Different in vitro and in vivo tools for elucidating the human metabolism of alpha-cathinone-derived drugs of abuse

2018 ◽  
Vol 10 (7) ◽  
pp. 1119-1130 ◽  
Author(s):  
Sascha K. Manier ◽  
Lilian H.J. Richter ◽  
Jan Schäper ◽  
Hans H. Maurer ◽  
Markus R. Meyer
Keyword(s):  
Drugs Of Abuse ◽  
Human Metabolism

scholarly journals Caenorhabditis elegans as an in vivo Model to Assess Amphetamine Tolerance

2021 ◽  
pp. 1-9
Author(s):  
Dayana Torres Valladares ◽  
Sirisha Kudumala ◽  
Murad Hossain ◽  
Lucia Carvelli
Keyword(s):  
Caenorhabditis Elegans ◽  
Molecular Mechanisms ◽  
Drugs Of Abuse ◽  
Genetic Model ◽  
In Vivo Model ◽  
C Elegans ◽  
Hyperactivity Disorder ◽  
In Vitro Data

Amphetamine is a potent psychostimulant also used to treat attention deficit/hyperactivity disorder and narcolepsy. In vivo and in vitro data have demonstrated that amphetamine increases the amount of extra synaptic dopamine by both inhibiting reuptake and promoting efflux of dopamine through the dopamine transporter. Previous studies have shown that chronic use of amphetamine causes tolerance to the drug. Thus, since the molecular mechanisms underlying tolerance to amphetamine are still unknown, an animal model to identify the neurochemical mechanisms associated with drug tolerance is greatly needed. Here we took advantage of a unique behavior caused by amphetamine in <i>Caenorhabditis elegans</i> to investigate whether this simple, but powerful, genetic model develops tolerance following repeated exposure to amphetamine. We found that at least 3 treatments with 0.5 mM amphetamine were necessary to see a reduction in the amphetamine-induced behavior and, thus, to promote tolerance. Moreover, we found that, after intervals of 60/90 minutes between treatments, animals were more likely to exhibit tolerance than animals that underwent 10-minute intervals between treatments. Taken together, our results show that <i>C. elegans</i> is a suitable system to study tolerance to drugs of abuse such as amphetamines.

scholarly journals Microdialysis of skeletal muscle at rest

1999 ◽  
Vol 58 (4) ◽  
pp. 919-923 ◽  
Author(s):  
Jan Henriksson
Keyword(s):  
Skeletal Muscle ◽  
Blood Flow ◽  
Human Skeletal Muscle ◽  
Human Metabolism ◽  
High Expectations ◽  
Perfusate Flow ◽  
Muscle Research ◽  
Interstitial Glucose

Techniques in human skeletal muscle research are by necessity predominantly 'descriptive'.Microdialysis has raised high expectations that it could meet the demand for a method that allows 'mechanistic' investigations to be performed in human skeletal muscle. In the present review, some views are given on how well the initial expectations on the use of the microdialysis technique in skeletal muscle have been fulfilled, and the areas in which additional work is needed in order to validate microdialysis as an important metabolic technique in this tissue. The microdialysis catheter has been equated to an artificial blood vessel, which is introduced into the tissue. By means of this 'vessel' the concentrations of compounds in the interstitial space can be monitored. The concentration of substances in the collected samples is dependent on the rate of perfusate flow. When perfusate flow is slow enough to allow complete equilibration between interstitial and perfusate fluids, the concentration in the perfusate is maximal and identical to the interstitial concentration. Microdialysis data may be influenced by changes in blood flow, especially in instances where the tissue diffusivity limits the recovery in vivo, i.e. when recovery in vitro is 100 %, whereas the recovery in vivo is less than 100 %. Microdialysis data indicate that a significant arterial-interstitial glucose concentration gradient exists in skeletal muscle but not in adipose tissue at rest. While the concentrations of glucose and lactate in the dialysate from skeletal muscle are close to the expected values, the glycerol values obtained for muscle are still puzzling. Ethanol added to the perfusate will be cleared by the tissue at a rate that is determined by the nutritive blood flow (the microdialysis ethanol technique). It is concluded that microdialysis of skeletal muscle has become an important technique for mechanistic studies in human metabolism and nutrition.

scholarly journals Morphine-induced synaptic plasticity in the VTA is reversed by HDAC inhibition

2016 ◽  
Vol 116 (3) ◽  
pp. 1093-1103 ◽  
Author(s):  
Michael E. Authement ◽  
Ludovic D. Langlois ◽  
Haifa Kassis ◽  
Shawn Gouty ◽  
Matthieu Dacher ◽  
...  
Keyword(s):  
Behavioral Plasticity ◽  
Drugs Of Abuse ◽  
Patch Clamp Recording ◽  
Whole Cell Patch Clamp ◽  
Synaptic Changes ◽  
Induced Changes ◽  
And Behavior ◽  
H3 Acetylation

Dopamine (DA) dysfunction originating from the ventral tegmental area (VTA) occurs as a result of synaptic abnormalities following consumption of drugs of abuse and underlies behavioral plasticity associated with drug abuse. Drugs of abuse can cause changes in gene expression through epigenetic mechanisms in the brain that underlie some of the lasting neuroplasticity and behavior associated with addiction. Here we investigated the function of histone acetylation and histone deacetylase (HDAC)2 in the VTA in recovery of morphine-induced synaptic modifications following a single in vivo exposure to morphine. Using a combination of immunohistochemistry, Western blot, and whole cell patch-clamp recording in rat midbrain slices, we show that morphine increased HDAC2 activity in VTA DA neurons and reduced histone H3 acetylation at lysine 9 (Ac-H3K9) in the VTA 24 h after the injection. Morphine-induced synaptic changes at glutamatergic synapses involved endocannabinoid signaling to reduce GABAergic synaptic strength onto VTA DA neurons. Both plasticities were recovered by in vitro incubation of midbrain slices with a class I-specific HDAC inhibitor (HDACi), CI-994, through an increase in acetylation of histone H3K9. Interestingly, HDACi incubation also increased levels of Ac-H3K9 and triggered GABAergic and glutamatergic plasticities in DA neurons of saline-treated rats. Our results suggest that acute morphine-induced changes in VTA DA activity and synaptic transmission engage HDAC2 activity locally in the VTA to maintain synaptic modifications through histone hypoacetylation.

In vitro and in vivo human metabolism of a synthetic cannabinoid EAM-2201 detected by LC–quadrupole-ion trap-MS/MS and high-resolution LC–Orbitrap-MS/MS

2019 ◽  
Vol 37 (2) ◽  
pp. 432-442 ◽  
Author(s):  
Kayoko Minakata ◽  
Itaru Yamagishi ◽  
Koutaro Hasegawa ◽  
Hideki Nozawa ◽  
Masako Suzuki ◽  
...  
Keyword(s):  
High Resolution ◽  
Ion Trap ◽  
Quadrupole Ion Trap ◽  
Synthetic Cannabinoid ◽  
Human Metabolism ◽  
Orbitrap Ms

scholarly journals In vitro and in vivo human metabolism and pharmacokinetics of S‐ and R‐praziquantel

2020 ◽  
Vol 8 (4) ◽  
Author(s):  
Nyasha Nicole Kapungu ◽  
Xueqing Li ◽  
Charles Nhachi ◽  
Collen Masimirembwa ◽  
Roslyn Stella Thelingwani
Keyword(s):  
Human Metabolism

In Vitro and In Vivo Sequestration of Phencyclidine by Me4Cucurbit[8]uril

2020 ◽  
Author(s):  
Steven Murkli ◽  
Jared Klemm ◽  
Adam T. Brockett ◽  
Michael Shuster ◽  
Volker Briken ◽  
...  
Keyword(s):  
Drugs Of Abuse ◽  
In Vivo Efficacy ◽  
In Vitro Binding ◽  
In Vivo Assays ◽  
Vitro Binding ◽  
Efficacy Studies

This work describes the in vitro binding of CB[8] and Me4CB[8] toward a panel of 10 drugs of abuse, and in vitro and in vivo assays to demonstrate the biocompatibility of Me4CB[8]. In vivo efficacy studies show that Me4CB[8] can control the hyper locomotion of animals treated with PCP.

scholarly journals A dopamine-induced gene expression signature regulates neuronal function and cocaine response

2020 ◽  
Vol 6 (26) ◽  
pp. eaba4221 ◽  
Author(s):  
Katherine E. Savell ◽  
Jennifer J. Tuscher ◽  
Morgan E. Zipperly ◽  
Corey G. Duke ◽  
Robert A. Phillips ◽  
...  
Keyword(s):  
Gene Expression ◽  
Large Scale ◽  
Drugs Of Abuse ◽  
Transcriptional Response ◽  
Gene Expression Signature ◽  
Receptor Activation ◽  
Early Gene ◽  
Behavioral Adaptations

Drugs of abuse elevate dopamine levels in the nucleus accumbens (NAc) and alter transcriptional programs believed to promote long-lasting synaptic and behavioral adaptations. Here, we leveraged single-nucleus RNA-sequencing to generate a comprehensive molecular atlas of cell subtypes in the NAc, defining both sex-specific and cell type–specific responses to acute cocaine experience in a rat model system. Using this transcriptional map, we identified an immediate early gene expression program that is up-regulated following cocaine experience in vivo and dopamine receptor activation in vitro. Multiplexed induction of this gene program with a large-scale CRISPR-dCas9 activation strategy initiated a secondary synapse-centric transcriptional profile, altered striatal physiology in vitro, and enhanced cocaine sensitization in vivo. Together, these results define the transcriptional response to cocaine with cellular precision and demonstrate that drug-responsive gene programs can potentiate both physiological and behavioral adaptations to drugs of abuse.

scholarly journals Recent trends in drugs of abuse metabolism studies for mass spectrometry–based analytical screening procedures

2021 ◽  
Author(s):  
Lea Wagmann ◽  
Tanja M. Gampfer ◽  
Markus R. Meyer
Keyword(s):  
Drugs Of Abuse ◽  
Synthetic Cannabinoids ◽  
New Psychoactive Substances ◽  
In Vivo Models ◽  
Mass Spectral ◽  
Recent Developments ◽  
Recent Trends ◽  
Spectral Libraries

AbstractThe still increasing number of drugs of abuse, particularly the so-called new psychoactive substances (NPS), poses an analytical challenge for clinical and forensic toxicologists but also for doping control. NPS usually belong to various classes such as synthetic cannabinoids, phenethylamines, opioids, or benzodiazepines. Like other xenobiotics, NPS undergo absorption, distribution, metabolism, and excretion processes after consumption, but only very limited data concerning their toxicokinetics and safety properties is available once they appear on the market. The inclusion of metabolites in mass spectral libraries is often crucial for the detection of NPS especially in urine screening approaches. Authentic human samples may represent the gold standard for identification of metabolites but are often not available and clinical studies cannot be performed due to ethical concerns. However, numerous alternative in vitro and in vivo models are available. This trends article will give an overview on selected models, discuss current studies, and highlight recent developments.

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