Introduction:N-2-methoxy-benzylated ("NBOMe") analogues of phenethylamine are a group of new psychoactive substances (NPS) with reported strong psychedelic effects in sub-milligram doses linked to a number of severe intoxications, including fatal ones. In our present work, we provide a detailed investigation of pharmacokinetics and acute behavioural effects of 2C-B-Fly-NBOMe (2-(8-bromo-2,3,6,7-tetrahydrobenzo [1,2-b:4,5-b']difuran-4-yl)-N-[(2-methoxybenzyl]ethan-1-amine), an analogue of popular psychedelic entactogen 2C-B (4-Bromo-2,5-dimethoxyphenethylamine). Methods: All experiments were conducted on adult male Wistar rats. Pharmacokinetic parameters of 2C-B-Fly-NBOMe (1 mg/kg subcutaneously; s. c.) in blood serum and brain tissue were analysed over 24 h using liquid chromatography-mass spectrometry (LC/MS). For examination of behavioural parameters in open field test (OFT) and prepulse inhibition (PPI) of acoustic startle reaction (ASR), 2C-B-Fly-NBOMe (0.2, 1 and 5 mg/kg s. c.) was administered in two temporal onsets: 15 and 60 min after administration. Thermoregulatory changes were evaluated in individually and group-housed animals over 8 h following the highest dose used in behavioural experiments (5 mg/kg s. c.). Results: Peak drug concentrations were detected 30 and 60 min after the drug application in serum (28 ng/ml) and brain tissue (171 ng/g), respectively. The parental compound was still present in the brain 8 h after administration. Locomotor activity was dose-dependently reduced by the drug in both temporal testing onsets. ASR was also strongly disrupted in both temporal onsets, drug's effect on PPI was weaker. 2C-B-Fly-NBOMe did not cause any significant thermoregulatory changes. Discussion: Our results suggest that 2C-B-Fly-NBOMe penetrates animal brain tissue in a relatively slow manner, induces significant inhibitory effects on motor performance, and attenuates sensorimotor gating. Its overall profile is similar to closely related analogue 2C-B and other NBOMe substances.
- Publikační typ
- časopisecké články MeSH
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
Naphthylpyrovalerone (naphyrone) is a pyrovalerone cathinone that potently inhibits monoamine transporters and provides stimulatory-entactogenic effects. Little is known about the safety of naphyrone or its effects in vivo, and more research is needed to acquire knowledge about its fundamental effects on physiology and behaviour. Our objective was to investigate naphyrone's pharmacokinetics, acute toxicity, hyperthermic potential and stimulatory and psychotomimetic properties in vivo in male Wistar rats. Pharmacokinetics after 1 mg/kg subcutaneous (sc.) naphyrone were measured over 6 h in serum, the brain, liver and lungs. Rectal temperature (degree Celsius) was measured over 10 h in group-versus individually housed rats after 20 mg/kg sc. In the behavioural experiments, 5, 10 or 20 mg/kg of naphyrone was administered 15 or 60 min prior to testing. Stimulation was assessed in the open field, and sensorimotor processing in a prepulse inhibition (PPI) task. Peak concentrations of naphyrone in serum and tissue were reached at 30 min, with a long-lasting elevation in the brain/serum ratio, consistent with observations of lasting hyperlocomotion in the open field and modest increases in body temperature. Administration of 20 mg/kg transiently enhanced PPI. Naphyrone crosses the blood-brain barrier rapidly and is eliminated slowly, and its long-lasting effects correspond to its pharmacokinetics. No specific signs of acute toxicity were observed; therefore, clinical care and harm-reduction guidance should be in line with that available for other stimulants and cathinones.
- MeSH
- krysa rodu rattus MeSH
- pentanony farmakokinetika farmakologie MeSH
- potkani Wistar MeSH
- pyrrolidiny farmakokinetika farmakologie MeSH
- stimulanty centrálního nervového systému farmakokinetika farmakologie MeSH
- tělesná teplota účinky léků MeSH
- termoregulace účinky léků MeSH
- zakázané drogy farmakokinetika farmakologie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
1. Methylone (3,4-methylenedioxy-N-methylcathinone, MDMC), which appeared on the illicit drug market in 2004, is a frequently abused synthetic cathinone derivative. Known metabolic pathways of MDMC include N-demethylation to normethylone (3,4-methylenedioxycathinone, MDC), aliphatic chain hydroxylation and oxidative demethylenation followed by monomethylation and conjugation with glucuronic acid and/or sulphate. 2. Three new phase II metabolites, amidic conjugates of MDC with succinic, glutaric and adipic acid, were identified in the urine of rats dosed subcutaneously with MDMC.HCl (20 mg/kg body weight) by LC-ESI-HRMS using synthetic reference standards to support identification. 3. The main portion of administered MDMC was excreted unchanged. Normethylone, was a major urinary metabolite, of which a minor part was conjugated with dicarboxylic acids. 4. Previously identified ring-opened metabolites 4-hydroxy-3-methoxymethcathinone (4-OH-3-MeO-MC), 3-hydroxy-4-methoxymeth-cathinone (3-OH-4-MeO-MC) and 3,4-dihydroxymethcathinone (3,4-di-OH-MC) mostly in conjugated form with glucuronic and/or sulphuric acids were also detected. 5. Also, ring-opened metabolites derived from MDC, namely, 4-hydroxy-3-methoxycathinone (4-OH-3-MeO-C), 3-hydroxy-4-methoxycathinone (3-OH-4-MeO-C) and 3,4-dihydroxycathinone (3,4-di-OH-C) were identified for the first time in vivo.
- MeSH
- krysa rodu rattus MeSH
- kyseliny dikarboxylové metabolismus MeSH
- methamfetamin analogy a deriváty farmakokinetika farmakologie MeSH
- metylace MeSH
- nové syntetické drogy farmakokinetika farmakologie MeSH
- potkani Wistar MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
3,4-methylenedioxypyrovalerone (MDPV) is a potent pyrovalerone cathinone that is substituted for amphetamines by recreational users. We report a comprehensive and detailed description of the effects of subcutaneous MDPV (1-4 mg/kg) on pharmacokinetics, biodistribution and metabolism, acute effects on thermoregulation under isolated and aggregated conditions, locomotion (open field) and sensory gating (prepulse inhibition, PPI). All studies used male Wistar rats. Pharmacokinetics after single dose of 2 mg/kg MDPV was measured over 6 h in serum, brain and lungs. The biotransformation study recorded 24 h urinary levels of MDPV and its metabolites after 4 mg/kg. The effect of 2 mg/kg and 4 mg/kg on body temperature (°C) was measured over 12 h in group- vs. individually-housed rats. In the open field, locomotion (cm) and its spatial distribution were assessed. In PPI, acoustic startle response (ASR), habituation, and PPI were measured (AVG amplitudes). In behavioural experiments, 1, 2, or 4 mg/kg MDPV was administered 15 or 60 min prior to testing. Thermoregulation and behavioural data were analysed using factorial analysis of variance (ANOVA). Peak concentrations of MDPV in sera, lung and brain tissue were reached in under 30 min. While negligible levels of metabolites were detected in tissues, the major metabolites in urine were demethylenyl-MDPV and demethylenyl-methyl-MDPV at levels three-four times higher than the parent drug. We also established a MDPV brain/serum ratio ~2 lasting for ~120 min, consistent with our behavioural observations of locomotor activation and disrupted spatial distribution of behaviour as well as moderate increases in body temperature (exacerbated in group-housed animals). Finally, 4 mg/kg induced stereotypy in the open field and transiently disrupted PPI. Our findings, along with previous research suggest that MDPV is rapidly absorbed, readily crosses the blood-brain barrier and is excreted primarily as metabolites. MDPV acts as a typical stimulant with modest hyperthermic and psychomimetic properties, consistent with a primarily dopaminergic mechanism of action. Since no specific signs of acute toxicity were observed, even at the highest doses used, clinical care and harm-reduction guidance should be in line with that available for other stimulants and cathinones.
- Publikační typ
- časopisecké články MeSH
Mephedrone (MEPH) is a synthetic cathinone derivative with effects that mimic MDMA and/or cocaine. Our study in male Wistar rats provides detailed investigations of MEPH's and its primary metabolite nor-mephedrone's (nor-MEPH) pharmacokinetics and bio-distribution to four different substrates (serum, brain, lungs, and liver), as well as comparative analysis of their effects on locomotion [open field test (OFT)] and sensorimotor gating [prepulse inhibition of acoustic startle reaction (PPI ASR)]. Furthermore, in order to mimic the crowded condition where MEPH is typically taken (e.g., clubs), the acute effect of MEPH on thermoregulation in singly- and group-housed rats was evaluated. Pharmacokinetics of MEPH and nor-MEPH after MEPH (5 mg/kg, sc.) were analyzed over 8 h using liquid chromatography with mass spectrometry. MEPH (2.5, 5, or 20 mg/kg, sc.) and nor-MEPH (5 mg/kg, sc.) were administered 5 or 40 min before the behavioral testing in the OFT and PPI ASR; locomotion and its spatial distribution, ASR, habituation and PPI itself were quantified. The effect of MEPH on rectal temperature was measured after 5 and 20 mg/kg, sc. Both MEPH and nor-MEPH were detected in all substrates, with the highest levels detected in lungs. Mean brain: serum ratios were 1:1.19 (MEPH) and 1:1.91 (nor-MEPH), maximum concentrations were observed at 30 min; at 2 and 4 h after administration, nor-MEPH concentrations were higher compared to the parent drug. While neither of the drugs disrupted PPI, both increased locomotion and affected its spatial distribution. The effects of MEPH were dose dependent, rapid, and short-lasting, and the intensity of locomotor stimulant effects was comparable between MEPH and nor-MEPH. Despite the disappearance of behavioral effects within 40 min after administration, MEPH induced rectal temperature elevations that persisted for 3 h even in singly housed rats. To conclude, we observed a robust, short-lasting, and most likely synergistic stimulatory effect of both drugs which corresponded to brain pharmacokinetics. The dissociation between the duration of behavioral and hyperthermic effects is indicative of the possible contribution of nor-MEPH or other biologically active metabolites. This temporal dissociation may be related to the risk of prolonged somatic toxicity when stimulatory effects are no longer present.
- Publikační typ
- časopisecké články 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
1. 5,6-Methylenedioxy-2-aminoindane (MDAI) is a member of aminoindane drug family with serotoninergic effect, which appeared on illicit drug market as a substitute for banned stimulating and entactogenic drugs. 2. Metabolism of MDAI, which has been hitherto unexplored, was studied in rats dosed with a subcutaneous dose of 20 mg MDAI.HCl/kg body weight. The urine of rats was collected within 24 h after dosing for analyses by HPLC-ESI-HRMS and GC/MS. 3. The main metabolic pathways proceeding in parallel were found to be oxidative demethylenation followed by O-methylation and N-acetylation. These pathways gave rise to five metabolites, namely, 5,6-dihydroxy-2-aminoindane, 5-hydroxy-6-methoxy-2-aminoindane, N-acetyl-5,6-methylenedioxy-2-aminoindane, N-acetyl-5,6-dihydroxy-2-aminoindane and N-acetyl-5-hydroxy-6-methoxy-2-aminoindane, which were found predominantly in the form of corresponding glucuronides and sulphates. However, the main portion of administered MDAI was excreted unchanged. 4. Minor metabolites formed primarily by hydroxylation at various sites include cis- and trans-1-hydroxy-5,6-methylenedioxy-2-aminoindane, 5,6-methylenedioxyindan-2-ol and 4-hydroxy-5,6-methylenedioxy-2-aminoindane. 5. Identification of all metabolites except for glucuronides, sulphates and tentatively identified 4-hydroxy-5,6-methylenedioxy-2-aminoindane was supported by synthesised reference standards.
- MeSH
- indany moč MeSH
- krysa rodu rattus MeSH
- odhalování abúzu drog metody MeSH
- zakázané drogy moč MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Metabolic profile of mephedrone (4-methylmethcathinone, 4-MMC), a frequently abused recreational drug, was determined in rats in vivo. The urine of rats dosed with a subcutaneous bolus dose of 20mg 4-MMC/kg was analysed by LC/MS. Ten phase I and five phase II metabolites were identified by comparison of their retention times and MS(2) spectra with those of authentic reference standards and/or with the MS(2) spectra of previously identified metabolites. The main metabolic pathway was N-demethylation leading to normephedrone (4-methylcathinone, 4-MC) which was further conjugated with succinic, glutaric and adipic acid. Other phase I metabolic pathways included oxidation of the 4-methyl group, carbonyl reduction leading to dihydro-metabolites and ω-oxidation at the position 3'. Five of the metabolites detected, namely, 4-carboxynormephedrone (4-carboxycathinone, 4-CC), 4-carboxydihydronormephedrone (4-carboxynorephedrine, 4-CNE), hydroxytolyldihydro-normephedrone (4-hydroxymethylnorephedrine, 4-OH-MNE) and conjugates of 4-MC with glutaric and adipic acid, have not been reported as yet. The last two conjugates represent a novel, hitherto unexploited, type of phase II metabolites in mammals together with an analogous succinic acid conjugate of 4-MC identified by Pozo et al. (2015). These conjugates might be potentially of great importance in the metabolism of other psychoactive amines.
- MeSH
- adipáty metabolismus MeSH
- chromatografie kapalinová MeSH
- glutaráty metabolismus MeSH
- hmotnostní spektrometrie MeSH
- krysa rodu rattus MeSH
- kyselina jantarová metabolismus MeSH
- kyseliny dikarboxylové metabolismus MeSH
- metabolom MeSH
- methamfetamin analogy a deriváty chemie toxicita moč MeSH
- potkani Wistar MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- xenobiotika chemie toxicita moč MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Methoxetamine (MXE) is a novel psychoactive compound (NPS) that emerged in 2010 as a substitute for the dissociative anaesthetic ketamine. MXE has a reputation of carrying a lower risk of harm than ketamine, however a number of deaths have been reported. Currently very little is known about the psychopharmacological effects of this compound or its toxicity; therefore we tested, in Wistar rats, the effects of MXE in a series of behavioural tasks, measured its pharmacokinetics and urinary metabolites. Locomotor activity and its spatial characteristics (in the open field) and sensorimotor gating (prepulse inhibition; PPI) were evaluated after 5, 10 and 40mg/kg subcutaneous (sc.) MXE. Pharmacokinetics and brain: serum ratios were evaluated after 10mg/kg sc. MXE so that peak drug concentration data could be used to complement interpretation of maximal behavioural effects. Finally, quantification of metabolites in rat urine collected over 24h was performed after single bolus of MXE 40mg/kg sc. 5 and 10mg/kg MXE induced significant locomotor stimulation, in addition it increased thigmotaxis and decreased time spent in the centre of the open field (indicative of anxiogenesis). By contrast, 40mg/kg reduced locomotion and increased time spent in the centre of the arena, suggesting sedation/anaesthesia or stereotypy. The duration of effects was present for at least 60-90min, although for 5mg/kg, locomotion diminished after 60min. MXE decreased baseline acoustic startle response (ASR) and disrupted PPI, irrespective of testing-onset. MXE (all doses) reduced habituation but only at 60min. Maximal brain levels of MXE were observed 30min after administration, remained high at 60min and progressively declined to around zero after six hours. MXE accumulated in the brain; the brain: serum ratio was between 2.06 and 2.93 throughout the whole observation. The most abundant urinary metabolite was O-desmethylmethoxetamine followed by normethoxetamine. To conclude, MXE acts behaviourally as a typical dissociative anaesthetic with stimulant and anxiogenic effects at lower doses, sedative/anaesthetic effects at higher doses, and as a disruptor of sensorimotor gating. Its duration of action exceeds that of ketamine which is consistent with reports from MXE users. The accumulation of the drug in brain tissue might reflect MXE's stronger potency compared to ketamine and indicate increased toxicity.
- MeSH
- akustická stimulace MeSH
- cyklohexanony metabolismus farmakologie MeSH
- cyklohexylaminy metabolismus farmakologie MeSH
- krysa rodu rattus MeSH
- lokomoce účinky léků MeSH
- mozek účinky léků metabolismus MeSH
- pátrací chování účinky léků MeSH
- potkani Wistar MeSH
- prepulsní inhibice účinky léků MeSH
- psychotropní léky metabolismus 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
- přehledy MeSH
