Methylone (3,4-methylenedioxy-N-methylcathinone) is a synthetic cathinone analog of the recreational drug ecstasy. Although it is marketed to recreational users as relatively safe, fatalities due to hyperthermia, serotonin syndrome, and multi-organ system failure have been reported. Since psychopharmacological data remain scarce, we have focused our research on pharmacokinetics, and on a detailed evaluation of temporal effects of methylone and its metabolite nor-methylone on behavior and body temperature in rats. Methylone [5, 10, 20, and 40 mg/kg subcutaneously (s.c.)] and nor-methylone (10 mg/kg s.c.) were used in adolescent male Wistar rats across three behavioral/physiological procedures and in two temporal windows from administration (15 and 60 min) in order to test: locomotor effects in the open field, sensorimotor gating in the test of prepulse inhibition (PPI), and effects on rectal temperature in individually and group-housed rats. Serum and brain pharmacokinetics after 10 mg/kg s.c. over 8 h were analyzed using liquid chromatography mass spectrometry. Serum and brain levels of methylone and nor-methylone peaked at 30 min after administration, both drugs readily penetrated the brain with serum: brain ratio 1:7.97. Methylone dose-dependently increased overall locomotion. It also decrease the amount of time spent in the center of open field arena in dose 20 mg/kg and additionally this dose induced stereotyped circling around the arena walls. The maximum of effects corresponded to the peak of its brain concentrations. Nor-methylone had approximately the same behavioral potency. Methylone also has weak potency to disturb PPI. Behavioral testing was not performed with 40 mg/kg, because it was surprisingly lethal to some animals. Methylone 10 and 20 mg/kg s.c. induced hyperthermic reaction which was more pronounced in group-housed condition relative to individually housed rats. To conclude, methylone increased exploration and/or decreased anxiety in the open field arena and with nor-methylone had short duration of action with effects typical for mixed indirect dopamine-serotonin agonists such as 3,4-metyhlenedioxymethamphetamine (MDMA) or amphetamine. Given the fact that the toxicity was even higher than the known for MDMA and that it can cause hyperthermia it possess a threat to users with the risk for serotonin syndrome especially when used in crowded conditions.

• Keywords
• behavior, bk-3,4-metyhlenedioxymethamphetamine, cathinones, metabolites, methylone, nor-methylone, novel psychoactive substances, pharmacokinetics,
• Publication type
• Journal Article 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.

• Keywords
• 4-methylmethcathinone, Wistar rat, mephedrone, nor-mephedrone, open field, pharmacokinetics, prepulse inhibition, thermoregulation,
• Publication type
• Journal Article MeSH

RATIONALE AND OBJECTIVES: Behavioral, neurochemical and pharmaco-EEG profiles of a new synthetic drug 4-bromo-2,5-dimethoxyphenethylamine (2C-B) in rats were examined. MATERIALS AND METHODS: Locomotor effects, prepulse inhibition (PPI) of acoustic startle reaction (ASR), dopamine and its metabolite levels in nucleus accumbens (NAc), EEG power spectra and coherence in freely moving rats were analysed. Amphetamine was used as a reference compound. RESULTS: 2C-B had a biphasic effect on locomotion with initial inhibitory followed by excitatory effect; amphetamine induced only hyperlocomotion. Both drugs induced deficits in the PPI; however they had opposite effects on ASR. 2C-B increased dopamine but decreased 3,4-dihydroxyphenylacetic acid (DOPAC) in the NAc. Low doses of 2C-B induced a decrease in EEG power spectra and coherence. On the contrary, high dose of 2C-B 50 mg/kg had a temporally biphasic effect with an initial decrease followed by an increase in EEG power; decrease as well as increase in EEG coherence was observed. Amphetamine mainly induced an increase in EEG power and coherence in theta and alpha bands. Increases in the theta and alpha power and coherence in 2C-B and amphetamine were temporally linked to an increase in locomotor activity and DA levels in NAc. CONCLUSIONS: 2C-B is a centrally active compound similar to other hallucinogens, entactogens and stimulants. Increased dopamine and decreased DOPAC in the NAc may reflect its psychotomimetic and addictive potential and monoaminoxidase inhibition. Alterations in brain functional connectivity reflected the behavioral and neurochemical changes produced by the drug; a correlation between EEG changes and locomotor behavior was observed.

• MeSH
• Amphetamine pharmacology   MeSH
• Behavior, Animal drug effects   MeSH
• Dimethoxyphenylethylamine administration & dosage   analogs & derivatives   pharmacology   MeSH
• Dopamine metabolism   MeSH
• Electroencephalography MeSH
• Hallucinogens administration & dosage   pharmacology   MeSH
• Rats MeSH
• 3,4-Dihydroxyphenylacetic Acid metabolism   MeSH
• Nucleus Accumbens drug effects   metabolism   MeSH
• Motor Activity drug effects   MeSH
• Rats, Wistar MeSH
• Reflex, Startle drug effects   MeSH
• Dose-Response Relationship, Drug MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Comparative Study MeSH
• Names of Substances
• 2-(4-bromo-2,5-dimethoxyphenyl)ethylamine MeSH Browser
• Amphetamine MeSH
• Dimethoxyphenylethylamine MeSH
• Dopamine MeSH
• Hallucinogens MeSH
• 3,4-Dihydroxyphenylacetic Acid MeSH

RATIONALE: Mescaline is a nonselective serotonin receptor agonist. It has relatively delayed onset of action and prolonged duration. Mescaline attenuates various behavioral parameters in rats; however, no information is available about its pharmacokinetics in rats and its relation to the behavioral changes produced by the drug. OBJECTIVES: The present study evaluates the spontaneous locomotor activity and sensorimotor gating in relation to mescaline concentrations in the serum and the brain of rats MATERIALS AND METHODS: Behavioral changes induced by mescaline [10, 20, and 100 mg/kg subcutaneously (s.c.)] were evaluated in an open-field test and testing of the prepulse inhibition of acoustic startle reaction (PPI) 15 and 60 min after drug administration. The time disposition of mescaline 20 mg/kg s.c. in rat serum and brain homogenates was analyzed by gas chromatography-mass spectrometry. RESULTS: Mescaline produced significant inhibitory effects on locomotion in low doses and a biphasic effect with the highest dose. In the PPI test, only when tested 60 min after drug administration, all doses of mescaline disrupted PPI. Besides the experimental protocol, we have observed that approximately 50% of animals receiving 100 mg/kg died within 12 h post-injection. The serum levels of mescaline rapidly increased within 30 min and subsequently quickly decreased; however, the brain concentrations reached a maximum 1 h after administration and remained high for an additional 60 min. CONCLUSIONS: Mescaline had a delayed onset of the main behavioral changes in rats compared to other hallucinogens. Behavioral changes correlated with the pharmacokinetics of the drug.

• MeSH
• Time Factors MeSH
• Habituation, Psychophysiologic drug effects   MeSH
• Hallucinogens pharmacokinetics   toxicity   MeSH
• Inhibition, Psychological MeSH
• Injections, Subcutaneous MeSH
• Rats MeSH
• Mescaline pharmacokinetics   toxicity   MeSH
• Metabolic Clearance Rate physiology   MeSH
• Brain drug effects   metabolism   MeSH
• Orientation drug effects   MeSH
• Gas Chromatography-Mass Spectrometry MeSH
• Motor Activity drug effects   MeSH
• Rats, Wistar MeSH
• Reflex, Startle drug effects   MeSH
• Dose-Response Relationship, Drug MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Hallucinogens MeSH
• Mescaline MeSH