyses of the mean power, topographic brain-mapping, and functional connectivity revealed that all of the psychedelics irrespective of the structural family induced overall and time-dependent global decrease/desynchronization of EEG activity and disconnection within 1-40 Hz. Major changes in activity were localized on the large areas of the frontal and sensorimotor cortex showing some subtle spatial patterns characterizing each substance. A rebound of occipital theta (4-8 Hz) activity was detected at later stages after treatment with mescaline and LSD. Connectivity analyses showed an overall decrease in global connectivity for both the components of cross-spectral and phase-lagged coherence. Since our results show almost identical effects to those known from human EEG/MEG studies, we conclude that our method has robust translational validity.

• MeSH
• elektroencefalografie MeSH
• krysa rodu rattus MeSH
• LSD * farmakologie   MeSH
• meskalin * MeSH
• psilocybin analogy a deriváty   farmakologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Metabolic and behavioural effects of, and interactions between Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) are influenced by dose and administration route. Therefore we investigated, in Wistar rats, effects of pulmonary, oral and subcutaneous (sc.) THC, CBD and THC+CBD. Concentrations of THC, its metabolites 11-OH-THC and THC-COOH, and CBD in serum and brain were determined over 24h, locomotor activity (open field) and sensorimotor gating (prepulse inhibition, PPI) were also evaluated. In line with recent knowledge we expected metabolic and behavioural interactions between THC and CBD. While cannabinoid serum and brain levels rapidly peaked and diminished after pulmonary administration, sc. and oral administration produced long-lasting levels of cannabinoids with oral reaching the highest brain levels. Except pulmonary administration, CBD inhibited THC metabolism resulting in higher serum/brain levels of THC. Importantly, following sc. and oral CBD alone treatments, THC was also detected in serum and brain. S.c. cannabinoids caused hypolocomotion, oral treatments containing THC almost complete immobility. In contrast, oral CBD produced mild hyperlocomotion. CBD disrupted, and THC tended to disrupt PPI, however their combination did not. In conclusion, oral administration yielded the most pronounced behavioural effects which corresponded to the highest brain levels of cannabinoids. Even though CBD potently inhibited THC metabolism after oral and sc. administration, unexpectedly it had minimal impact on THC-induced behaviour. Of central importance was the novel finding that THC can be detected in serum and brain after administration of CBD alone which, if confirmed in humans and given the increasing medical use of CBD-only products, might have important legal and forensic ramifications.

• MeSH
• akustická stimulace MeSH
• analýza rozptylu MeSH
• aplikace inhalační MeSH
• aplikace orální MeSH
• časové faktory MeSH
• fixní kombinace léků MeSH
• injekce subkutánní MeSH
• kanabidiol aplikace a dávkování   farmakokinetika   MeSH
• krysa rodu rattus MeSH
• mozek účinky léků   metabolismus   MeSH
• pátrací chování účinky léků   MeSH
• plynová chromatografie s hmotnostně spektrometrickou detekcí MeSH
• potkani Wistar MeSH
• prepulsní inhibice účinky léků   MeSH
• tetrahydrokanabinol aplikace a dávkování   farmakokinetika   MeSH
• tkáňová distribuce účinky léků   MeSH
• způsoby aplikace léků MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Psilocybin has recently attracted a great deal of attention as a clinical research and therapeutic tool. The aim of this paper is to bridge two major knowledge gaps regarding its behavioural pharmacology - sex differences and the underlying receptor mechanisms. We used psilocin (0.25, 1 and 4 mg/kg), an active metabolite of psilocybin, in two behavioural paradigms - the open-field test and prepulse inhibition (PPI) of the acoustic startle reaction. Sex differences were evaluated with respect to the phase of the female cycle. The contribution of serotonin receptors in the behavioural action was tested in male rats with selective serotonin receptor antagonists: 5-HT1A receptor antagonist (WAY100635 1 mg/kg), 5-HT2A receptor antagonist (MDL100907 0.5 mg/kg), 5-HT2B receptor antagonist (SB215505 1 mg/kg) and 5-HT2C receptor antagonist (SB242084 1 mg/kg). Psilocin induced dose-dependent inhibition of locomotion and suppression of normal behaviour in rats (behavioural serotonin syndrome, impaired PPI). The effects were more pronounced in male rats than in females. The inhibition of locomotion was normalized by 5-HT1A and 5-HT2B/C antagonists; however, PPI was not affected significantly by these antagonists. Our findings highlight an important issue of sex-specific reactions to psilocin and that apart from 5-HT2A-mediated effects 5-HT1A and 5-HT2C/B receptors also play an important role. These findings have implications for recent clinical trials.

• MeSH
• antagonisté serotoninu farmakologie   MeSH
• estrální cyklus fyziologie   MeSH
• halucinogeny aplikace a dávkování   farmakologie   MeSH
• krysa rodu rattus MeSH
• lokomoce účinky léků   MeSH
• potkani Wistar MeSH
• psilocybin aplikace a dávkování   analogy a deriváty   farmakologie   MeSH
• receptory serotoninové účinky léků   metabolismus   MeSH
• serotonin metabolismus   MeSH
• sexuální faktory MeSH
• úleková reakce účinky léků   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH

Intracerebroventikulární aplikace agregovaného P-amyloidu je považována za model časného stádia Alzheimerovy demence. Dospělým potkaním samcům byl do postranních komor aplikován agregovaný (25-35)-(3-amyloidový fragment a následně byl imunohistochemicky zjištován jeho vliv na proliferaci a přežívání nově vzniklých buněk v hipokampu (anti-BrdU) a na aktivaci mikroglie (anti-CDUb). (25-35)-p-amyloidový fragment vyvolal zvýšenou proliferaci buněk v hipokampu a také dalších částech mozku (kůra, okolí mozkových komor). Dvě třetiny BrdU-pozitivních buněk byly detekovány ještě 3 týdny po proliferaci. Oblasti zvýšené proliferace odpovídaly oblastem s výskytem aktivované mikroglie.

Intracerebroventricular application of aggregated  -amyloid is considered to be a model of an early stage of Alzheimer disease. Adult male rats were administrered with aggregated (25-35)-  -amyloid fragment into lateral ventricles and subsequently its influence on proliferation and survival of new cells in the hippocampus (anti-BrdU) and on microglial ac- tivation (anti-CD11b) was investigated. (25-35)-  -amyloid fragment indu- ced an increase in cell proliferation in the hippocampus as well as in other brain regions (cortex, periventricular area). Two thirds of BrdU-positive cells were still detected 3 weeks after cell proliferation. The regions of incre- ased proliferation corresponded with the occurence of activated microglia.

• Publikační typ
• abstrakt z konference MeSH

Naším hlavním cílem bylo prozkoumat v animálním modelu u potkana akutní účinky delta-9-tetrahydrokanabinolu (THC) na lokomocní aktivitu (test otevřeného pole) a senzorimotorické zpracování informací (prepulzní inhibice akustické úlekové reakce, PPI ASR). Smyslem experimentu bylo zjistit, zda akutní účinky THC mohou indukovat psychóze podobné chování. V našich experimentech jsme prokázali, že THC u potkanů narušilo normální chování v testu otevřeného pole a současně vedlo k narušení PPI ASR. Vzhledem k podobnosti těchto nálezů s nálezy u schizofrenních pacientů a v jiných modelech psychóz tyto výsledky podporují relevanci akutních účinků THC jako modelu psychózy.

Our main aim was to examine the effect of acute administration of delta-9-tetrahydrocannabinol (THC) on locomotor activity (open field test) and sensorimotor gating (prepulse inhibition of acoustic startle reaction, PPI ASR) in animal model in rats. The purpose of the experiment was to determine whether acute effects of THC administra- tion can induce psychosis-like behavior. Our experiments showed that THC altered normal behavior in the open field test and at the same time it disrupted PPI ASR. When we take into consideration the resemblance of these findings to the data acquired from schizophrenic patients and other models of psychosis these results support the relevancy of acute effects of THC as a model of psychosis.

• Publikační typ
• abstrakt z konference MeSH

Smyslem této studie bylo zhodnotit behaviorální účinky vybraných nových syntetických drog (NSD) a jejich vliv na termoregulaci v ammálnim modelu. Měřili jsme lokomoční aktivitu zvířat, senzorimotorické zpracování informací a změnu tělesné teploty (za podmínky. kdy byla zvířata izolována, a za podmínky, kdy byla ve skupinách). Testované substance byly mefedron, methylon, 5,6-methylendioxy-2-aminoindan (MDAI) a para-methoxymetamfetamin (PMMA). Všechny substance měly stimulační účinky, narušovaly senzorimotorické zpracování informací a indukovaly hypertermii (výrazněji u zvířat ve skupinách). Nejúčinnějším simulantem byla droga mefedron. MDAI a PMMA pak nejvýrazněji narušovaly senzorimotorické zpracování informací. Poslední dvě zmíněné substance také nejvíce zvyšovaly tělesnou teplotu. Nejméně potentní substancí byla droga methylon.

The purpose of this study was to elucidate behavioral effects and the effects on thermoregulation of selected new synthetic drugs (NSD) in animal model. Locomotor activity, sensorimotor gating and change in body temperature (under isolated and crowded conditions) were evalua- ted. The compounds tested were: mephedrone, methylone, 5,6-methyle- nedioxy-2-aminoindane (MDAI) and para-methoxymethamphetamine (PMMA). All NSD had stimulatory effects, disrupted sensorimotor gating and induced hyperthermia (more pronounced under crowded condition). Mephedrone was the most powerful stimulant. On the contrary MDAI and PMMA were the most potent in disrupting sensorimotor gating and in inducing hyperthermia. Methylon had the lowest potency.

• Publikační typ
• abstrakt z konference MeSH

Tato studie zkoumala vliv halucinogenu psilocinu a specifických antagonistů na EEG u potkana. EEG signál byl zaznamenaván subdurálními elektrodami z kůry potkaního mozku a posléze kvantitativně analyzován. Psilocin způsobil pokles spektrálního výkonu i funkční konektivity. Antagonisté serotonergních receptoru do různé míry normalizovaly tyto změny. Studie potvrzuje validitu animálního serotonergního modelu psychózy a naznačuje možnosti vývoje antipsychotické léčby.

This study explored the impact of hallucinogen psilocin and specific antagonists on EEG in rats. EEG signal was recorded from the cortex of the rat brain and subsequently quantitatively analyzed. Psilocin caused the decrement of spectral power and functional connectivity. Serotonin antagonists normalized these changes to varying degrees. The study confirms validity of animal serotonergic model of psychosis and suggests the possibility of developing treatment.

• Publikační typ
• abstrakt z konference MeSH

V této studii jsme hodnotili, zda-li intracerebroventrikulární (ICV) aplikace (25-35)-P-amyloid fragmentu (AP25.35) vyvolá změny v EEG záznamu a změny v kognitivních a exploračních schopnostech potkanů, které by odpovídaly animálnímu modelu Alzheimerovy demence (AD). EEG záznam byl registrován z 12 aktivních elektrod, následně byl podroben spektrální a koherenční analýze, behaviorální parametry byly hodnoceny v testu rozpoznání nového objektu (novel object recognition test, NOR). Všechny experimenty byly provedeny 4 týdny od ICV aplikace Ap25- 35 a 1 týden po implantaci elektrod. Ap25- 35 zvyšoval relativní výkon v pásmech beta, vysoká beta a gama, dále byl zjevný pík v theta pásmu při 6 Hz. V pásmu delta došlo k mírnému snížení relativního výkonu. AP25 35 aplikace dále významně snižovala koherence. V behaviorální studii pak AP25-35 indukoval výrazné změny v chování, zejména snížení až vymizení základních exploračních aktivit, zkrácení lokomoce a vymizení habituace. Z toho důvodu nebylo ani možné u těchto je¬ dinců hodnotit krátkodobou paměť. Naše nálezy v tomto modelu částečně odpovídají nálezům u AD.

In our study we evaluated whether intracerebroventricular (ICV) application of (25-35)-  -amyloid fragment (A  25-35 ) induces changes in rat's EEG signal, cognitive and explorative skills that would correspond to animal model of Alzheimer ́s disease (AD). The EEG signals were registered from 12 active electrodes. Signal was then analyzed by spectral and coherence analysis. Behavioral parameters were measured in the novel object recognition test (NOR). All the experiments were performed 4 week after ICV application of A  25-35 and 1 week after implantation of EEG electrodes. A  25-35 increased the relative power of beta, high beta and gamma, induced significant 6Hz peak in theta band. Slight depres- sion of relative power occurred in the delta band. A significant decrease of coherence also occurred after A  25-35 application. A  25-35 induced also significant changes in the behavior, especially diminution of basic explorative activities, reduction of locomotion and loss of habituation. Because of these alterations animals did not fulfill the criteria for analysis of short term memory in NOR. Our results particularly correspond to the findings found in patients with AD.

• Publikační typ
• abstrakt z konference MeSH