RATIONALE: Mescaline is a classical psychedelic compound with a phenylethylamine structure that primarily acts on serotonin 5-HT2A/C receptors, but also binds to 5-HT1A and 5-HT2B receptors. Despite being the first psychedelic ever isolated and synthesized, the precise role of different serotonin receptor subtypes in its behavioral pharmacology is not fully understood. OBJECTIVES: In this study, we aimed to investigate how selective antagonists of 5-HT2A, 5-HT2B, 5-HT2C, and 5-HT1A receptors affect the behavioral changes induced by subcutaneous administration of mescaline (at doses of 10, 20, and 100 mg/kg) in rats. METHODS: We used adult male Wistar rats in all our experiments. We evaluated locomotor activity using the open field test, and assessed sensorimotor gating deficits by measuring prepulse inhibition (PPI) of acoustic startle reaction (ASR). RESULTS: While the highest dose of mescaline induced hyperlocomotion (p < 0.001), which almost all the other antagonists reversed (p < 0.05-0.001), the PPI deficits were selectively normalized by the 5-HT2A antagonist (p < 0.05-0.01). The 5-HT2C antagonist partially reversed the small PPI deficit induced by lower doses of mescaline (p = 0.0017). CONCLUSION: Our findings suggest that mescaline-induced changes in behavior are primarily mediated by the 5-HT2A receptor subtype, with less pronounced contributions from the 5-HT2C receptor. The other antagonists had limited effects.

• Klíčová slova
• Locomotor activity, Mescaline, Sensorimotor gating, Serotonin receptors,
• MeSH
• antagonisté serotoninových receptorů 5-HT2 farmakologie   MeSH
• antagonisté serotoninu farmakologie   MeSH
• chování zvířat * účinky léků   MeSH
• halucinogeny farmakologie   aplikace a dávkování   MeSH
• krysa rodu Rattus MeSH
• lokomoce účinky léků   MeSH
• meskalin * farmakologie   MeSH
• pohybová aktivita účinky léků   MeSH
• potkani Wistar * MeSH
• prepulsní inhibice účinky léků   MeSH
• receptor serotoninový 5-HT2A * metabolismus   účinky léků   MeSH
• receptor serotoninový 5-HT2C * metabolismus   účinky léků   MeSH
• úleková 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
• Názvy látek
• antagonisté serotoninových receptorů 5-HT2 MeSH
• antagonisté serotoninu MeSH
• halucinogeny MeSH
• meskalin * MeSH
• receptor serotoninový 5-HT2A * MeSH
• receptor serotoninový 5-HT2C * MeSH

Chronic methamphetamine (meth) abuse often turns into a compulsive drug-taking disorder accompanied by persistent cognitive deficits and re-occurring psychosis. Possible common neurobiological substrates underlying meth-induced deficits and schizophrenia remain poorly understood. Serotonin 2A (5-HT2A) and metabotropic glutamate 2 (mGlu2) receptors co-regulate psychosis-like behaviors and cognitive function in animals. Therefore, in the present study we examined the effects of chronic exposure to three different drugs known to produce persistent deficits in sensorimotor gating and cognition [meth, phencyclidine (PCP) and MK-801] on the expression of 5-HT2A and mGlu2 within the rat medial prefrontal cortex (mPFC), dorsal hippocampus (dHPC) and perirhinal cortex (PRh). Adult male rats underwent 14 days of: (a) meth self-administration (6 h/day), (b) phencyclidine (PCP; 5 mg/kg, twice/day) administration, or (c) MK-801 (0.3 mg/kg, twice/day) administration. Seven days after the discontinuation of drug administration, tissues of interest were collected for protein expression analysis. We found that despite different pharmacological mechanism of action, chronic meth, PCP, and MK-801 similarly dysregulated 5-HT2A and mGlu2, as indicated by an increase in the 5-HT2A/mGlu2 expression ratio in the mPFC (all three tested drugs), PRh (meth and PCP), and dHPC (MK-801 only). Complementary changes in G-protein expression (increase in Gαq and decrease in Gαi) were also observed in the mPFC of meth animals. Finally, we found that 5-HT2A/mGlu2 cooperation can be mediated in part by the formation of the receptor heteromer in some, but not all cortical regions. In summary, these data suggest that a shift towards increased availability (and G-protein coupling) of cortical 5-HT2A vs. mGlu2 receptors may represent a common neurobiological mechanism underlying the emergence of psychosis and cognitive deficits observed in subjects with meth use disorder and schizophrenia.

• Klíčová slova
• 5-HT2A, Heterocomplex, MK-801, Methamphetamine, Phencyclidine, mGlu2,
• MeSH
• dizocilpinmaleát farmakologie   MeSH
• fencyklidin farmakologie   MeSH
• imunoprecipitace MeSH
• krysa rodu Rattus MeSH
• methamfetamin aplikace a dávkování   farmakologie   MeSH
• perirhinální mozková kůra účinky léků   metabolismus   MeSH
• potkani Long-Evans MeSH
• potkani Wistar MeSH
• prefrontální mozková kůra účinky léků   metabolismus   MeSH
• protilátky imunologie   MeSH
• receptor serotoninový 5-HT2A imunologie   metabolismus   MeSH
• receptory metabotropního glutamátu metabolismus   MeSH
• reprodukovatelnost výsledků 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
• srovnávací studie MeSH
• Názvy látek
• dizocilpinmaleát MeSH
• fencyklidin MeSH
• metabotropic glutamate receptor 2 MeSH Prohlížeč
• methamfetamin MeSH
• protilátky MeSH
• receptor serotoninový 5-HT2A MeSH
• receptory metabotropního glutamátu MeSH

Pergolide, terguride and N,N'-spacer-linked oligomers of both have been tested for their ability to interact with 5 hydroxytryptamine(HT)2A receptors of rat tail artery. Pergolide was a potent partial agonist (pEC50 7.5, Emax 55 %) and antagonized 5-HT-induced contractions (pKp 7.2). Pergolide dimer 3 with a p-xylene spacer between the indole nitrogens (N-1) displayed somewhat lower agonist potency than pergolide (pEC50 7.0, Emax 55 %, pKp 6.6). The contractile responses to pergolide and dimer 3 were antagonized by the 5-HT2A receptor antagonist ketanserin (pA2 9.4, 9.1). In contrast to pergolide dimer 3, pergolide dimers 5 and 9 with an alkyl and an aralkyl spacer between the piperidine nitrogens (N-6) lacked agonism and displayed low affinity at 5-HT2A receptors (pA2 < 5.5). Terguride behaved as an insurmountable antagonist of 5-HT (pA2 8.4). Oligomers of terguride showed 5 to 50-fold lower affinity. It is concluded that pergolide and terguride show a high affinity for 5-HT2A receptors, but dimerization (oligomerization) of both drugs fails to increase affinity.

• MeSH
• agonisté dopaminu chemie   metabolismus   farmakologie   MeSH
• arterie účinky léků   metabolismus   MeSH
• dimerizace MeSH
• krysa rodu Rattus MeSH
• lisurid analogy a deriváty   chemie   metabolismus   farmakologie   MeSH
• ocas krevní zásobení   MeSH
• peptidové fragmenty chemie   metabolismus   farmakologie   MeSH
• pergolid chemie   metabolismus   farmakologie   MeSH
• potkani Wistar MeSH
• receptor serotoninový 5-HT2A metabolismus   MeSH
• serotonin farmakologie   MeSH
• vazokonstrikce 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
• Názvy látek
• agonisté dopaminu MeSH
• dironyl MeSH Prohlížeč
• lisurid MeSH
• peptidové fragmenty MeSH
• pergolid MeSH
• receptor serotoninový 5-HT2A MeSH
• serotonin MeSH

A single dose of the serotonin 2A receptor (5-HT2AR) agonist psilocybin can have long-lasting beneficial effects on mood, personality, and potentially on mindfulness, but underlying mechanisms are unknown. Here, we for the first time conduct a study that assesses psilocybin effects on cerebral 5-HT2AR binding with [11C]Cimbi-36 positron emission tomography (PET) imaging and on personality and mindfulness. Ten healthy and psychedelic-naïve volunteers underwent PET neuroimaging of 5-HT2AR at baseline (BL) and one week (1W) after a single oral dose of psilocybin (0.2-0.3 mg/kg). Personality (NEO PI-R) and mindfulness (MAAS) questionnaires were completed at BL and at three-months follow-up (3M). Paired t-tests revealed statistically significant increases in personality Openness (puncorrected = 0.04, mean change [95%CI]: 4.2[0.4;∞]), which was hypothesized a priori to increase, and mindfulness (pFWER = 0.02, mean change [95%CI]: 0.5 [0.2;0.7]). Although 5-HT2AR binding at 1W versus BL was similar across individuals (puncorrected = 0.8, mean change [95%CI]: 0.007 [-0.04;0.06]), a post hoc linear regression analysis showed that change in mindfulness and 5-HT2AR correlated negatively (β [95%CI] = -5.0 [-9.0; -0.9], pFWER= 0.046). In conclusion, we confirm that psilocybin intake is associated with long-term increases in Openness and - as a novel finding - mindfulness, which may be a key element of psilocybin therapy. Cerebral 5-HT2AR binding did not change across individuals but the negative association between changes in 5-HT2AR binding and mindfulness suggests that individual change in 5-HT2AR levels after psilocybin is variable and represents a potential mechanism influencing long-term effects of psilocybin on mindfulness.

• Klíčová slova
• 5-HT2AR, Mindfulness, PET, Personality, Psilocybin,
• MeSH
• benzylaminy MeSH
• dospělí MeSH
• fenethylaminy MeSH
• halucinogeny aplikace a dávkování   farmakologie   MeSH
• lidé MeSH
• magnetická rezonanční tomografie MeSH
• mladý dospělý MeSH
• neokortex diagnostické zobrazování   účinky léků   metabolismus   MeSH
• neuropsychologické testy MeSH
• osobnost účinky léků   MeSH
• osobnostní testy MeSH
• pozitronová emisní tomografie MeSH
• psilocybin aplikace a dávkování   farmakologie   MeSH
• receptor serotoninový 5-HT2A účinky léků   metabolismus   MeSH
• všímavost * MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• benzylaminy MeSH
• Cimbi-36 MeSH Prohlížeč
• fenethylaminy MeSH
• halucinogeny MeSH
• HTR2A protein, human MeSH Prohlížeč
• psilocybin MeSH
• receptor serotoninový 5-HT2A MeSH

Epidemiological and clinical studies suggest that asthma is associated with adverse cardiovascular outcomes, but its mechanism is uncertain. 5-Hydroxytryptamine (5-HT) is a mediator involved in asthma and in cardiovascular functioning. Thus, in the present study, we explored whether allergic sensitization in guinea pigs modifies 5-HT-induced contractile responses and 5-HT2A receptor expression in thoracic aorta rings. We found that sensitization produced a significant increase of 100 microM 5-HT-induced contractions of aorta rings (~27 % greater contraction than in non-sensitized animals, p<0.05). Preincubation with 10 nM ketanserin (a 5-HT2A receptor antagonist) reduced by ~30 % (p=0.003) and ~36 % (p=0.005) the area under the curve of 5-HT-induced contractions in aortas from non-sensitized and sensitized animals, respectively. There were no differences between sensitized and non-sensitized animals with respect to mRNA (qPCR) and protein (Western blot) expression of 5-HT2A receptor in thoracic aortas. We concluded that in this guinea pig model of asthma, allergic sensitization is not confined to airways, but also affects arterial contractile responses to 5-HT; changes in the expression of the 5-HT2A receptor appear not to be involved in this phenomenon.

• MeSH
• aorta patofyziologie   MeSH
• bronchiální astma patofyziologie   MeSH
• modely nemocí na zvířatech MeSH
• morčata MeSH
• receptor serotoninový 5-HT2A fyziologie   MeSH
• serotonin fyziologie   MeSH
• svaly hladké cévní patofyziologie   MeSH
• zvířata MeSH
• Check Tag
• morčata MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• receptor serotoninový 5-HT2A MeSH
• serotonin MeSH

Anorexia nervosa is a serious psychiatric disorder characterized by the inability to maintain normal body weight. The frequently studied polymorphisms in the serotonin 5-HT2A receptor gene (-1438A/G) and in serotonin transporter 5-HTT gene (LPR, VNTR) have led to controversial results in different populations. The aim of the study was to address association of the above-mentioned polymorphisms with anorexia nervosa in the Czech population. We genotyped a well-defined group of 75 patients with anorexia nervosa (average age of 25.39 years, SD 6.18; average BMI 14.65 (SD 1.38)). The control group consisted of 65 Caucasian healthy females (average age 25.76 years, SD 5.12; average BMI 20.69, SD 1.85). The 5-HT2A receptor -1438A/G polymorphism analysis showed a trend for the association with odds ratios for risk allele A being in the same direction. In combination with a previously published Polish cohort, the allelic test reached a suggestive borderline (P = 0.0362, chi2 statistics, 1 df). In meta-analysis which included all published results for allelic tests, the resulting P value was highly significant (0.0003, chi2 statistics, 1 df). Using quantitative association of 5-HTR2A polymorphism with BMI in the Czech sample, a borderline association (P = 0.055) was observed. In 5-HTT, LPR polymorphism analysis, unlike in 5-HT2A, neither allelic nor quantitative association with BMI for the bi-allelic 5-HTT marker was observed. Results of this study support previous reports of a significant role of the A allele (-1438A/G, 5-HT2A receptor) as a risk factor in anorexia nervosa.

• MeSH
• alely MeSH
• dospělí MeSH
• frekvence genu MeSH
• genotyp MeSH
• lidé MeSH
• membránové transportní proteiny pro serotonin genetika   MeSH
• mentální anorexie genetika   MeSH
• mladý dospělý MeSH
• optimální tělesná hmotnost MeSH
• polymorfismus genetický * MeSH
• receptor serotoninový 5-HT2A genetika   MeSH
• serotonin genetika   MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mladý dospělý MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• metaanalýza MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Česká republika MeSH
• Názvy látek
• membránové transportní proteiny pro serotonin MeSH
• receptor serotoninový 5-HT2A MeSH
• serotonin MeSH

AIMS: Serotonin (5-HT) is capable of reducing the oxidative burst of professional phagocytes. In this study, we investigated whether 5-HT mediates this modulation via 5-HT receptors (5-HTR) or whether this is due instead to 5-HT antioxidative properties. MAIN METHODS: The leukocytes or polymorphonuclear leukocytes (PMNL) were isolated from human blood, and their ability to produce reactive oxygen species (ROS) after 5-HT or its agonist treatment was tested by luminol-enhanced chemiluminescence (CL) analysis. KEY FINDINGS: It was found that 5-HTR(2) agonist DOI hydrochloride does not have any antioxidative properties, despite its ability to inhibit the CL response of activated human total leukocytes. On the other hand, DOI hydrochloride was unable to inhibit the CL response of activated human PMNL. It seems that the reduction of the oxidative burst of professional phagocytes was evoked by the activation of 5-HTR not on the neutrophil surface but on the surface of different leukocytes, which produced anti-inflammatory cytokines with NADPH oxidase activity modulating properties. SIGNIFICANCE: Platelets and activated PMNL are in tight contact at sites of inflammation. 5-HT released from platelets might have a protective function against PMNL-derived oxidative stress and oxidative damages.

• MeSH
• agonisté serotoninových receptorů 5-HT2 * MeSH
• amfetaminy farmakologie   MeSH
• antioxidancia farmakologie   MeSH
• krysa rodu Rattus MeSH
• kultivované buňky MeSH
• leukocyty účinky léků   MeSH
• lidé MeSH
• neutrofily účinky léků   MeSH
• respirační vzplanutí účinky léků   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• 2,5-dimethoxy-N,N-dimethyl-4-iodoamphetamine MeSH Prohlížeč
• agonisté serotoninových receptorů 5-HT2 * MeSH
• amfetaminy MeSH
• antioxidancia MeSH

Dizocilpine (MK-801; 0.3 mg/kg i.p.)-induced disruption in prepulse inhibition of the acoustic startle response (PPI) can be preferentially restored by "atypical" antipsychotics. In contrast, some findings indicate that not all of the "atypical" antipsychotics, such as clozapine and risperidone, are effective in restoring the NMDA antagonist-induced deficits in PPI. In our study, we evaluated the effect of four different "atypical" antipsychotic drugs on deficits in PPI induced by MK-801. Zotepine and risperidone have high affinities to D2-like and 5-HT2A receptors, while clozapine and olanzapine have multipharmacological profiles with the highest affinities to serotonin 5-HT1A,2A/2C receptors and muscarinic receptors. Results have shown that MK-801 disrupted PPI and increased the ASR in rats. Our results showed no effect of zotepine (1 and 2 mg/kg) and risperidone (0.1 and 1 mg/kg) on disrupted PPI by MK-801. Administration of clozapine (5 and 10 mg/kg) and olanzapine (2.5 and 5 mg/kg) restored the deficits in PPI induced by MK-801. Additionally, we found a decrease of approximately 46% in PPI after administration of clozapine (5 mg/kg) and olanzapine (2.5 and 5 mg/kg) without MK-801 treatment. In summary, the four "atypical" antipsychotics had different efficacies to restore the disrupted PPI by MK-801. Only clozapine and olanzapin restored the MK-801-induced deficits in PPI.

• MeSH
• akustická stimulace MeSH
• antagonisté excitačních aminokyselin farmakologie   MeSH
• antipsychotika farmakologie   MeSH
• benzodiazepiny farmakologie   MeSH
• dibenzothiepiny farmakologie   MeSH
• dizocilpinmaleát antagonisté a inhibitory   farmakologie   MeSH
• klozapin farmakologie   MeSH
• krysa rodu Rattus MeSH
• olanzapin MeSH
• potkani Wistar MeSH
• receptor serotoninový 5-HT2A účinky léků   MeSH
• receptory dopaminu D2 agonisté   MeSH
• receptory muskarinové účinky léků   MeSH
• risperidon farmakologie   MeSH
• úleková 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
• Názvy látek
• antagonisté excitačních aminokyselin MeSH
• antipsychotika MeSH
• benzodiazepiny MeSH
• dibenzothiepiny MeSH
• dizocilpinmaleát MeSH
• klozapin MeSH
• olanzapin MeSH
• receptor serotoninový 5-HT2A MeSH
• receptory dopaminu D2 MeSH
• receptory muskarinové MeSH
• risperidon MeSH
• zotepine MeSH Prohlížeč

The serotonergic psychedelics psilocybin, LSD and DMT hold great promise for the development of new treatments for psychiatric conditions such as major depressive disorder, addiction and end-of-life anxiety. Previous studies in both animals and humans have confirmed the effects of these drugs on neuronal activity and plasticity. However, the understanding of the mechanisms of action of these substances is limited. Here we show rapid effects of psychedelics on presynaptic properties, using live cell imaging at the level of single synapses in primary rat cortical neurons. Using the genetically encoded reporter of synaptic vesicle fusion synaptopHluorin, we detected a reduced fraction of synaptic vesicles that fused in response to mild or strong electrical stimulation 3-30 min after application of serotonergic psychedelics. These effects were transient and no longer present 24 h after treatment. While DMT only reduced the total recycling pool, LSD and psilocin also reduced the size of the readily releasable vesicle pool. Imaging with the sensors for glutamate, iGluSnFR, and presynaptic calcium, synGCaMP6, showed that while psilocin and DMT increased evoked glutamate release, LSD and psilocin reduced evoked presynaptic calcium levels. Interestingly, psilocin also affected short-term plasticity leading to a depression of responses to paired stimuli. The rapid and drug-specific modulation of glutamatergic neurotransmission described in this study may contribute to distinct anxiolytic and antidepressant properties of serotonergic psychedelics.

• Klíčová slova
• 5‐HT2A, fluorescent sensors, neurotransmitter release, presynaptic, short‐term plasticity, synaptic vesicles,
• MeSH
• halucinogeny * farmakologie   MeSH
• krysa rodu Rattus MeSH
• kultivované buňky MeSH
• kyselina glutamová * metabolismus   MeSH
• LSD farmakologie   MeSH
• mozková kůra * účinky léků   metabolismus   cytologie   MeSH
• neurony * účinky léků   metabolismus   MeSH
• potkani Sprague-Dawley MeSH
• psilocybin farmakologie   MeSH
• serotoninové látky farmakologie   MeSH
• synaptické vezikuly účinky léků   metabolismus   MeSH
• tryptaminy farmakologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• halucinogeny * MeSH
• kyselina glutamová * MeSH
• LSD MeSH
• psilocybin MeSH
• serotoninové látky MeSH
• tryptaminy MeSH

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.

• Klíčová slova
• global functional connectivity (GFC), model of acute psychosis, phase-lagged coherence, power spectra, psilocybin/psilocin, quantitative EEG, serotonergic psychedelics,
• Publikační typ
• časopisecké články MeSH