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Biological Psychiatry. Cognitive... Sep 2022Patients with psychotic disorders present alterations in thalamocortical intrinsic functional connectivity as measured by resting-state functional magnetic resonance...
BACKGROUND
Patients with psychotic disorders present alterations in thalamocortical intrinsic functional connectivity as measured by resting-state functional magnetic resonance imaging. Specifically, thalamic intrinsic functional connectivity is increased with sensorimotor cortices (hyperconnectivity) and decreased with prefrontal limbic cortices (hypoconnectivity). Psychedelics such as lysergic acid diethlyamide (LSD) elicit similar thalamocortical hyperconnectivity with sensorimotor areas in healthy volunteers. It is unclear whether LSD also induces thalamocortical hypoconnectivity with prefrontal limbic cortices, because current findings are equivocal. Thalamocortical hyperconnectivity was associated with psychotic symptoms in patients and substance-induced altered states of consciousness in healthy volunteers. Thalamocortical dysconnectivity is likely evoked by altered neurotransmission, e.g., via dopaminergic excess in psychotic disorders and serotonergic agonism in psychedelic-induced states. It is unclear whether thalamocortical dysconnectivity is also elicited by amphetamine-type substances, broadly releasing monoamines (i.e., dopamine, norepinephrine) but producing fewer perceptual effects than psychedelics.
METHODS
We administrated LSD, d-amphetamine, and 3,4-methylenedioxymethamphetamine (MDMA) in 28 healthy volunteers and investigated their effects on thalamic intrinsic functional connectivity with 2 brain networks (auditory-sensorimotor and salience networks, corresponding to sensorimotor and prefrontal limbic cortices, respectively), using a double-blind, placebo-controlled, crossover design.
RESULTS
All active substances elicited auditory-sensorimotor-thalamic hyperconnectivity compared with placebo, despite predominantly distinct pharmacological actions and subjective effects. LSD-induced effects correlated with subjective changes in perception, indicating a link between hyperconnectivity and psychedelic-type perceptual alterations. Unlike d-amphetamine and MDMA, which induced hypoconnectivity with the salience network, LSD elicited hyperconnectivity. D-amphetamine and MDMA evoked similar thalamocortical dysconnectivity patterns.
CONCLUSIONS
Psychedelics, empathogens, and psychostimulants evoke thalamocortical hyperconnectivity with sensorimotor areas, akin to findings in patients with psychotic disorders.
Topics: Cross-Over Studies; Dextroamphetamine; Double-Blind Method; Hallucinogens; Humans; Lysergic Acid; Lysergic Acid Diethylamide; N-Methyl-3,4-methylenedioxyamphetamine
PubMed: 35500840
DOI: 10.1016/j.bpsc.2022.04.003 -
Molecules (Basel, Switzerland) Oct 2023The aim of this study was to develop and optimize a chiral HPLC-MS/MS method for quantitative analysis of ()-/()-salbutamol and ()-/()-salbutamol-4'--sulfate in human...
Development of an HPLC-MS/MS Method for Chiral Separation and Quantitation of ()- and ()-Salbutamol and Their Sulfoconjugated Metabolites in Urine to Investigate Stereoselective Sulfonation.
The aim of this study was to develop and optimize a chiral HPLC-MS/MS method for quantitative analysis of ()-/()-salbutamol and ()-/()-salbutamol-4'--sulfate in human urine to allow for bioanalytical quantitation of the targeted analytes and investigations of stereoselectivity in the sulfonation pathway of human phase Ⅱ metabolism. For analytical method development, a systematic screening of columns and mobile phases to develop a separation via enantiomerically selective high performance liquid chromatography was performed. Electrospray ionization settings were optimized via multiple-step screening and a full factorial design-of-experiment. Both approaches were performed matrix-assisted and the predicted values were compared. The full factorial design was superior in terms of prediction power and knowledge generation. Performing a longitudinal excretion study in one healthy volunteer allowed for the calculation of excretion rates for all four targeted analytes. For this proof-of-concept, either racemic salbutamol or enantiopure levosalbutamol was administered perorally or via inhalation, respectively. A strong preference for sulfonation of ()-salbutamol for inhalation and peroral application was found in experiments. In previous studies phenol sulfotransferase 1A3 was described to be mainly responsible for salbutamol sulfonation in humans. Thus, in vitro and in silico investigations of the stereoselectivity of sulfotransferase 1A3 complemented the study and confirmed these findings.
Topics: Humans; Albuterol; Chromatography, High Pressure Liquid; Tandem Mass Spectrometry; Levalbuterol; Administration, Inhalation; Stereoisomerism
PubMed: 37894685
DOI: 10.3390/molecules28207206 -
Chemical Research in Toxicology Jan 20162,5-Dimethoxy-N-benzylphenethylamines (NBOMes) are very potent 5-HT2AR agonists. Illicit use of these psychedelic compounds has emerged in recent years, and several...
2,5-Dimethoxy-N-benzylphenethylamines (NBOMes) are very potent 5-HT2AR agonists. Illicit use of these psychedelic compounds has emerged in recent years, and several fatalities have been linked to their recreational use. In its [(11)C]-labeled form, one NBOMe (25B-NBOMe) was recently developed as a PET-ligand for clinical investigations of 5HT2AR ([(11)C]Cimbi-36). Herein, we have identified the phase I and phase II metabolites of 25B-NBOMe in pigs as well as in humans. We find that the primary route of metabolism is 5'-demethylation, followed by conjugation to glucuronic acid. Carbon-11 labeling of 25B-NBOMe in three different positions followed by in vivo evaluation in pigs and humans corroborated these findings.
Topics: Animals; Hallucinogens; Humans; Microsomes, Liver; Molecular Structure; Phenethylamines; Positron-Emission Tomography; Swine
PubMed: 26669514
DOI: 10.1021/acs.chemrestox.5b00450 -
Fa Yi Xue Za Zhi Dec 2019Objective To establish a method to identify unknown samples based on combined use of gas chromatography-mass spectrometry (GC-MS), high resolution mass spectrometry...
Objective To establish a method to identify unknown samples based on combined use of gas chromatography-mass spectrometry (GC-MS), high resolution mass spectrometry (HRMS) and nuclear magnetic resonance spectrum (NMR) technique. Methods The unknown samples were dissolved in methanol solution containing internal standard SKF525A and detected by GC-MS and HRMS. The mixed samples were separated and purified by silica gel column chromatography, and then dissolved in methanol-d4 solution for structural analysis of H nuclear magnetic resonance spectroscopy (H NMR). Results The characteristic fragment ions () were 86.1 (base peak), 71.2, 121.1, and 149.0, and the accurate mass number of molecular ion peak was measured by HRMS to be 236.128 89. By combined use of data analysis and database comparison, a new psychoactive substance of the cathinone class, Dibutylone, was detected in the sample, and the sample also contained a small amount of caffeine. The sample was purified, then identified using H NMR, and was further confirmed to be Dibutylone. In addition, the GC-MS retention time and characteristic fragment ions of the main components of the sample were consistent with those of Dibutylone reference material. Conclusion The method established in this study can be used for the identification of Dibutylone in mixed samples.
Topics: Chromatography, Liquid; Gas Chromatography-Mass Spectrometry; Magnetic Resonance Spectroscopy; Mass Spectrometry; N-Methyl-3,4-methylenedioxyamphetamine; Psychotropic Drugs
PubMed: 31970954
DOI: 10.12116/j.issn.1004-5619.2019.06.007 -
The Science of the Total Environment Mar 20223,4-Methylenedioxymethamphetamine (MDMA) and amphetamine are commonly used psychoactive stimulants. Illegal manufacture of these substances, mainly located in the...
3,4-Methylenedioxymethamphetamine (MDMA) and amphetamine are commonly used psychoactive stimulants. Illegal manufacture of these substances, mainly located in the Netherlands and Belgium, generates large amounts of chemical waste which is disposed in the environment or released in sewer systems. Retrospective analysis of high-resolution mass spectrometry (HRMS) data was implemented to detect synthesis markers of MDMA and amphetamine production in wastewater samples. Specifically, suspect and non-target screening, combined with a prioritization approach based on similarity measures between detected features and mass loads of MDMA and amphetamine was implemented. Two hundred and thirty-five 24 h-composite wastewater samples collected from a treatment plant in the Netherlands between 2016 and 2018 were analyzed by liquid chromatography coupled to high-resolution mass spectrometry. Samples were initially separated into two groups (i.e., baseline consumption versus dumping) based on daily loads of MDMA and amphetamine. Significance testing and fold-changes were used to find differences between features in the two groups. Then, associations between peak areas of all features and MDMA or amphetamine loads were investigated across the whole time series using various measures (Euclidian distance, Pearson's correlation coefficient, Spearman's rank correlation coefficient, distance correlation and maximum information coefficient). This unsupervised and unbiased approach was used for prioritization of features and allowed the selection of 28 presumed markers of production of MDMA and amphetamine. These markers could potentially be used to detect dumps in sewer systems, help in determining the synthesis route and track down the waste in the environment.
Topics: Amphetamine; Chromatography, Liquid; N-Methyl-3,4-methylenedioxyamphetamine; Retrospective Studies; Substance Abuse Detection; Wastewater
PubMed: 34871677
DOI: 10.1016/j.scitotenv.2021.152139 -
Neuropsychopharmacology : Official... Feb 20173,4-Methylenedioxy-N-methylcathinone (methylone) is a new psychoactive substance and the β-keto analog of 3,4-methylenedioxy-N-methylamphetamine (MDMA). It is well...
3,4-Methylenedioxy-N-methylcathinone (methylone) is a new psychoactive substance and the β-keto analog of 3,4-methylenedioxy-N-methylamphetamine (MDMA). It is well established that MDMA metabolism produces bioactive metabolites. Here we tested the hypothesis that methylone metabolism in rats can form bioactive metabolites. First, we examined the pharmacokinetics (PKs) of methylone and its metabolites after subcutaneous (sc) methylone administration (3, 6, 12 mg/kg) to male rats fitted with intravenous (iv) catheters for repeated blood sampling. Plasma specimens were assayed by liquid chromatography tandem mass spectrometry to quantify methylone and its phase I metabolites: 3,4-methylenedioxycathinone (MDC), 3,4-dihydroxy-N-methylcathinone (HHMC), and 4-hydroxy-3-methoxy-N-methylcathinone (HMMC). The biological activity of methylone and its metabolites was then compared using in vitro transporter assays and in vivo microdialysis in rat nucleus accumbens. For the PK study, we found that methylone and MDC peaked early (T=15-45 min) and were short lived (t=60-90 min), while HHMC and HMMC peaked later (T=60-120 min) and persisted (t=120-180 min). Area-under-the-curve values for methylone and MDC were greater than dose-proportional, suggesting non-linear accumulation. Methylone produced significant locomotor activation, which was correlated with plasma methylone, MDC, and HHMC concentrations. Methylone, MDC, and HHMC were substrate-type releasers at monoamine transporters as determined in vitro, but only methylone and MDC (1, 3 mg/kg, iv) produced significant elevations in brain extracellular dopamine and 5-HT in vivo. Our findings demonstrate that methylone is extensively metabolized in rats, but MDC is the only centrally active metabolite that could contribute to overall effects of the drug in vivo.
Topics: Animals; Behavior, Animal; Brain; Central Nervous System Stimulants; Male; Methamphetamine; Microdialysis; Rats; Rats, Sprague-Dawley
PubMed: 27658484
DOI: 10.1038/npp.2016.213 -
Nuclear Medicine and Biology 2018Fluorine-18 labeled positron emission tomography (PET) tracers were developed to obtain more insight into the function of P-glycoprotein (P-gp) in relation to various...
INTRODUCTION
Fluorine-18 labeled positron emission tomography (PET) tracers were developed to obtain more insight into the function of P-glycoprotein (P-gp) in relation to various conditions. They allow research in facilities without a cyclotron as they can be transported with a half-life of 110 min. As the metabolic stability of previously reported tracers [F]1 and [F]2 was poor, the purpose of this study was to improve this stability using deuterium substitution, creating verapamil analogs [F]1-d, [F]2-d, [F]3-d and [F]3-d.
METHODS
The following deuterium containing tracers were synthesized and evaluated in mice and rats: [F]1-d, [F]2-d, [F]3-d and [F]3-d.
RESULTS
The deuterated analogs [F]2-d, [F]3-d and [F]3-d showed increased metabolic stability compared with their non-deuterated counterparts. The increased metabolic stability of the methyl containing analogs [F]3-d and [F]3-d might be caused by steric hindrance for enzymes.
CONCLUSION
The striking similar in vivo behavior of [F]3-d to that of (R)-[C]verapamil, and its improved metabolic stability compared with the other fluorine-18 labeled tracers synthesized, supports the potential clinical translation of [F]3-d as a PET radiopharmaceutical for P-gp evaluation.
Topics: Animals; Drug Stability; Fluorine Radioisotopes; Isotope Labeling; Male; Positron-Emission Tomography; Radioactive Tracers; Radiochemistry; Rats; Rats, Wistar; Verapamil
PubMed: 30056279
DOI: 10.1016/j.nucmedbio.2018.06.009 -
Environment International Aug 2023The market for illicit drugs and new psychoactive substances (NPS) has grown significantly and people attending festivals have been identified as being at high risk...
The market for illicit drugs and new psychoactive substances (NPS) has grown significantly and people attending festivals have been identified as being at high risk (high extent and frequency of substance use). Traditional public health surveillance data sources have limitations (high costs, long implementation times, and ethical issues) and wastewater-based epidemiology (WBE) can cost-effectively support surveillance efforts. Influent wastewater samples were analyzed for NPS and illicit drug consumption collected during New Year period (from 29-Dec-2021 to 4-Jan-2022) and a summer Festival (from 29-June-2022 to 12-July-2022) in a large city in Spain. Samples were analyzed for phenethylamines, cathinones, opioids, benzodiazepines, plant-based NPS, dissociatives, and the illicit drugs methamphetamine, MDA, MDMA, ketamine, heroin, cocaine, and pseudoephedrine by liquid chromatography mass spectrometry. High consumption rates of specific NPS and established illicit drugs were identified at the peak of each event. Furthermore, a dynamic change in NPS use (presence and absence of substances) was detected over a period of six months. Eleven NPS, including synthetic cathinones, benzodiazepines, plant-based NPS and dissociatives, and seven illicit drugs were found across both the New Year and summer Festival. Statistically significant differences (p < 0.05) were seen for 3-MMC (New Year vs summer Festival), eutylone (New Year vs summer Festival), cocaine (summer Festival vs normal week and summer Festival vs New Year), MDMA (New Year vs normal week and summer Festival vs normal week), heroin (summer Festival vs New Year) and pseudoephedrine (summer Festival vs New Year). This WBE study assessed the prevalence of NPS and illicit drugs at festivals following the reduction of the COVID-19 pandemic restrictions highlighting the high use of specific substances at the peak of each event. This approach identified in a cost-effective and timely manner without any ethical issues the most used drugs and changes in use patterns and, thus, can complement public health information.
Topics: Humans; Illicit Drugs; Holidays; N-Methyl-3,4-methylenedioxyamphetamine; Prevalence; Heroin; Pandemics; Pseudoephedrine; COVID-19; Substance-Related Disorders; Cocaine; Psychotropic Drugs
PubMed: 37399770
DOI: 10.1016/j.envint.2023.108075 -
Pharmacology, Biochemistry, and Behavior Apr 2019Methamphetamine addiction is characterized by compulsive binges of drug intake despite adverse life consequences. A model of methamphetamine self-administration that... (Review)
Review
Methamphetamine addiction is characterized by compulsive binges of drug intake despite adverse life consequences. A model of methamphetamine self-administration that includes contingent footshocks to constitute adverse consequences has helped to segregate rats that reduce or stop lever pressing for methamphetamine (sensitive) from those that continue to lever press for the drug (resistant) in the presence of negative outcomes. We have observed differential DNA hydroxymethylation and increased expression of potassium channel mRNAs in the nucleus accumbens of sensitive compared to resistant rats, suggesting a role of these channels in suppressing methamphetamine intake. There were also significant increases in nerve growth factor (NGF) expression and activation of its downstream signaling pathway (NGF-TrkA and p75NTR/MAPK signaling) in only the dorsal striatum of sensitive rats after a month of abstinence. In contrast, oxytocin mRNA expression was increased in only the nucleus accumbens of resistant rats compared to sensitive rats euthanized after that time. These results indicate that footshocks can differentiate two behavioral phenotypes with differential biochemical and epigenetic consequences in the ventral and dorsal striatum.
Topics: Animals; Brain; Epigenesis, Genetic; Methamphetamine; Rats; Substance Withdrawal Syndrome; Transcription, Genetic
PubMed: 30797763
DOI: 10.1016/j.pbb.2019.02.009 -
Microbial Biotechnology Jul 2023Multidrug efflux pumps are among the main Pseudomonas aeruginosa antibiotic-resistance determinants. Besides, efflux pumps are also involved in other relevant activities...
Multidrug efflux pumps are among the main Pseudomonas aeruginosa antibiotic-resistance determinants. Besides, efflux pumps are also involved in other relevant activities of bacterial physiology, including the quorum sensing-mediated regulation of bacterial virulence. Nevertheless, despite the relevance of efflux pumps in bacterial physiology, their interconnection with bacterial metabolism remains obscure. The effect of several metabolites on the expression of P. aeruginosa efflux pumps, and on the virulence and antibiotic resistance of this bacterium, was studied. Phenylethylamine was found to be both inducer and substrate of MexCD-OprJ, an efflux pump involved in P. aeruginosa antibiotic resistance and in extrusion of precursors of quorum-sensing signals. Phenylethylamine did not increase antibiotic resistance; however, the production of the toxin pyocyanin, the tissue-damaging protease LasB and swarming motility were reduced in the presence of this metabolite. This decrease in virulence potential was mediated by a reduction of lasI and pqsABCDE expression, which encode the proteins that synthesise the signalling molecules of two quorum-sensing regulatory pathways. This work sheds light on the interconnection between virulence and antibiotic-resistance determinants, mediated by bacterial metabolism, and points to phenylethylamine as an anti-virulence metabolite to be considered in the study of therapies against P. aeruginosa infections.
Topics: Humans; Pseudomonas aeruginosa; Virulence; Quorum Sensing; Drug Resistance, Multiple, Bacterial; Anti-Bacterial Agents; Phenethylamines; Virulence Factors; Bacterial Proteins; Pseudomonas Infections; Biofilms
PubMed: 36976480
DOI: 10.1111/1751-7915.14252