2023
Niello, Marco; Sideromenos, Spyridon; Gradisch, Ralph; Shea, Ronan O; Schwazer, Jakob; Maier, Julian; Kastner, Nina; Sandtner, Walter; Jäntsch, Kathrin; Lupica, Carl R; Hoffman, Alexander F; Lubec, Gert; Loland, Claus J; Stockner, Thomas; Pollak, Daniela D; Baumann, Michael H; Sitte, Harald H
Persistent binding at dopamine transporters determines sustained psychostimulant effects Journal Article
In: Proc Natl Acad Sci U S A, vol. 120, no. 6, pp. e2114204120, 2023, ISSN: 1091-6490.
@article{pmid36730201,
title = {Persistent binding at dopamine transporters determines sustained psychostimulant effects},
author = {Marco Niello and Spyridon Sideromenos and Ralph Gradisch and Ronan O Shea and Jakob Schwazer and Julian Maier and Nina Kastner and Walter Sandtner and Kathrin Jäntsch and Carl R Lupica and Alexander F Hoffman and Gert Lubec and Claus J Loland and Thomas Stockner and Daniela D Pollak and Michael H Baumann and Harald H Sitte},
url = {https://pubmed.ncbi.nlm.nih.gov/36730201/},
doi = {10.1073/pnas.2114204120},
issn = {1091-6490},
year = {2023},
date = {2023-02-01},
urldate = {2023-02-01},
journal = {Proc Natl Acad Sci U S A},
volume = {120},
number = {6},
pages = {e2114204120},
abstract = {Psychostimulants interacting with the dopamine transporter (DAT) can be used illicitly or for the treatment of specific neuropsychiatric disorders. However, they can also produce severe and persistent adverse events. Often, their pharmacological properties in vitro do not fully correlate to their pharmacological profile in vivo. Here, we investigated the pharmacological effects of enantiomers of pyrovalerone, α-pyrrolidinovalerophenone, and 3,4-methylenedioxypyrovalerone as compared to the traditional psychostimulants cocaine and methylphenidate, using a variety of in vitro, computational, and in vivo approaches. We found that in vitro drug-binding kinetics at DAT correlate with the time-course of in vivo psychostimulant action in mice. In particular, a slow dissociation (i.e., slow ) of -enantiomers of pyrovalerone analogs from DAT predicts their more persistent in vivo effects when compared to cocaine and methylphenidate. Overall, our findings highlight the critical importance of drug-binding kinetics at DAT for determining the in vivo profile of effects produced by psychostimulant drugs.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Psychostimulants interacting with the dopamine transporter (DAT) can be used illicitly or for the treatment of specific neuropsychiatric disorders. However, they can also produce severe and persistent adverse events. Often, their pharmacological properties in vitro do not fully correlate to their pharmacological profile in vivo. Here, we investigated the pharmacological effects of enantiomers of pyrovalerone, α-pyrrolidinovalerophenone, and 3,4-methylenedioxypyrovalerone as compared to the traditional psychostimulants cocaine and methylphenidate, using a variety of in vitro, computational, and in vivo approaches. We found that in vitro drug-binding kinetics at DAT correlate with the time-course of in vivo psychostimulant action in mice. In particular, a slow dissociation (i.e., slow ) of -enantiomers of pyrovalerone analogs from DAT predicts their more persistent in vivo effects when compared to cocaine and methylphenidate. Overall, our findings highlight the critical importance of drug-binding kinetics at DAT for determining the in vivo profile of effects produced by psychostimulant drugs.
2021
Schindler, Charles W; Thorndike, Eric B; Partilla, John S; Rice, Kenner C; Baumann, Michael H
Amphetamine-like Neurochemical and Cardiovascular Effects of α-Ethylphenethylamine Analogs Found in Dietary Supplements Journal Article
In: Journal of Pharmacology and Experimental Therapeutics, vol. 376, no. 1, pp. 118–126, 2021, ISSN: 0022-3565.
@article{Schindler118,
title = {Amphetamine-like Neurochemical and Cardiovascular Effects of \textit{α}-Ethylphenethylamine Analogs Found in Dietary Supplements},
author = {Charles W Schindler and Eric B Thorndike and John S Partilla and Kenner C Rice and Michael H Baumann},
url = {https://pubmed.ncbi.nlm.nih.gov/33082158/},
doi = {10.1124/jpet.120.000129},
issn = {0022-3565},
year = {2021},
date = {2021-01-01},
journal = {Journal of Pharmacology and Experimental Therapeutics},
volume = {376},
number = {1},
pages = {118--126},
publisher = {American Society for Pharmacology and Experimental Therapeutics},
abstract = {Dietary supplements often contain additives not listed on the label, including α-ethyl homologs of amphetamine such as N,α-diethylphenethylamine (DEPEA). Here, we examined the neurochemical and cardiovascular effects of α-ethylphenethylamine (AEPEA), N-methyl-α-ethylphenethylamine (MEPEA), and DEPEA as compared with the effects of amphetamine. All drugs were tested in vitro using uptake inhibition and release assays for monoamine transporters. As expected, amphetamine acted as a potent and efficacious releasing agent at dopamine transporters (DAT) and norepinephrine transporters (NET) in vitro. AEPEA and MEPEA were also releasers at catecholamine transporters, with greater potency at NET than DAT. DEPEA displayed fully efficacious release at NET but weak partial release at DAT (i.e., 40% of maximal effect). In freely moving, conscious male rats fitted with biotelemetry transmitters for physiologic monitoring, amphetamine (0.1–3.0 mg/kg, s.c.) produced robust dose-related increases in blood pressure (BP), heart rate (HR), and motor activity. AEPEA (1–10 mg/kg, s.c.) produced significant increases in BP but not HR or activity, whereas DEPEA and MEPEA (1–10 mg/kg, s.c.) increased BP, HR, and activity. In general, the phenethylamine analogs were approximately 10-fold less potent than amphetamine. Our results show that α-ethylphenethylamine analogs are biologically active. Although less potent than amphetamine, they produce cardiovascular effects that could pose risks to humans. Given that MEPEA and DEPEA increased locomotor activity, these substances may also have significant abuse potential.SIGNIFICANCE STATEMENT The α-ethyl homologs of amphetamine have significant cardiovascular, behavioral, and neurochemical effects in rats. Given that these compounds are often not listed on the ingredient labels of dietary supplements, these compounds could pose a risk to humans using these products.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Dietary supplements often contain additives not listed on the label, including α-ethyl homologs of amphetamine such as N,α-diethylphenethylamine (DEPEA). Here, we examined the neurochemical and cardiovascular effects of α-ethylphenethylamine (AEPEA), N-methyl-α-ethylphenethylamine (MEPEA), and DEPEA as compared with the effects of amphetamine. All drugs were tested in vitro using uptake inhibition and release assays for monoamine transporters. As expected, amphetamine acted as a potent and efficacious releasing agent at dopamine transporters (DAT) and norepinephrine transporters (NET) in vitro. AEPEA and MEPEA were also releasers at catecholamine transporters, with greater potency at NET than DAT. DEPEA displayed fully efficacious release at NET but weak partial release at DAT (i.e., 40% of maximal effect). In freely moving, conscious male rats fitted with biotelemetry transmitters for physiologic monitoring, amphetamine (0.1–3.0 mg/kg, s.c.) produced robust dose-related increases in blood pressure (BP), heart rate (HR), and motor activity. AEPEA (1–10 mg/kg, s.c.) produced significant increases in BP but not HR or activity, whereas DEPEA and MEPEA (1–10 mg/kg, s.c.) increased BP, HR, and activity. In general, the phenethylamine analogs were approximately 10-fold less potent than amphetamine. Our results show that α-ethylphenethylamine analogs are biologically active. Although less potent than amphetamine, they produce cardiovascular effects that could pose risks to humans. Given that MEPEA and DEPEA increased locomotor activity, these substances may also have significant abuse potential.SIGNIFICANCE STATEMENT The α-ethyl homologs of amphetamine have significant cardiovascular, behavioral, and neurochemical effects in rats. Given that these compounds are often not listed on the ingredient labels of dietary supplements, these compounds could pose a risk to humans using these products.
2020
Baumann, Michael H; Tocco, Graziella; Papsun, Donna M; Mohr, Amanda L; Fogarty, Melissa F; Krotulski, Alex J
U-47700 and Its Analogs: Non-Fentanyl Synthetic Opioids Impacting the Recreational Drug Market Journal Article
In: Brain Sciences, vol. 10, no. 11, 2020, ISSN: 2076-3425.
@article{brainsci10110895,
title = {U-47700 and Its Analogs: Non-Fentanyl Synthetic Opioids Impacting the Recreational Drug Market},
author = {Michael H Baumann and Graziella Tocco and Donna M Papsun and Amanda L Mohr and Melissa F Fogarty and Alex J Krotulski},
url = {https://pubmed.ncbi.nlm.nih.gov/33238449/},
doi = {10.3390/brainsci10110895},
issn = {2076-3425},
year = {2020},
date = {2020-01-01},
journal = {Brain Sciences},
volume = {10},
number = {11},
abstract = {The recreational use of opioid drugs is a global threat to public health and safety. In particular, an epidemic of opioid overdose fatalities is being driven by illicitly manufactured fentanyl, while novel synthetic opioids (NSOs) are appearing on recreational drug markets as standalone products, adulterants in heroin, or ingredients in counterfeit drug preparations. Trans-3,4-dichloro-N-[2-(dimethylamino)cyclohexyl]-N-methylbenzamide (U-47700) is a prime example of a non-fentanyl NSO that is associated with numerous intoxications and fatalities. Here, we review the medicinal chemistry, preclinical pharmacology, clandestine availability, methods for detection, and forensic toxicology of U-47700 and its analogs. An up-to-date summary of the human cases involving U-47700 intoxication and death are described. The evidence demonstrates that U-47700 is a potent μ-opioid receptor agonist, which poses a serious risk for overdosing and death. However, most analogs of U-47700 appear to be less potent and have been detected infrequently in forensic specimens. U-47700 represents a classic example of how chemical entities from the medicinal chemistry or patent literature can be diverted for use in recreational drug markets. Lessons learned from the experiences with U-47700 can inform scientists, clinicians, and policymakers who are involved with responding to the spread and impact of NSOs.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
The recreational use of opioid drugs is a global threat to public health and safety. In particular, an epidemic of opioid overdose fatalities is being driven by illicitly manufactured fentanyl, while novel synthetic opioids (NSOs) are appearing on recreational drug markets as standalone products, adulterants in heroin, or ingredients in counterfeit drug preparations. Trans-3,4-dichloro-N-[2-(dimethylamino)cyclohexyl]-N-methylbenzamide (U-47700) is a prime example of a non-fentanyl NSO that is associated with numerous intoxications and fatalities. Here, we review the medicinal chemistry, preclinical pharmacology, clandestine availability, methods for detection, and forensic toxicology of U-47700 and its analogs. An up-to-date summary of the human cases involving U-47700 intoxication and death are described. The evidence demonstrates that U-47700 is a potent μ-opioid receptor agonist, which poses a serious risk for overdosing and death. However, most analogs of U-47700 appear to be less potent and have been detected infrequently in forensic specimens. U-47700 represents a classic example of how chemical entities from the medicinal chemistry or patent literature can be diverted for use in recreational drug markets. Lessons learned from the experiences with U-47700 can inform scientists, clinicians, and policymakers who are involved with responding to the spread and impact of NSOs.
Brandt, Simon D; Walters, Hailey M; Partilla, John S; Blough, Bruce E; Kavanagh, Pierce V; Baumann, Michael H
In: Psychopharmacology, vol. 237, no. 12, pp. 3703–3714, 2020, ISBN: 1432-2072.
@article{Brandt:2020aa,
title = {The psychoactive aminoalkylbenzofuran derivatives, 5-APB and 6-APB, mimic the effects of 3,4-methylenedioxyamphetamine (MDA) on monoamine transmission in male rats},
author = {Simon D Brandt and Hailey M Walters and John S Partilla and Bruce E Blough and Pierce V Kavanagh and Michael H Baumann},
url = {https://pubmed.ncbi.nlm.nih.gov/32875347/},
doi = {10.1007/s00213-020-05648-z},
isbn = {1432-2072},
year = {2020},
date = {2020-01-01},
journal = {Psychopharmacology},
volume = {237},
number = {12},
pages = {3703--3714},
abstract = {The nonmedical use of new psychoactive substances (NPS) is a worldwide public health concern. The so-called ``benzofury''compounds, 5-(2-aminopropyl)benzofuran (5-APB) and 6-(2-aminopropyl)benzofuran (6-APB), are NPS with stimulant-like properties in human users. These substances are known to interact with monoamine transporters and 5-HT receptors in transfected cells, but less is known about their effects in animal models.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
The nonmedical use of new psychoactive substances (NPS) is a worldwide public health concern. The so-called ``benzofury''compounds, 5-(2-aminopropyl)benzofuran (5-APB) and 6-(2-aminopropyl)benzofuran (6-APB), are NPS with stimulant-like properties in human users. These substances are known to interact with monoamine transporters and 5-HT receptors in transfected cells, but less is known about their effects in animal models.
Truver, Michael T; Smith, Christina R; Garibay, Nancy; Kopajtic, Theresa A; Swortwood, Madeleine J; Baumann, Michael H
Pharmacodynamics and pharmacokinetics of the novel synthetic opioid, U-47700, in male rats Journal Article
In: Neuropharmacology, vol. 177, pp. 108195, 2020, ISSN: 0028-3908.
@article{TRUVER2020108195,
title = {Pharmacodynamics and pharmacokinetics of the novel synthetic opioid, U-47700, in male rats},
author = {Michael T Truver and Christina R Smith and Nancy Garibay and Theresa A Kopajtic and Madeleine J Swortwood and Michael H Baumann},
url = {https://pubmed.ncbi.nlm.nih.gov/32533977/},
doi = {https://doi.org/10.1016/j.neuropharm.2020.108195},
issn = {0028-3908},
year = {2020},
date = {2020-01-01},
journal = {Neuropharmacology},
volume = {177},
pages = {108195},
abstract = {Novel synthetic opioids are appearing in recreational drug markets worldwide as adulterants in heroin or ingredients in counterfeit analgesic medications. Trans-3,4-dichloro-N-[2-(dimethylamino)cyclohexyl]-N-methyl-benzamide (U-47700) is an example of a non-fentanyl synthetic opioid linked to overdose deaths. Here, we examined the pharmacodynamics and pharmacokinetics of U-47700 in rats. Male Sprague-Dawley rats were fitted with intravenous (i.v.) catheters and subcutaneous (s.c.) temperature transponders under ketamine/xylazine anesthesia. One week later, rats received s.c. injections of U-47700 HCl (0.3, 1.0 or 3.0 mg/kg) or saline, and blood samples (0.3 mL) were withdrawn via i.v. catheters at 15, 30, 60, 120, 240, 480 min post-injection. Pharmacodynamic effects were assessed at each blood withdrawal, and plasma was assayed for U-47700 and its metabolites by liquid chromatography tandem mass spectrometry. U-47700 induced dose-related increases in hot plate latency (ED50 = 0.5 mg/kg) and catalepsy (ED50 = 1.7 mg/kg), while the 3.0 mg/kg dose also caused hypothermia. Plasma levels of U-47700 rose linearly as dose increased, with maximal concentration (Cmax) achieved by 15--38 min. Cmax values for N-desmethyl-U-47700 and N,N-didesmethyl-U-47700 were delayed but reached levels in the same range as the parent compound. Pharmacodynamic effects were correlated with plasma U-47700 and its N-desmethyl metabolite. Using radioligand binding assays, U-47700 displayed high affinity for μ-opioid receptors (Ki = 11.1 nM) whereas metabolites were more than 18-fold weaker. Our data reveal that U-47700 induces typical μ-opioid effects which are related to plasma concentrations of the parent compound. Given its high potency, U-47700 poses substantial risk to humans who are inadvertently exposed to the drug.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Novel synthetic opioids are appearing in recreational drug markets worldwide as adulterants in heroin or ingredients in counterfeit analgesic medications. Trans-3,4-dichloro-N-[2-(dimethylamino)cyclohexyl]-N-methyl-benzamide (U-47700) is an example of a non-fentanyl synthetic opioid linked to overdose deaths. Here, we examined the pharmacodynamics and pharmacokinetics of U-47700 in rats. Male Sprague-Dawley rats were fitted with intravenous (i.v.) catheters and subcutaneous (s.c.) temperature transponders under ketamine/xylazine anesthesia. One week later, rats received s.c. injections of U-47700 HCl (0.3, 1.0 or 3.0 mg/kg) or saline, and blood samples (0.3 mL) were withdrawn via i.v. catheters at 15, 30, 60, 120, 240, 480 min post-injection. Pharmacodynamic effects were assessed at each blood withdrawal, and plasma was assayed for U-47700 and its metabolites by liquid chromatography tandem mass spectrometry. U-47700 induced dose-related increases in hot plate latency (ED50 = 0.5 mg/kg) and catalepsy (ED50 = 1.7 mg/kg), while the 3.0 mg/kg dose also caused hypothermia. Plasma levels of U-47700 rose linearly as dose increased, with maximal concentration (Cmax) achieved by 15--38 min. Cmax values for N-desmethyl-U-47700 and N,N-didesmethyl-U-47700 were delayed but reached levels in the same range as the parent compound. Pharmacodynamic effects were correlated with plasma U-47700 and its N-desmethyl metabolite. Using radioligand binding assays, U-47700 displayed high affinity for μ-opioid receptors (Ki = 11.1 nM) whereas metabolites were more than 18-fold weaker. Our data reveal that U-47700 induces typical μ-opioid effects which are related to plasma concentrations of the parent compound. Given its high potency, U-47700 poses substantial risk to humans who are inadvertently exposed to the drug.
Schindler, Charles W; Thorndike, Eric B; Walters, Hailey M; Walther, Donna; Rice, Kenner C; Baumann, Michael H
Stereoselective neurochemical, behavioral, and cardiovascular effects of α-pyrrolidinovalerophenone enantiomers in male rats Journal Article
In: Addiction Biology, vol. 25, no. 6, pp. e12842, 2020, (e12842 AB-05-2019-0122.R2).
@article{https://doi.org/10.1111/adb.12842,
title = {Stereoselective neurochemical, behavioral, and cardiovascular effects of α-pyrrolidinovalerophenone enantiomers in male rats},
author = {Charles W Schindler and Eric B Thorndike and Hailey M Walters and Donna Walther and Kenner C Rice and Michael H Baumann},
url = {https://pubmed.ncbi.nlm.nih.gov/31724254/},
doi = {https://doi.org/10.1111/adb.12842},
year = {2020},
date = {2020-01-01},
journal = {Addiction Biology},
volume = {25},
number = {6},
pages = {e12842},
abstract = {Abstract The synthetic cathinone α-pyrrolidinovalerophenone (α-PVP) continues to be abused despite being banned by regulatory agencies. The abused formulation of α-PVP is a racemic mixture consisting of two enantiomers, S-α-PVP and R-α-PVP. In this study, we investigated the neurochemical, behavioral, and cardiovascular effects of racemic α-PVP and its enantiomers in male rats. Racemic α-PVP blocked the uptake of both dopamine and norepinephrine ex vivo, but did not block the uptake of serotonin (5-HT), at their respective transporters. S-α-PVP was slightly more potent than racemic α-PVP, while R-α-PVP was 10 to 20 times less potent at blocking dopamine and norepinephrine uptake. In microdialysis studies, racemic and S-α-PVP increased extracellular dopamine levels in the nucleus accumbens, but not levels of 5-HT. Racemic and S-α-PVP also increased locomotor activity. When tested at the same doses, S-α-PVP produced larger effects than racemic α-PVP. R-α-PVP also increased extracellular dopamine levels and locomotor activity, but only at 30 times higher doses than S-α-PVP. Racemic and S-α-PVP were self-administered by rats at 0.03 mg/kg/injection, whereas R-α-PVP was self-administered at a 10 times higher dose. Dose-effect determinations following acquisition suggested that R-α-PVP was at least 30 times less potent than S-α-PVP. Finally, racemic and S-α-PVP increased blood pressure and heart rate at doses approximately 30 times less than was required for R-α-PVP to produce similar effects. These results show that the neurochemical, behavioral, and cardiovascular effects of racemic α-PVP most likely reflect the actions of S isomer.},
note = {e12842 AB-05-2019-0122.R2},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Abstract The synthetic cathinone α-pyrrolidinovalerophenone (α-PVP) continues to be abused despite being banned by regulatory agencies. The abused formulation of α-PVP is a racemic mixture consisting of two enantiomers, S-α-PVP and R-α-PVP. In this study, we investigated the neurochemical, behavioral, and cardiovascular effects of racemic α-PVP and its enantiomers in male rats. Racemic α-PVP blocked the uptake of both dopamine and norepinephrine ex vivo, but did not block the uptake of serotonin (5-HT), at their respective transporters. S-α-PVP was slightly more potent than racemic α-PVP, while R-α-PVP was 10 to 20 times less potent at blocking dopamine and norepinephrine uptake. In microdialysis studies, racemic and S-α-PVP increased extracellular dopamine levels in the nucleus accumbens, but not levels of 5-HT. Racemic and S-α-PVP also increased locomotor activity. When tested at the same doses, S-α-PVP produced larger effects than racemic α-PVP. R-α-PVP also increased extracellular dopamine levels and locomotor activity, but only at 30 times higher doses than S-α-PVP. Racemic and S-α-PVP were self-administered by rats at 0.03 mg/kg/injection, whereas R-α-PVP was self-administered at a 10 times higher dose. Dose-effect determinations following acquisition suggested that R-α-PVP was at least 30 times less potent than S-α-PVP. Finally, racemic and S-α-PVP increased blood pressure and heart rate at doses approximately 30 times less than was required for R-α-PVP to produce similar effects. These results show that the neurochemical, behavioral, and cardiovascular effects of racemic α-PVP most likely reflect the actions of S isomer.
2019
Bergh, Marianne Skov-Skov; Bogen, Inger Lise; Garibay, Nancy; Baumann, Michael H
Evidence for nonlinear accumulation of the ultrapotent fentanyl analog, carfentanil, after systemic administration to male rats Journal Article
In: Neuropharmacology, vol. 158, pp. 107596, 2019, ISSN: 0028-3908.
@article{BERGH2019107596,
title = {Evidence for nonlinear accumulation of the ultrapotent fentanyl analog, carfentanil, after systemic administration to male rats},
author = {Marianne Skov-Skov Bergh and Inger Lise Bogen and Nancy Garibay and Michael H Baumann},
url = {https://pubmed.ncbi.nlm.nih.gov/30965021/},
doi = {https://doi.org/10.1016/j.neuropharm.2019.04.002},
issn = {0028-3908},
year = {2019},
date = {2019-01-01},
journal = {Neuropharmacology},
volume = {158},
pages = {107596},
abstract = {The current opioid overdose crisis is being exacerbated by illicitly manufactured fentanyl and its analogs. Carfentanil is a fentanyl analog that is 10,000-times more potent than morphine, but limited information is available about its pharmacology. The present study had two aims: 1) to validate a method for quantifying carfentanil and its metabolite norcarfentanil in small-volume samples, and 2) to use the method for examining pharmacodynamic-pharmacokinetic relationships in rats. The analytical method involved liquid-liquid extraction of plasma samples followed by quantitation of carfentanil and norcarfentanil using ultra-high-performance liquid chromatography coupled to tandem mass spectrometry (UHPLC-MS/MS). The method was validated following SWGTOX guidelines, and both analytes displayed limits of detection and quantification at 7.5 and 15 pg/mL, respectively. Male Sprague-Dawley rats fitted with jugular catheters and temperature transponders received subcutaneous carfentanil (1, 3 and 10 μg/kg) or saline. Repeated blood specimens were obtained over 8 h, along with pharmacodynamic measures including core temperature and catalepsy scores. Carfentanil produced dose-related hypothermia and catalepsy that lasted up to 8 h. Carfentanil Cmax occurred at 15 min whereas metabolite Cmax was at 1--2 h. Concentrations of both analytes increased in a dose-related fashion, but area-under-the-curve values were much greater than predicted after 10 μg/kg. Plasma half-life for carfentanil increased at higher doses. Our findings reveal that carfentanil produces marked hypothermia and catalepsy, which is accompanied by nonlinear accumulation of the drug at high doses. We hypothesize that impaired clearance of carfentanil in humans could contribute to life-threatening effects of this ultrapotent opioid agonist. This article is part of the Special Issue entitled `New Vistas in Opioid Pharmacology'.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
The current opioid overdose crisis is being exacerbated by illicitly manufactured fentanyl and its analogs. Carfentanil is a fentanyl analog that is 10,000-times more potent than morphine, but limited information is available about its pharmacology. The present study had two aims: 1) to validate a method for quantifying carfentanil and its metabolite norcarfentanil in small-volume samples, and 2) to use the method for examining pharmacodynamic-pharmacokinetic relationships in rats. The analytical method involved liquid-liquid extraction of plasma samples followed by quantitation of carfentanil and norcarfentanil using ultra-high-performance liquid chromatography coupled to tandem mass spectrometry (UHPLC-MS/MS). The method was validated following SWGTOX guidelines, and both analytes displayed limits of detection and quantification at 7.5 and 15 pg/mL, respectively. Male Sprague-Dawley rats fitted with jugular catheters and temperature transponders received subcutaneous carfentanil (1, 3 and 10 μg/kg) or saline. Repeated blood specimens were obtained over 8 h, along with pharmacodynamic measures including core temperature and catalepsy scores. Carfentanil produced dose-related hypothermia and catalepsy that lasted up to 8 h. Carfentanil Cmax occurred at 15 min whereas metabolite Cmax was at 1--2 h. Concentrations of both analytes increased in a dose-related fashion, but area-under-the-curve values were much greater than predicted after 10 μg/kg. Plasma half-life for carfentanil increased at higher doses. Our findings reveal that carfentanil produces marked hypothermia and catalepsy, which is accompanied by nonlinear accumulation of the drug at high doses. We hypothesize that impaired clearance of carfentanil in humans could contribute to life-threatening effects of this ultrapotent opioid agonist. This article is part of the Special Issue entitled `New Vistas in Opioid Pharmacology'.
Halberstadt, Adam L; Brandt, Simon D; Walther, Donna; Baumann, Michael H
2-Aminoindan and its ring-substituted derivatives interact with plasma membrane monoamine transporters and α2-adrenergic receptors Journal Article
In: Psychopharmacology, vol. 236, no. 3, pp. 989–999, 2019, ISBN: 1432-2072.
@article{Halberstadt:2019aa,
title = {2-Aminoindan and its ring-substituted derivatives interact with plasma membrane monoamine transporters and α_{2}-adrenergic receptors},
author = {Adam L Halberstadt and Simon D Brandt and Donna Walther and Michael H Baumann},
url = {https://pubmed.ncbi.nlm.nih.gov/30904940/},
doi = {10.1007/s00213-019-05207-1},
isbn = {1432-2072},
year = {2019},
date = {2019-01-01},
journal = {Psychopharmacology},
volume = {236},
number = {3},
pages = {989--999},
abstract = {Over the last decade, many new psychostimulant analogues have appeared on the recreational drug market and most are derivatives of amphetamine or cathinone. Another class of designer drugs is derived from the 2-aminoindan structural template. Several members of this class, including the parent compound 2-aminoindan (2-AI), have been sold as designer drugs. Another aminoindan derivative, 5-methoxy-2-aminoindan (5-MeO-AI or MEAI), is the active ingredient in a product marketed online as an alcohol substitute.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Over the last decade, many new psychostimulant analogues have appeared on the recreational drug market and most are derivatives of amphetamine or cathinone. Another class of designer drugs is derived from the 2-aminoindan structural template. Several members of this class, including the parent compound 2-aminoindan (2-AI), have been sold as designer drugs. Another aminoindan derivative, 5-methoxy-2-aminoindan (5-MeO-AI or MEAI), is the active ingredient in a product marketed online as an alcohol substitute.
Schindler, Charles W; Thorndike, Eric B; Rice, Kenner C; Partilla, John S; Baumann, Michael H
The Supplement Adulterant β-Methylphenethylamine Increases Blood Pressure by Acting at Peripheral Norepinephrine Transporters Journal Article
In: Journal of Pharmacology and Experimental Therapeutics, vol. 369, no. 3, pp. 328–336, 2019, ISSN: 0022-3565.
@article{Schindler328,
title = {The Supplement Adulterant \textit{β}-Methylphenethylamine Increases Blood Pressure by Acting at Peripheral Norepinephrine Transporters},
author = {Charles W Schindler and Eric B Thorndike and Kenner C Rice and John S Partilla and Michael H Baumann},
url = {https://pubmed.ncbi.nlm.nih.gov/30898867/},
doi = {10.1124/jpet.118.255976},
issn = {0022-3565},
year = {2019},
date = {2019-01-01},
journal = {Journal of Pharmacology and Experimental Therapeutics},
volume = {369},
number = {3},
pages = {328--336},
publisher = {American Society for Pharmacology and Experimental Therapeutics},
abstract = {β-Methylphenethylamine [(BMPEA), 2-phenylpropan-1-amine] is a structural isomer of amphetamine (1-phenylpropan-2-amine) that has been identified in preworkout and weight loss supplements, yet little information is available about its pharmacology. Here, the neurochemical and cardiovascular effects of BMPEA and its analogs, N-methyl-2-phenylpropan-1-amine (MPPA) and N,N-dimethyl-2-phenylpropan-1-amine (DMPPA), were compared with structurally related amphetamines. As expected, amphetamine and methamphetamine were potent substrate-type releasing agents at dopamine transporters (DATs) and norepinephrine transporters (NETs) in rat brain synaptosomes. BMPEA and MPPA were also substrates at DATs and NETs, but they were at least 10-fold less potent than amphetamine. DMPPA was a weak substrate only at NETs. Importantly, the releasing actions of BMPEA and MPPA were more potent at NETs than DATs. Amphetamine produced significant dose-related increases in blood pressure (BP), heart rate (HR), and locomotor activity in conscious rats fitted with surgically implanted biotelemetry transmitters. BMPEA, MPPA, and DMPPA produced increases in BP that were similar to the effects of amphetamine, but the compounds failed to substantially affect HR or activity. The hypertensive effect of BMPEA was reversed by the α-adrenergic antagonist prazosin but not the ganglionic blocker chlorisondamine. Radioligand binding at various G protein–coupled receptors did not identify nontransporter sites of action that could account for cardiovascular effects of BMPEA or its analogs. Our results show that BMPEA, MPPA, and DMPPA are biologically active. The compounds are unlikely to be abused due to weak effects at DATs, but they could produce adverse cardiovascular effects via substrate activity at peripheral NET sites.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
β-Methylphenethylamine [(BMPEA), 2-phenylpropan-1-amine] is a structural isomer of amphetamine (1-phenylpropan-2-amine) that has been identified in preworkout and weight loss supplements, yet little information is available about its pharmacology. Here, the neurochemical and cardiovascular effects of BMPEA and its analogs, N-methyl-2-phenylpropan-1-amine (MPPA) and N,N-dimethyl-2-phenylpropan-1-amine (DMPPA), were compared with structurally related amphetamines. As expected, amphetamine and methamphetamine were potent substrate-type releasing agents at dopamine transporters (DATs) and norepinephrine transporters (NETs) in rat brain synaptosomes. BMPEA and MPPA were also substrates at DATs and NETs, but they were at least 10-fold less potent than amphetamine. DMPPA was a weak substrate only at NETs. Importantly, the releasing actions of BMPEA and MPPA were more potent at NETs than DATs. Amphetamine produced significant dose-related increases in blood pressure (BP), heart rate (HR), and locomotor activity in conscious rats fitted with surgically implanted biotelemetry transmitters. BMPEA, MPPA, and DMPPA produced increases in BP that were similar to the effects of amphetamine, but the compounds failed to substantially affect HR or activity. The hypertensive effect of BMPEA was reversed by the α-adrenergic antagonist prazosin but not the ganglionic blocker chlorisondamine. Radioligand binding at various G protein–coupled receptors did not identify nontransporter sites of action that could account for cardiovascular effects of BMPEA or its analogs. Our results show that BMPEA, MPPA, and DMPPA are biologically active. The compounds are unlikely to be abused due to weak effects at DATs, but they could produce adverse cardiovascular effects via substrate activity at peripheral NET sites.
2018
Baumann, Michael H; Kopajtic, Theresa A; Madras, Bertha K
Pharmacological Research as a Key Component in Mitigating the Opioid Overdose Crisis Journal Article
In: Trends in Pharmacological Sciences, vol. 39, no. 12, pp. 995–998, 2018, ISBN: 0165-6147.
@article{Baumann:2018aa,
title = {Pharmacological Research as a Key Component in Mitigating the Opioid Overdose Crisis},
author = {Michael H Baumann and Theresa A Kopajtic and Bertha K Madras},
url = {https://pubmed.ncbi.nlm.nih.gov/30454770/},
doi = {10.1016/j.tips.2018.09.006},
isbn = {0165-6147},
year = {2018},
date = {2018-12-01},
booktitle = {Trends in Pharmacological Sciences},
journal = {Trends in Pharmacological Sciences},
volume = {39},
number = {12},
pages = {995--998},
publisher = {Elsevier},
abstract = {The United States is experiencing an epidemic of opioid overdose deaths. Many of the recent fatalities are associated with illicitly manufactured fentanyl, which is being added to heroin and counterfeit pain pills. The crisis is further exacerbated by the emergence of an increasing number of novel synthetic opioids (NSOs), including various fentanyl analogs and non-fentanyl compounds that display potent agonist actions at the ?-opioid receptor. Importantly, most users are unaware of their exposure to fentanyl and NSOs. Stemming the tide of opioid-related fatalities will require a coordinated multidisciplinary response from policy makers, law enforcement personnel, first responders, treatment providers, family members, and scientists. To this end, basic research in pharmacology can contribute significantly to mitigating the crisis through efforts to characterize the biological effects of NSOs, discover more effective antidotes for overdose rescue, and develop safer medications for treating addiction and alleviating pain.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
The United States is experiencing an epidemic of opioid overdose deaths. Many of the recent fatalities are associated with illicitly manufactured fentanyl, which is being added to heroin and counterfeit pain pills. The crisis is further exacerbated by the emergence of an increasing number of novel synthetic opioids (NSOs), including various fentanyl analogs and non-fentanyl compounds that display potent agonist actions at the ?-opioid receptor. Importantly, most users are unaware of their exposure to fentanyl and NSOs. Stemming the tide of opioid-related fatalities will require a coordinated multidisciplinary response from policy makers, law enforcement personnel, first responders, treatment providers, family members, and scientists. To this end, basic research in pharmacology can contribute significantly to mitigating the crisis through efforts to characterize the biological effects of NSOs, discover more effective antidotes for overdose rescue, and develop safer medications for treating addiction and alleviating pain.
Elmore, Joshua S; Decker, Ann M; Sulima, Agnieszka; Rice, Kenner C; Partilla, John S; Blough, Bruce E; Baumann, Michael H
Comparative neuropharmacology of N-(2-methoxybenzyl)-2,5-dimethoxyphenethylamine (NBOMe) hallucinogens and their 2C counterparts in male rats. Journal Article
In: Neuropharmacology, 2018, ISSN: 1873-7064 (Electronic); 0028-3908 (Linking).
@article{Elmore:2018ab,
title = {Comparative neuropharmacology of N-(2-methoxybenzyl)-2,5-dimethoxyphenethylamine (NBOMe) hallucinogens and their 2C counterparts in male rats.},
author = {Joshua S Elmore and Ann M Decker and Agnieszka Sulima and Kenner C Rice and John S Partilla and Bruce E Blough and Michael H Baumann},
url = {https://www.ncbi.nlm.nih.gov/pubmed/29501528},
doi = {10.1016/j.neuropharm.2018.02.033},
issn = {1873-7064 (Electronic); 0028-3908 (Linking)},
year = {2018},
date = {2018-03-01},
journal = {Neuropharmacology},
address = {Designer Drug Research Unit, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD, 21224, USA.},
abstract = {2,5-Dimethoxyphenethylamines (2C compounds) are 5-HT2A/2C receptor agonists that induce hallucinogenic effects. N-methoxybenzylation of 2C compounds markedly increases their affinity for 5-HT2A receptors, and two such analogs, 2-(4-chloro-2,5-dimethoxyphenyl)-N-[(2-methoxyphenyl)methyl]ethanamine (25C-NBOMe) and 2-(4-iodo-2,5-dimethoxyphenyl)-N-[(2-methoxyphenyl)methyl]ethanamine (25I-NBOMe), have emerged in recreational drug markets. Here, we investigated the neuropharmacology of 25C-NBOMe and 25I-NBOMe in rats, as compared to their 2C analogs and the prototypical 5-HT2A/2C agonist 1-(4-iodo-2,5-dimethoxyphenyl)propan-2-amine (DOI). Compounds were tested in vitro using 5-HT2A receptor binding and calcium mobilization assays. For in vivo experiments, 25C-NBOMe (0.01-0.3mg/kg), 25I-NBOMe (0.01-0.3mg/kg), 2-(4-chloro-2,5-dimethoxyphenyl)ethanamine (2C-C) (0.1-3.0mg/kg), 2-(4-iodo-2,5-dimethoxyphenyl)ethanamine (2C-I) (0.1-3.0mg/kg) and DOI (0.03-1.0mg/kg) were administered subcutaneously (sc) to male rats, and 5-HT2A-mediated behaviors were assessed. NBOMes displayed higher affinity for 5-HT2A receptors than their 2C counterparts but were substantially weaker in functional assays. 25C-NBOMe and 25I-NBOMe were much more potent at inducing wet dog shakes (WDS) and back muscle contractions (BMC) when compared to 2C-C and 2C-I. Pretreatment with the selective 5-HT2A antagonist (R)-(2,3-dimethoxyphenyl)1-[2-(4-fluorophenyl)ethyl]-4-piperidinylmethanol (M100907) reversed behaviors produced by all agonists. Interestingly, binding affinities at the 5-HT2A receptor were significantly correlated with potencies to induce BMC but not WDS. Our findings show that NBOMes are highly potent 5-HT2A agonists in rats, similar to effects in mice, and consistent with the reported hallucinogenic effects in human users.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
2,5-Dimethoxyphenethylamines (2C compounds) are 5-HT2A/2C receptor agonists that induce hallucinogenic effects. N-methoxybenzylation of 2C compounds markedly increases their affinity for 5-HT2A receptors, and two such analogs, 2-(4-chloro-2,5-dimethoxyphenyl)-N-[(2-methoxyphenyl)methyl]ethanamine (25C-NBOMe) and 2-(4-iodo-2,5-dimethoxyphenyl)-N-[(2-methoxyphenyl)methyl]ethanamine (25I-NBOMe), have emerged in recreational drug markets. Here, we investigated the neuropharmacology of 25C-NBOMe and 25I-NBOMe in rats, as compared to their 2C analogs and the prototypical 5-HT2A/2C agonist 1-(4-iodo-2,5-dimethoxyphenyl)propan-2-amine (DOI). Compounds were tested in vitro using 5-HT2A receptor binding and calcium mobilization assays. For in vivo experiments, 25C-NBOMe (0.01-0.3mg/kg), 25I-NBOMe (0.01-0.3mg/kg), 2-(4-chloro-2,5-dimethoxyphenyl)ethanamine (2C-C) (0.1-3.0mg/kg), 2-(4-iodo-2,5-dimethoxyphenyl)ethanamine (2C-I) (0.1-3.0mg/kg) and DOI (0.03-1.0mg/kg) were administered subcutaneously (sc) to male rats, and 5-HT2A-mediated behaviors were assessed. NBOMes displayed higher affinity for 5-HT2A receptors than their 2C counterparts but were substantially weaker in functional assays. 25C-NBOMe and 25I-NBOMe were much more potent at inducing wet dog shakes (WDS) and back muscle contractions (BMC) when compared to 2C-C and 2C-I. Pretreatment with the selective 5-HT2A antagonist (R)-(2,3-dimethoxyphenyl)1-[2-(4-fluorophenyl)ethyl]-4-piperidinylmethanol (M100907) reversed behaviors produced by all agonists. Interestingly, binding affinities at the 5-HT2A receptor were significantly correlated with potencies to induce BMC but not WDS. Our findings show that NBOMes are highly potent 5-HT2A agonists in rats, similar to effects in mice, and consistent with the reported hallucinogenic effects in human users.
Elmore, Joshua S; Baumann, Michael H
Repeated Exposure to the "Spice" Cannabinoid JWH-018 Induces Tolerance and Enhances Responsiveness to 5-HT1A Receptor Stimulation in Male Rats. Journal Article
In: Front Psychiatry, vol. 9, pp. 55, 2018, ISSN: 1664-0640 (Print); 1664-0640 (Linking).
@article{Elmore:2018aa,
title = {Repeated Exposure to the "Spice" Cannabinoid JWH-018 Induces Tolerance and Enhances Responsiveness to 5-HT1A Receptor Stimulation in Male Rats.},
author = {Joshua S Elmore and Michael H Baumann},
url = {https://www.ncbi.nlm.nih.gov/pubmed/29535650},
doi = {10.3389/fpsyt.2018.00055},
issn = {1664-0640 (Print); 1664-0640 (Linking)},
year = {2018},
date = {2018-02-27},
journal = {Front Psychiatry},
volume = {9},
pages = {55},
address = {Designer Drug Research Unit, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD, United States.},
abstract = {Naphthalen-1-yl-(1-pentylindol-3-yl)methanone (JWH-018) is a synthetic compound found in psychoactive "spice" products that activates cannabinoid receptors. Preclinical evidence suggests that exposure to synthetic cannabinoids increases 5-HT2A/2C receptor function in the brain, an effect which might contribute to psychotic symptoms. Here, we hypothesized that repeated exposures to JWH-018 would enhance behavioral responsiveness to the 5-HT2A/2C receptor agonist DOI. Male Sprague-Dawley rats fitted with subcutaneously (sc) temperature transponders received daily injections of JWH-018 (1.0 mg/kg, sc) or its vehicle for seven consecutive days. Body temperature and catalepsy scores were determined at 1, 2, and 4 h post-injection each day. At 1 and 7 days after the final repeated treatment, rats received a challenge injection of either DOI (0.1 mg/kg, sc) or the 5-HT1A receptor agonist 8-OH-DPAT (0.3 mg/kg, sc), then temperature and behavioral responses were assessed. Behaviors induced by DOI included wet dog shakes and back muscle contractions (i.e., skin jerks), while behaviors induced by 8-OH-DPAT included ambulation, forepaw treading, and flat body posture. On the first day of repeated treatment, JWH-018 produced robust hypothermia and catalepsy which lasted up to 4 h, and these effects were significantly blunted by day 7 of treatment. Repeated exposure to JWH-018 did not affect behaviors induced by DOI, but behavioral and hypothermic responses induced by 8-OH-DPAT were significantly augmented 1 day after cessation of JWH-018 treatment. Collectively, our findings show that repeated treatment with JWH-018 produces tolerance to its hypothermic and cataleptic effects, which is accompanied by transient enhancement of 5-HT1A receptor sensitivity in vivo.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Naphthalen-1-yl-(1-pentylindol-3-yl)methanone (JWH-018) is a synthetic compound found in psychoactive "spice" products that activates cannabinoid receptors. Preclinical evidence suggests that exposure to synthetic cannabinoids increases 5-HT2A/2C receptor function in the brain, an effect which might contribute to psychotic symptoms. Here, we hypothesized that repeated exposures to JWH-018 would enhance behavioral responsiveness to the 5-HT2A/2C receptor agonist DOI. Male Sprague-Dawley rats fitted with subcutaneously (sc) temperature transponders received daily injections of JWH-018 (1.0 mg/kg, sc) or its vehicle for seven consecutive days. Body temperature and catalepsy scores were determined at 1, 2, and 4 h post-injection each day. At 1 and 7 days after the final repeated treatment, rats received a challenge injection of either DOI (0.1 mg/kg, sc) or the 5-HT1A receptor agonist 8-OH-DPAT (0.3 mg/kg, sc), then temperature and behavioral responses were assessed. Behaviors induced by DOI included wet dog shakes and back muscle contractions (i.e., skin jerks), while behaviors induced by 8-OH-DPAT included ambulation, forepaw treading, and flat body posture. On the first day of repeated treatment, JWH-018 produced robust hypothermia and catalepsy which lasted up to 4 h, and these effects were significantly blunted by day 7 of treatment. Repeated exposure to JWH-018 did not affect behaviors induced by DOI, but behavioral and hypothermic responses induced by 8-OH-DPAT were significantly augmented 1 day after cessation of JWH-018 treatment. Collectively, our findings show that repeated treatment with JWH-018 produces tolerance to its hypothermic and cataleptic effects, which is accompanied by transient enhancement of 5-HT1A receptor sensitivity in vivo.
2017
Schindler, Charles W; Gramling, Benjamin R; Justinova, Zuzana; Thorndike, Eric B; Baumann, Michael H
Synthetic cannabinoids found in "spice" products alter body temperature and cardiovascular parameters in conscious male rats. Journal Article
In: Drug Alcohol Depend, vol. 179, pp. 387–394, 2017, ISSN: 1879-0046 (Electronic); 0376-8716 (Linking).
@article{Schindler:2017aa,
title = {Synthetic cannabinoids found in "spice" products alter body temperature and cardiovascular parameters in conscious male rats.},
author = {Charles W Schindler and Benjamin R Gramling and Zuzana Justinova and Eric B Thorndike and Michael H Baumann},
url = {https://www.ncbi.nlm.nih.gov/pubmed/28846955},
doi = {10.1016/j.drugalcdep.2017.07.029},
issn = {1879-0046 (Electronic); 0376-8716 (Linking)},
year = {2017},
date = {2017-10-01},
journal = {Drug Alcohol Depend},
volume = {179},
pages = {387--394},
address = {Designer Drug Research Unit, Intramural Research Program, National Institute on Drug Abuse, Baltimore, MD, United States; Preclinical Pharmacology Section, Intramural Research Program, National Institute on Drug Abuse, Baltimore, MD, United States. Electronic address: cschind@helix.nih.gov.},
abstract = {BACKGROUND: The misuse of synthetic cannabinoids is a persistent public health concern. Because these drugs target the same cannabinoid receptors as the active ingredient of marijuana, Delta(9)-tetrahydrocannabinol (THC), we compared the effects of synthetic cannabinoids and THC on body temperature and cardiovascular parameters. METHODS: Biotelemetry transmitters for the measurement of body temperature or blood pressure (BP) were surgically implanted into separate groups of male rats. THC and the synthetic cannabinoids CP55,940, JWH-018, AM2201 and XLR-11 were injected s.c., and rats were placed into isolation cubicles for 3h. RESULTS: THC and synthetic cannabinoids produced dose-related decreases in body temperature that were most prominent in the final 2h of the session. The rank order of potency was CP55,940>AM2201=JWH-018>THC=XLR-11. The cannabinoid inverse agonist rimonabant antagonized the hypothermic effect of all compounds. Synthetic cannabinoids elevated BP in comparison to vehicle treatment during the first h of the session, while heart rate was unaffected. The rank order of potency for BP increases was similar to that seen for hypothermia. Hypertensive effects of CP55,940 and JWH-018 were not antagonized by rimonabant or the neutral antagonist AM4113. However, the BP responses to both drugs were antagonized by pretreatment with either the ganglionic blocker hexamethonium or the alpha1 adrenergic antagonist prazosin. CONCLUSIONS: Our results show that synthetic cannabinoids produce hypothermia in rats by a mechanism involving cannabinoid receptors, while they increase BP by a mechanism independent of these sites. The hypertensive effect appears to involve central sympathetic outflow.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
BACKGROUND: The misuse of synthetic cannabinoids is a persistent public health concern. Because these drugs target the same cannabinoid receptors as the active ingredient of marijuana, Delta(9)-tetrahydrocannabinol (THC), we compared the effects of synthetic cannabinoids and THC on body temperature and cardiovascular parameters. METHODS: Biotelemetry transmitters for the measurement of body temperature or blood pressure (BP) were surgically implanted into separate groups of male rats. THC and the synthetic cannabinoids CP55,940, JWH-018, AM2201 and XLR-11 were injected s.c., and rats were placed into isolation cubicles for 3h. RESULTS: THC and synthetic cannabinoids produced dose-related decreases in body temperature that were most prominent in the final 2h of the session. The rank order of potency was CP55,940>AM2201=JWH-018>THC=XLR-11. The cannabinoid inverse agonist rimonabant antagonized the hypothermic effect of all compounds. Synthetic cannabinoids elevated BP in comparison to vehicle treatment during the first h of the session, while heart rate was unaffected. The rank order of potency for BP increases was similar to that seen for hypothermia. Hypertensive effects of CP55,940 and JWH-018 were not antagonized by rimonabant or the neutral antagonist AM4113. However, the BP responses to both drugs were antagonized by pretreatment with either the ganglionic blocker hexamethonium or the alpha1 adrenergic antagonist prazosin. CONCLUSIONS: Our results show that synthetic cannabinoids produce hypothermia in rats by a mechanism involving cannabinoid receptors, while they increase BP by a mechanism independent of these sites. The hypertensive effect appears to involve central sympathetic outflow.
Solis, Ernesto Jr; Partilla, John S; Sakloth, Farhana; Ruchala, Iwona; Schwienteck, Kathryn L; Felice, Louis J De; Eltit, Jose M; Glennon, Richard A; Negus, Stevens S; Baumann, Michael H
N-Alkylated Analogs of 4-Methylamphetamine (4-MA) Differentially Affect Monoamine Transporters and Abuse Liability. Journal Article
In: Neuropsychopharmacology, vol. 42, no. 10, pp. 1950–1961, 2017, ISSN: 1740-634X (Electronic); 0893-133X (Linking).
@article{Solis:2017aa,
title = {N-Alkylated Analogs of 4-Methylamphetamine (4-MA) Differentially Affect Monoamine Transporters and Abuse Liability.},
author = {Ernesto Jr Solis and John S Partilla and Farhana Sakloth and Iwona Ruchala and Kathryn L Schwienteck and Louis J De Felice and Jose M Eltit and Richard A Glennon and Stevens S Negus and Michael H Baumann},
url = {https://www.ncbi.nlm.nih.gov/pubmed/28530234},
doi = {10.1038/npp.2017.98},
issn = {1740-634X (Electronic); 0893-133X (Linking)},
year = {2017},
date = {2017-09-01},
journal = {Neuropsychopharmacology},
volume = {42},
number = {10},
pages = {1950--1961},
address = {In Vivo Electrophysiology Unit, Behavioral Neuroscience Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD, USA.},
abstract = {Clandestine chemists synthesize novel stimulant drugs by exploiting structural templates known to target monoamine transporters for dopamine, norepinephrine, and serotonin (DAT, NET, and SERT, respectively). 4-Methylamphetamine (4-MA) is an emerging drug of abuse that interacts with transporters, but limited structure-activity data are available for its analogs. Here we employed uptake and release assays in rat brain synaptosomes, voltage-clamp current measurements in cells expressing transporters, and calcium flux assays in cells coexpressing transporters and calcium channels to study the effects of increasing N-alkyl chain length of 4-MA on interactions at DAT, NET, and SERT. In addition, we performed intracranial self-stimulation in rats to understand how the chemical modifications affect abuse liability. All 4-MA analogs inhibited uptake at DAT, NET, and SERT, but lengthening the amine substituent from methyl to ethyl, propyl, and butyl produced a stepwise decrease in potency. N-methyl 4-MA was an efficacious substrate-type releaser at DAT that evoked an inward depolarizing current and calcium influx, whereas other analogs did not exhibit these effects. N-methyl and N-ethyl 4-MA were substrates at NET, whereas N-propyl and N-butyl 4-MA were not. All analogs acted as SERT substrates, though N-butyl 4-MA had very weak effects. Intracranial self-stimulation in rats showed that elongating the N-alkyl chain decreased abuse-related effects in vivo that appeared to parallel reductions in DAT activity. Overall, converging lines of evidence show that lengthening the N-alkyl substituent of 4-MA reduces potency to inhibit transporters, eliminates substrate activity at DAT and NET, and decreases abuse liability of the compounds.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Clandestine chemists synthesize novel stimulant drugs by exploiting structural templates known to target monoamine transporters for dopamine, norepinephrine, and serotonin (DAT, NET, and SERT, respectively). 4-Methylamphetamine (4-MA) is an emerging drug of abuse that interacts with transporters, but limited structure-activity data are available for its analogs. Here we employed uptake and release assays in rat brain synaptosomes, voltage-clamp current measurements in cells expressing transporters, and calcium flux assays in cells coexpressing transporters and calcium channels to study the effects of increasing N-alkyl chain length of 4-MA on interactions at DAT, NET, and SERT. In addition, we performed intracranial self-stimulation in rats to understand how the chemical modifications affect abuse liability. All 4-MA analogs inhibited uptake at DAT, NET, and SERT, but lengthening the amine substituent from methyl to ethyl, propyl, and butyl produced a stepwise decrease in potency. N-methyl 4-MA was an efficacious substrate-type releaser at DAT that evoked an inward depolarizing current and calcium influx, whereas other analogs did not exhibit these effects. N-methyl and N-ethyl 4-MA were substrates at NET, whereas N-propyl and N-butyl 4-MA were not. All analogs acted as SERT substrates, though N-butyl 4-MA had very weak effects. Intracranial self-stimulation in rats showed that elongating the N-alkyl chain decreased abuse-related effects in vivo that appeared to parallel reductions in DAT activity. Overall, converging lines of evidence show that lengthening the N-alkyl substituent of 4-MA reduces potency to inhibit transporters, eliminates substrate activity at DAT and NET, and decreases abuse liability of the compounds.
Prekupec, Matthew P; Mansky, Peter A; Baumann, Michael H
Misuse of Novel Synthetic Opioids: A Deadly New Trend. Journal Article
In: J Addict Med, vol. 11, no. 7, pp. 256–265, 2017.
@article{Prekupec2017,
title = {Misuse of Novel Synthetic Opioids: A Deadly New Trend. },
author = {Matthew P Prekupec and Peter A Mansky and Michael H Baumann},
url = {https://www.ncbi.nlm.nih.gov/pubmed/28590391},
doi = {10.1097/ADM.0000000000000324},
year = {2017},
date = {2017-07-15},
journal = {J Addict Med},
volume = {11},
number = {7},
pages = {256--265},
abstract = {Novel synthetic opioids (NSOs) include various analogs of fentanyl and newly emerging non-fentanyl compounds. Together with illicitly manufactured fentanyl (IMF), these drugs have caused a recent spike in overdose deaths, whereas deaths from prescription opioids have stabilized. NSOs are used as stand-alone products, as adulterants in heroin, or as constituents of counterfeit prescription medications. During 2015 alone, there were 9580 deaths from synthetic opioids other than methadone. Most of these fatalities were associated with IMF rather than diverted pharmaceutical fentanyl. In opioid overdose cases, where the presence of fentanyl analogs was examined, analogs were implicated in 17% of fatalities. Recent data from law enforcement sources show increasing confiscation of acetylfentanyl, butyrylfentanyl, and furanylfentanyl, in addition to non-fentanyl compounds such as U-47700. Since 2013, deaths from NSOs in the United States were 52 for acetylfentanyl, 40 for butyrylfentanyl, 128 for furanylfentanyl, and 46 for U-47700. All of these substances induce a classic opioid toxidrome, which can be reversed with the competitive antagonist naloxone. However, due to the putative high potency of NSOs and their growing prevalence, it is recommended to forgo the 0.4 mg initial dose of naloxone and start with 2 mg. Because NSOs offer enormous profit potential, and there is strong demand for their use, these drugs are being trafficked by organized crime. NSOs present major challenges for medical professionals, law enforcement agencies, and policymakers. Resources must be distributed equitably to enhance harm reduction though public education, medication-assisted therapies, and improved access to naloxone.
},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Novel synthetic opioids (NSOs) include various analogs of fentanyl and newly emerging non-fentanyl compounds. Together with illicitly manufactured fentanyl (IMF), these drugs have caused a recent spike in overdose deaths, whereas deaths from prescription opioids have stabilized. NSOs are used as stand-alone products, as adulterants in heroin, or as constituents of counterfeit prescription medications. During 2015 alone, there were 9580 deaths from synthetic opioids other than methadone. Most of these fatalities were associated with IMF rather than diverted pharmaceutical fentanyl. In opioid overdose cases, where the presence of fentanyl analogs was examined, analogs were implicated in 17% of fatalities. Recent data from law enforcement sources show increasing confiscation of acetylfentanyl, butyrylfentanyl, and furanylfentanyl, in addition to non-fentanyl compounds such as U-47700. Since 2013, deaths from NSOs in the United States were 52 for acetylfentanyl, 40 for butyrylfentanyl, 128 for furanylfentanyl, and 46 for U-47700. All of these substances induce a classic opioid toxidrome, which can be reversed with the competitive antagonist naloxone. However, due to the putative high potency of NSOs and their growing prevalence, it is recommended to forgo the 0.4 mg initial dose of naloxone and start with 2 mg. Because NSOs offer enormous profit potential, and there is strong demand for their use, these drugs are being trafficked by organized crime. NSOs present major challenges for medical professionals, law enforcement agencies, and policymakers. Resources must be distributed equitably to enhance harm reduction though public education, medication-assisted therapies, and improved access to naloxone.
Elmore, Joshua S; Dillon-Carter, Ora; Partilla, John S; Ellefsen, Kayla N; Concheiro, Marta; Suzuki, Masaki; Rice, Kenner C; Huestis, Marilyn A; Baumann, Michael H
Pharmacokinetic Profiles and Pharmacodynamic Effects for Methylone and Its Metabolites in Rats. Journal Article
In: Neuropsychopharmacology, vol. 42, no. 3, pp. 649–660, 2017, ISSN: 1740-634X (Electronic); 0893-133X (Linking).
@article{Elmore:2017aa,
title = {Pharmacokinetic Profiles and Pharmacodynamic Effects for Methylone and Its Metabolites in Rats.},
author = {Joshua S Elmore and Ora Dillon-Carter and John S Partilla and Kayla N Ellefsen and Marta Concheiro and Masaki Suzuki and Kenner C Rice and Marilyn A Huestis and Michael H Baumann},
url = {https://www.ncbi.nlm.nih.gov/pubmed/27658484},
doi = {10.1038/npp.2016.213},
issn = {1740-634X (Electronic); 0893-133X (Linking)},
year = {2017},
date = {2017-02-01},
journal = {Neuropsychopharmacology},
volume = {42},
number = {3},
pages = {649--660},
address = {Designer Drug Research Unit, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD, USA.},
abstract = {3,4-Methylenedioxy-N-methylcathinone (methylone) is a new psychoactive substance and the beta-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 (Tmax=15-45 min) and were short lived (t1/2=60-90 min), while HHMC and HMMC peaked later (Tmax=60-120 min) and persisted (t1/2=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.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
3,4-Methylenedioxy-N-methylcathinone (methylone) is a new psychoactive substance and the beta-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 (Tmax=15-45 min) and were short lived (t1/2=60-90 min), while HHMC and HMMC peaked later (Tmax=60-120 min) and persisted (t1/2=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.
2016
Schindler, Charles W; Thorndike, Eric B; Suzuki, Masaki; Rice, Kenner C; Baumann, Michael H
Pharmacological mechanisms underlying the cardiovascular effects of the "bath salt" constituent 3,4-methylenedioxypyrovalerone (MDPV). Journal Article
In: Br J Pharmacol, vol. 173, no. 24, pp. 3492–3501, 2016, ISSN: 1476-5381 (Electronic); 0007-1188 (Linking).
@article{Schindler:2016ab,
title = {Pharmacological mechanisms underlying the cardiovascular effects of the "bath salt" constituent 3,4-methylenedioxypyrovalerone (MDPV).},
author = {Charles W Schindler and Eric B Thorndike and Masaki Suzuki and Kenner C Rice and Michael H Baumann},
url = {https://www.ncbi.nlm.nih.gov/pubmed/27714779},
doi = {10.1111/bph.13640},
issn = {1476-5381 (Electronic); 0007-1188 (Linking)},
year = {2016},
date = {2016-12-01},
journal = {Br J Pharmacol},
volume = {173},
number = {24},
pages = {3492--3501},
address = {Preclinical Pharmacology Section, National Institutes of Health, National Institute on Drug Abuse, Intramural Research Program, Baltimore, MD.},
abstract = {BACKGROUND AND PURPOSE: 3,4-Methylenedioxypyrovalerone (MDPV) is a synthetic cathinone with stimulatory cardiovascular effects that can lead to serious medical complications. Here, we examined the pharmacological mechanisms underlying these cardiovascular actions of MDPV in conscious rats. EXPERIMENTAL APPROACH: Male Sprague-Dawley rats had telemetry transmitters surgically implanted for the measurement of BP and heart rate (HR). On test days, rats were placed individually in standard isolation cubicles. Following drug treatment, cardiovascular parameters were monitored for 3 h sessions. KEY RESULTS: Racemic MDPV (0.3-3.0 mg.kg(-1) ) increased BP and HR in a dose-dependent manner. The S(+) enantiomer (0.3-3.0 mg.kg(-1) ) of MDPV produced similar effects, while the R(-) enantiomer (0.3-3.0 mg.kg(-1) ) had no effects. Neither of the hydroxylated phase I metabolites of MDPV altered cardiovascular parameters significantly from baseline. Pretreatment with the ganglionic blocker chlorisondamine (1 and 3 mg.kg(-1) ) antagonized the increases in BP and HR produced by 1 mg.kg(-1) MDPV. The alpha1 -adrenoceptor antagonist prazosin (0.3 mg.kg(-1) ) attenuated the increase in BP following MDPV, while the beta-adrenoceptor antagonists propranolol (1 mg.kg(-1) ) and atenolol (1 and 3 mg.kg(-1) ) attenuated the HR increases. CONCLUSIONS AND IMPLICATIONS: The S(+) enantiomer appeared to mediate the cardiovascular effects of MDPV, while the metabolites of MDPV did not alter BP or HR significantly; MDPV increased BP and HR through activation of central sympathetic outflow. Mixed-action alpha/beta-adrenoceptor antagonists may be useful as treatments in counteracting the adverse cardiovascular effects of MDPV.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
BACKGROUND AND PURPOSE: 3,4-Methylenedioxypyrovalerone (MDPV) is a synthetic cathinone with stimulatory cardiovascular effects that can lead to serious medical complications. Here, we examined the pharmacological mechanisms underlying these cardiovascular actions of MDPV in conscious rats. EXPERIMENTAL APPROACH: Male Sprague-Dawley rats had telemetry transmitters surgically implanted for the measurement of BP and heart rate (HR). On test days, rats were placed individually in standard isolation cubicles. Following drug treatment, cardiovascular parameters were monitored for 3 h sessions. KEY RESULTS: Racemic MDPV (0.3-3.0 mg.kg(-1) ) increased BP and HR in a dose-dependent manner. The S(+) enantiomer (0.3-3.0 mg.kg(-1) ) of MDPV produced similar effects, while the R(-) enantiomer (0.3-3.0 mg.kg(-1) ) had no effects. Neither of the hydroxylated phase I metabolites of MDPV altered cardiovascular parameters significantly from baseline. Pretreatment with the ganglionic blocker chlorisondamine (1 and 3 mg.kg(-1) ) antagonized the increases in BP and HR produced by 1 mg.kg(-1) MDPV. The alpha1 -adrenoceptor antagonist prazosin (0.3 mg.kg(-1) ) attenuated the increase in BP following MDPV, while the beta-adrenoceptor antagonists propranolol (1 mg.kg(-1) ) and atenolol (1 and 3 mg.kg(-1) ) attenuated the HR increases. CONCLUSIONS AND IMPLICATIONS: The S(+) enantiomer appeared to mediate the cardiovascular effects of MDPV, while the metabolites of MDPV did not alter BP or HR significantly; MDPV increased BP and HR through activation of central sympathetic outflow. Mixed-action alpha/beta-adrenoceptor antagonists may be useful as treatments in counteracting the adverse cardiovascular effects of MDPV.
Mayer, F P; Wimmer, L; Dillon-Carter, O; Partilla, J S; Burchardt, N V; Mihovilovic, M D; Baumann, M H; Sitte, H H
Phase I metabolites of mephedrone display biological activity as substrates at monoamine transporters. Journal Article
In: Br J Pharmacol, vol. 173, no. 17, pp. 2657–2668, 2016, ISSN: 1476-5381 (Electronic); 0007-1188 (Linking).
@article{Mayer:2016aa,
title = {Phase I metabolites of mephedrone display biological activity as substrates at monoamine transporters.},
author = {F P Mayer and L Wimmer and O Dillon-Carter and J S Partilla and N V Burchardt and M D Mihovilovic and M H Baumann and H H Sitte},
url = {https://www.ncbi.nlm.nih.gov/pubmed/27391165},
doi = {10.1111/bph.13547},
issn = {1476-5381 (Electronic); 0007-1188 (Linking)},
year = {2016},
date = {2016-09-01},
journal = {Br J Pharmacol},
volume = {173},
number = {17},
pages = {2657--2668},
address = {Medical University of Vienna, Center for Physiology and Pharmacology, Institute of Pharmacology, Vienna, Austria.},
abstract = {BACKGROUND AND PURPOSE: 4-Methyl-N-methylcathinone (mephedrone) is a synthetic stimulant that acts as a substrate-type releaser at transporters for dopamine (DAT), noradrenaline (NET) and 5-HT (SERT). Upon systemic administration, mephedrone is metabolized to several phase I compounds: the N-demethylated metabolite, 4-methylcathinone (nor-mephedrone); the ring-hydroxylated metabolite, 4-hydroxytolylmephedrone (4-OH-mephedrone); and the reduced keto-metabolite, dihydromephedrone. EXPERIMENTAL APPROACH: We used in vitro assays to compare the effects of mephedrone and synthetically prepared metabolites on transporter-mediated uptake and release in HEK293 cells expressing human monoamine transporters and in rat brain synaptosomes. In vivo microdialysis was employed to examine the effects of i.v. metabolite injection (1 and 3 mg.kg(-1) ) on extracellular dopamine and 5-HT levels in rat nucleus accumbens. KEY RESULTS: In cells expressing transporters, mephedrone and its metabolites inhibited uptake, although dihydromephedrone was weak overall. In cells and synaptosomes, nor-mephedrone and 4-OH-mephedrone served as transportable substrates, inducing release via monoamine transporters. When administered to rats, mephedrone and nor-mephedrone produced elevations in extracellular dopamine and 5-HT, whereas 4-OH-mephedrone did not. Mephedrone and nor-mephedrone, but not 4-OH-mephedrone, induced locomotor activity. CONCLUSIONS AND IMPLICATIONS: Our results demonstrate that phase I metabolites of mephedrone are transporter substrates (i.e. releasers) at DAT, NET and SERT, but dihydromephedrone is weak in this regard. When administered in vivo, nor-mephedrone increases extracellular dopamine and 5-HT in the brain whereas 4-OH-mephedrone does not, suggesting the latter metabolite does not penetrate the blood-brain barrier. Future studies should examine the pharmacokinetics of nor-mephedrone to determine its possible contribution to the in vivo effects produced by mephedrone.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
BACKGROUND AND PURPOSE: 4-Methyl-N-methylcathinone (mephedrone) is a synthetic stimulant that acts as a substrate-type releaser at transporters for dopamine (DAT), noradrenaline (NET) and 5-HT (SERT). Upon systemic administration, mephedrone is metabolized to several phase I compounds: the N-demethylated metabolite, 4-methylcathinone (nor-mephedrone); the ring-hydroxylated metabolite, 4-hydroxytolylmephedrone (4-OH-mephedrone); and the reduced keto-metabolite, dihydromephedrone. EXPERIMENTAL APPROACH: We used in vitro assays to compare the effects of mephedrone and synthetically prepared metabolites on transporter-mediated uptake and release in HEK293 cells expressing human monoamine transporters and in rat brain synaptosomes. In vivo microdialysis was employed to examine the effects of i.v. metabolite injection (1 and 3 mg.kg(-1) ) on extracellular dopamine and 5-HT levels in rat nucleus accumbens. KEY RESULTS: In cells expressing transporters, mephedrone and its metabolites inhibited uptake, although dihydromephedrone was weak overall. In cells and synaptosomes, nor-mephedrone and 4-OH-mephedrone served as transportable substrates, inducing release via monoamine transporters. When administered to rats, mephedrone and nor-mephedrone produced elevations in extracellular dopamine and 5-HT, whereas 4-OH-mephedrone did not. Mephedrone and nor-mephedrone, but not 4-OH-mephedrone, induced locomotor activity. CONCLUSIONS AND IMPLICATIONS: Our results demonstrate that phase I metabolites of mephedrone are transporter substrates (i.e. releasers) at DAT, NET and SERT, but dihydromephedrone is weak in this regard. When administered in vivo, nor-mephedrone increases extracellular dopamine and 5-HT in the brain whereas 4-OH-mephedrone does not, suggesting the latter metabolite does not penetrate the blood-brain barrier. Future studies should examine the pharmacokinetics of nor-mephedrone to determine its possible contribution to the in vivo effects produced by mephedrone.
Schindler, Charles W; Thorndike, Eric B; Goldberg, Steven R; Lehner, Kurt R; Cozzi, Nicholas V; Brandt, Simon D; Baumann, Michael H
In: Psychopharmacology (Berl), vol. 233, no. 10, pp. 1981–1990, 2016, ISSN: 1432-2072 (Electronic); 0033-3158 (Linking).
@article{Schindler:2016aa,
title = {Reinforcing and neurochemical effects of the "bath salts" constituents 3,4-methylenedioxypyrovalerone (MDPV) and 3,4-methylenedioxy-N-methylcathinone (methylone) in male rats.},
author = {Charles W Schindler and Eric B Thorndike and Steven R Goldberg and Kurt R Lehner and Nicholas V Cozzi and Simon D Brandt and Michael H Baumann},
url = {https://www.ncbi.nlm.nih.gov/pubmed/26319160},
doi = {10.1007/s00213-015-4057-0},
issn = {1432-2072 (Electronic); 0033-3158 (Linking)},
year = {2016},
date = {2016-05-01},
journal = {Psychopharmacology (Berl)},
volume = {233},
number = {10},
pages = {1981--1990},
address = {Preclinical Pharmacology Section, Intramural Research Program of the National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD, 21224, USA. cschind@helix.nih.gov.},
abstract = {RATIONALE: 3,4-Methylenedioxypyrovalerone (MDPV) and 3,4-methylenedioxy-N-methylcathinone (methylone) are synthetic drugs found in so-called "bath salts" products. Both drugs exert their effects by interacting with monoamine transporter proteins. MDPV is a potent uptake blocker at transporters for dopamine and norepinephrine while methylone is a non-selective releaser at transporters for dopamine, norepinephrine, and serotonin (5-HT). OBJECTIVES: We hypothesized that prominent 5-HT-releasing actions of methylone would render this drug less reinforcing than MDPV. METHODS: To test this hypothesis, we compared behavioral effects of MDPV and methylone using intravenous (i.v.) self-administration on a fixed-ratio 1 schedule in male rats. Additionally, neurochemical effects of the drugs were examined using in vivo microdialysis in nucleus accumbens, in a separate cohort of rats. RESULTS: MDPV self-administration (0.03 mg/kg/inj) was acquired rapidly and reached 40 infusions per session, similar to the effects of cocaine (0.5 mg/kg/inj), by the end of training. In contrast, methylone self-administration (0.3 and 0.5 mg/kg/inj) was acquired slowly, and response rates only reached 20 infusions per session by the end of training. In dose substitution studies, MDPV and cocaine displayed typical inverted U-shaped dose-effect functions, but methylone did not. In vivo microdialysis revealed that i.v. MDPV (0.1 and 0.3 mg/kg) increased extracellular dopamine while i.v. methylone (1 and 3 mg/kg) increased extracellular dopamine and 5-HT. CONCLUSIONS: Our findings support the hypothesis that elevations in extracellular 5-HT in the brain can dampen positive reinforcing effects of cathinone-type drugs. Nevertheless, MDPV and methylone are both self-administered by rats, suggesting these drugs possess significant abuse liability in humans.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
RATIONALE: 3,4-Methylenedioxypyrovalerone (MDPV) and 3,4-methylenedioxy-N-methylcathinone (methylone) are synthetic drugs found in so-called "bath salts" products. Both drugs exert their effects by interacting with monoamine transporter proteins. MDPV is a potent uptake blocker at transporters for dopamine and norepinephrine while methylone is a non-selective releaser at transporters for dopamine, norepinephrine, and serotonin (5-HT). OBJECTIVES: We hypothesized that prominent 5-HT-releasing actions of methylone would render this drug less reinforcing than MDPV. METHODS: To test this hypothesis, we compared behavioral effects of MDPV and methylone using intravenous (i.v.) self-administration on a fixed-ratio 1 schedule in male rats. Additionally, neurochemical effects of the drugs were examined using in vivo microdialysis in nucleus accumbens, in a separate cohort of rats. RESULTS: MDPV self-administration (0.03 mg/kg/inj) was acquired rapidly and reached 40 infusions per session, similar to the effects of cocaine (0.5 mg/kg/inj), by the end of training. In contrast, methylone self-administration (0.3 and 0.5 mg/kg/inj) was acquired slowly, and response rates only reached 20 infusions per session by the end of training. In dose substitution studies, MDPV and cocaine displayed typical inverted U-shaped dose-effect functions, but methylone did not. In vivo microdialysis revealed that i.v. MDPV (0.1 and 0.3 mg/kg) increased extracellular dopamine while i.v. methylone (1 and 3 mg/kg) increased extracellular dopamine and 5-HT. CONCLUSIONS: Our findings support the hypothesis that elevations in extracellular 5-HT in the brain can dampen positive reinforcing effects of cathinone-type drugs. Nevertheless, MDPV and methylone are both self-administered by rats, suggesting these drugs possess significant abuse liability in humans.
Marusich, Julie A; Antonazzo, Kateland R; Blough, Bruce E; Brandt, Simon D; Kavanagh, Pierce V; Partilla, John S; Baumann, Michael H
In: Neuropharmacology, vol. 101, pp. 68–75, 2016, ISSN: 1873-7064 (Electronic); 0028-3908 (Linking).
@article{Marusich:2016aa,
title = {The new psychoactive substances 5-(2-aminopropyl)indole (5-IT) and 6-(2-aminopropyl)indole (6-IT) interact with monoamine transporters in brain tissue.},
author = {Julie A Marusich and Kateland R Antonazzo and Bruce E Blough and Simon D Brandt and Pierce V Kavanagh and John S Partilla and Michael H Baumann},
url = {https://www.ncbi.nlm.nih.gov/pubmed/26362361},
doi = {10.1016/j.neuropharm.2015.09.004},
issn = {1873-7064 (Electronic); 0028-3908 (Linking)},
year = {2016},
date = {2016-02-01},
journal = {Neuropharmacology},
volume = {101},
pages = {68--75},
address = {Center for Drug Discovery, RTI International, 3040 Cornwallis Rd, Research Triangle Park, NC 27709, USA. Electronic address: jmarusich@rti.org.},
abstract = {In recent years, use of psychoactive synthetic stimulants has grown rapidly. 5-(2-Aminopropyl)indole (5-IT) is a synthetic drug associated with a number of fatalities, that appears to be one of the newest 3,4-methylenedioxymethamphetamine (MDMA) replacements. Here, the monoamine-releasing properties of 5-IT, its structural isomer 6-(2-aminopropyl)indole (6-IT), and MDMA were compared using in vitro release assays at transporters for dopamine (DAT), norepinephrine (NET), and serotonin (SERT) in rat brain synaptosomes. In vivo pharmacology was assessed by locomotor activity and a functional observational battery (FOB) in mice. 5-IT and 6-IT were potent substrates at DAT, NET, and SERT. In contrast with the non-selective releasing properties of MDMA, 5-IT displayed greater potency for release at DAT over SERT, while 6-IT displayed greater potency for release at SERT over DAT. 5-IT produced locomotor stimulation and typical stimulant effects in the FOB similar to those produced by MDMA. Conversely, 6-IT increased behaviors associated with 5-HT toxicity. 5-IT likely has high abuse potential, which may be somewhat diminished by its slow onset of in vivo effects, whereas 6-IT may have low abuse liability, but enhanced risk for adverse effects. Results indicate that subtle differences in the chemical structure of transporter ligands can have profound effects on biological activity. The potent monoamine-releasing actions of 5-IT, coupled with its known inhibition of MAO A, could underlie its dangerous effects when administered alone, and in combination with other monoaminergic drugs or medications. Consequently, 5-IT and related compounds may pose substantial risk for abuse and serious adverse effects in human users.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
In recent years, use of psychoactive synthetic stimulants has grown rapidly. 5-(2-Aminopropyl)indole (5-IT) is a synthetic drug associated with a number of fatalities, that appears to be one of the newest 3,4-methylenedioxymethamphetamine (MDMA) replacements. Here, the monoamine-releasing properties of 5-IT, its structural isomer 6-(2-aminopropyl)indole (6-IT), and MDMA were compared using in vitro release assays at transporters for dopamine (DAT), norepinephrine (NET), and serotonin (SERT) in rat brain synaptosomes. In vivo pharmacology was assessed by locomotor activity and a functional observational battery (FOB) in mice. 5-IT and 6-IT were potent substrates at DAT, NET, and SERT. In contrast with the non-selective releasing properties of MDMA, 5-IT displayed greater potency for release at DAT over SERT, while 6-IT displayed greater potency for release at SERT over DAT. 5-IT produced locomotor stimulation and typical stimulant effects in the FOB similar to those produced by MDMA. Conversely, 6-IT increased behaviors associated with 5-HT toxicity. 5-IT likely has high abuse potential, which may be somewhat diminished by its slow onset of in vivo effects, whereas 6-IT may have low abuse liability, but enhanced risk for adverse effects. Results indicate that subtle differences in the chemical structure of transporter ligands can have profound effects on biological activity. The potent monoamine-releasing actions of 5-IT, coupled with its known inhibition of MAO A, could underlie its dangerous effects when administered alone, and in combination with other monoaminergic drugs or medications. Consequently, 5-IT and related compounds may pose substantial risk for abuse and serious adverse effects in human users.
