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Kenner C Rice - One of the best experts on this subject based on the ideXlab platform.
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Discriminative stimulus effects of 3,4-Methylenedioxypyrovalerone (MDPV) and structurally related synthetic cathinones.
Behavioural pharmacology, 2021Co-Authors: Robert W. Seaman, Kenner C Rice, Michelle R. Doyle, Agnieszka Sulima, Gregory T. CollinsAbstract:The 3,4-Methylenedioxypyrovalerone (MDPV), and other structurally related synthetic cathinones, are popular alternatives to prototypical illicit psychostimulants, such as cocaine and methamphetamine. These drugs are often referred to as 'bath salts' and function either as cocaine-like inhibitors of monoamine uptake, or amphetamine-like substrates for dopamine, norepinephrine and serotonin transporters. These studies used male Sprague-Dawley rats trained to discriminate MDPV from saline to evaluate the substitution profiles of structurally related synthetic cathinones, cocaine, and other direct-acting dopamine and noradrenergic receptor agonists in order to characterize the relative contributions of dopamine, norepinephrine and serotonin to the discriminative stimulus effects of MDPV. As expected, each of the cathinones and cocaine dose-dependently increased MDPV-appropriate responding, with a rank-order potency that was positively correlated with their potency to inhibit dopamine and norepinephrine, but not serotonin, a relationship that is consistent with the rank order to maintain self-administration. The dopamine D2/3 receptor-preferring agonist quinpirole produced a modest increase in MDPV-appropriate responding, whereas the dopamine D1/5 receptor agonist, SKF 82958, nonselective dopamine receptor agonist, apomorphine, as well as the α-1, and α-2 adrenergic receptor agonists, phenylephrine and clonidine, respectively, failed to increase MDPV-appropriate responding at doses smaller than those that suppressed responding altogether. Although these studies do not support a role for serotonergic or adrenergic systems in mediating/modulating the discriminative stimulus effects of MDPV, convergent evidence is provided to suggest that the discriminative stimulus effects of MDPV are primarily mediated by its capacity to inhibit dopamine uptake, and the subsequent activation of dopamine D2 or D3 receptors.
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The synthetic cathinone 3,4-Methylenedioxypyrovalerone increases impulsive action in rats.
Behavioural pharmacology, 2020Co-Authors: William S. Hyatt, Kenner C Rice, Caitlin E. Hirsh, Lauren Russell, Neha M. Chitre, Kevin S. Murnane, William E. FantegrossiAbstract:A previous study from our laboratory has shown that the selective catecholamine reuptake inhibitor 3,4-Methylenedioxypyrovalerone (MDPV) persistently alters impulsive choice as measured by delay discounting. To further understand the proimpulsive effects of MDPV, we examined its capacity to modulate a different impulsive measure - impulsive action - using a differential reinforcement of low rates of responding task with an inter-response time of 20 s. Three groups of male, Sprague-Dawley rats (n = 6) were first tested in daily sessions to understand the acute effects of cocaine (1.0-30.0 mg/kg), MDPV (0.1-3.0 mg/kg), or saline (1.0 ml/kg) on impulsive action. Both cocaine and MDPV increased impulsive action, most notably by decreasing timing error responses and response efficiency, but MDPV was more effective than cocaine. Additionally, MDPV suppressed operant responding in two of six animals at the highest dose tested. Next, the same animals received 10 postsession injections, once every other day, of either 30.0 mg/kg cocaine, 3.0 mg/kg MDPV, or 1.0 ml/kg saline based on their treatment group. An acute dose-effect redetermination was completed following the repeated administration studies, and once again MDPV and cocaine demonstrated proimpulsive effects. Interestingly, timing error responses were decreased in both MDPV and cocaine groups after an acute saline injection, potentially indicating persistent impulsive changes following the repeated administration phase of the experiment. These studies indicate that MDPV increases impulsive action acutely and that this increase may be potentiated following a series of repeated administrations.
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Repeated administration of synthetic cathinone 3,4-Methylenedioxypyrovalerone persistently increases impulsive choice in rats.
Behavioural pharmacology, 2019Co-Authors: William S. Hyatt, Kenner C Rice, Lauren Russell, Neha M. Chitre, Kevin S. Murnane, Michael D. Berquist, William E. FantegrossiAbstract:3,4-Methylenedioxypyrovalerone (MDPV) is a selective catecholamine reuptake inhibitor abused for its psychostimulant properties. This study examined if MDPV administration alters impulsive choice measured by delay discounting in rats. Three groups of rats were tested in daily delay discounting sessions to determine the effects of acute cocaine (1.0-30.0 mg/kg), MDPV (0.1-3.0 mg/kg), or saline on mean adjusted delay (MAD). Dose-dependent decreases in MAD were elicited only by acute MDPV, which also suppressed operant responding at the highest dose. Next, rats received post-session injections (30.0 mg/kg cocaine, 3.0 mg/kg MDPV, or saline) every other day for a total of 10 injections. MAD increased during saline treatment, did not change during cocaine treatment, and was reduced during MDPV treatment. In dose-effect re-determinations, no acute drug effects on MAD were observed, but compared to the initial dose-effect determination, MDPV suppressed operant responding in more animals, with zero animals completing trials at the highest dose. All saline and MDPV-treated subjects were sacrificed, and striatal and cortical dopamine levels were quantified by HPLC. These studies indicate that administration of MDPV may increase impulsive choice acutely and persistently. These proimpulsive effects are possibly mediated by increases in striatal dopamine turnover.
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Effects of orally self-administered bath salt constituent 3,4-Methylenedioxypyrovalerone (MDPV) in mice.
Drug and alcohol dependence, 2017Co-Authors: Brenda M. Gannon, Kenner C Rice, Lauren Russell, Meet S. Modi, William E. FantegrossiAbstract:Synthetic cathinones in bath salts products are psychostimulant drugs of abuse, and 3,4-Methylenedioxypyrovalerone (MDPV) is a common constituent of these products. Oral MDPV has been show to stimulate locomotor activity but reinforcing, locomotor and appetitive stimulus effects of oral MDPV are unknown. Choice procedures evaluated preference for 0.03, 0.10, 0.30, and 1.00mg/mL MDPV solutions versus 0.10mg/mL quinine solution or water. To verify that oral MDPV produced pharmacological effects, locomotor activity was monitored during and after consumption of water, quinine, or MDPV solutions. Conditioned place preference (CPP) tested the apparent appetitive effects of a preferred concentration of oral MDPV with locomotor stimulant effects (0.30mg/mL), using water as a control, and compared with results from intraperitoneally-administered MDPV. Consumption of MDPV solutions (0.03-1.00mg/mL) was low when the alternative fluid was water, but a history of MDPV consumption increased MDPV choice. When paired with a quinine control solution, MDPV solutions (0.03-0.30mg/mL) were almost exclusively preferred, and treatment with the catecholamine synthesis inhibitor αMPT decreased MDPV choice. Consumption of MDPV concentrations (0.1-1.0mg/mL) stimulated locomotor activity. Chronic (10day) access to 0.30mg/mL MDPV resulted in escalated consumption, but locomotor effects did not systematically change across the access period. Finally, consumption of 0.30mg/mL MDPV elicited CPP with a magnitude similar to the preference observed following intraperitoneal administration of MDPV. Consistent with human abuse patterns, oral MDPV has reinforcing effects in the mouse which are most likely related to its psychostimulant-like pharmacological profile.
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Reinforcing effects of abused ‘bath salts’ constituents 3,4-Methylenedioxypyrovalerone and α-pyrrolidinopentiophenone and their enantiomers
Behavioural pharmacology, 2017Co-Authors: Brenda M. Gannon, Kenner C Rice, Gregory T. CollinsAbstract:Synthetic cathinones found in abused ‘bath salts’ preparations are chiral molecules. Racemic 3,4-Methylenedioxypyrovalerone (MDPV) and α-pyrrolidinopentiophenone (α-PVP) are two common constituents of these preparations that have been reported to be highly effective reinforcers; however, the relativ
William E. Fantegrossi - One of the best experts on this subject based on the ideXlab platform.
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The synthetic cathinone 3,4-Methylenedioxypyrovalerone increases impulsive action in rats.
Behavioural pharmacology, 2020Co-Authors: William S. Hyatt, Kenner C Rice, Caitlin E. Hirsh, Lauren Russell, Neha M. Chitre, Kevin S. Murnane, William E. FantegrossiAbstract:A previous study from our laboratory has shown that the selective catecholamine reuptake inhibitor 3,4-Methylenedioxypyrovalerone (MDPV) persistently alters impulsive choice as measured by delay discounting. To further understand the proimpulsive effects of MDPV, we examined its capacity to modulate a different impulsive measure - impulsive action - using a differential reinforcement of low rates of responding task with an inter-response time of 20 s. Three groups of male, Sprague-Dawley rats (n = 6) were first tested in daily sessions to understand the acute effects of cocaine (1.0-30.0 mg/kg), MDPV (0.1-3.0 mg/kg), or saline (1.0 ml/kg) on impulsive action. Both cocaine and MDPV increased impulsive action, most notably by decreasing timing error responses and response efficiency, but MDPV was more effective than cocaine. Additionally, MDPV suppressed operant responding in two of six animals at the highest dose tested. Next, the same animals received 10 postsession injections, once every other day, of either 30.0 mg/kg cocaine, 3.0 mg/kg MDPV, or 1.0 ml/kg saline based on their treatment group. An acute dose-effect redetermination was completed following the repeated administration studies, and once again MDPV and cocaine demonstrated proimpulsive effects. Interestingly, timing error responses were decreased in both MDPV and cocaine groups after an acute saline injection, potentially indicating persistent impulsive changes following the repeated administration phase of the experiment. These studies indicate that MDPV increases impulsive action acutely and that this increase may be potentiated following a series of repeated administrations.
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Repeated administration of synthetic cathinone 3,4-Methylenedioxypyrovalerone persistently increases impulsive choice in rats.
Behavioural pharmacology, 2019Co-Authors: William S. Hyatt, Kenner C Rice, Lauren Russell, Neha M. Chitre, Kevin S. Murnane, Michael D. Berquist, William E. FantegrossiAbstract:3,4-Methylenedioxypyrovalerone (MDPV) is a selective catecholamine reuptake inhibitor abused for its psychostimulant properties. This study examined if MDPV administration alters impulsive choice measured by delay discounting in rats. Three groups of rats were tested in daily delay discounting sessions to determine the effects of acute cocaine (1.0-30.0 mg/kg), MDPV (0.1-3.0 mg/kg), or saline on mean adjusted delay (MAD). Dose-dependent decreases in MAD were elicited only by acute MDPV, which also suppressed operant responding at the highest dose. Next, rats received post-session injections (30.0 mg/kg cocaine, 3.0 mg/kg MDPV, or saline) every other day for a total of 10 injections. MAD increased during saline treatment, did not change during cocaine treatment, and was reduced during MDPV treatment. In dose-effect re-determinations, no acute drug effects on MAD were observed, but compared to the initial dose-effect determination, MDPV suppressed operant responding in more animals, with zero animals completing trials at the highest dose. All saline and MDPV-treated subjects were sacrificed, and striatal and cortical dopamine levels were quantified by HPLC. These studies indicate that administration of MDPV may increase impulsive choice acutely and persistently. These proimpulsive effects are possibly mediated by increases in striatal dopamine turnover.
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Effects of orally self-administered bath salt constituent 3,4-Methylenedioxypyrovalerone (MDPV) in mice.
Drug and alcohol dependence, 2017Co-Authors: Brenda M. Gannon, Kenner C Rice, Lauren Russell, Meet S. Modi, William E. FantegrossiAbstract:Synthetic cathinones in bath salts products are psychostimulant drugs of abuse, and 3,4-Methylenedioxypyrovalerone (MDPV) is a common constituent of these products. Oral MDPV has been show to stimulate locomotor activity but reinforcing, locomotor and appetitive stimulus effects of oral MDPV are unknown. Choice procedures evaluated preference for 0.03, 0.10, 0.30, and 1.00mg/mL MDPV solutions versus 0.10mg/mL quinine solution or water. To verify that oral MDPV produced pharmacological effects, locomotor activity was monitored during and after consumption of water, quinine, or MDPV solutions. Conditioned place preference (CPP) tested the apparent appetitive effects of a preferred concentration of oral MDPV with locomotor stimulant effects (0.30mg/mL), using water as a control, and compared with results from intraperitoneally-administered MDPV. Consumption of MDPV solutions (0.03-1.00mg/mL) was low when the alternative fluid was water, but a history of MDPV consumption increased MDPV choice. When paired with a quinine control solution, MDPV solutions (0.03-0.30mg/mL) were almost exclusively preferred, and treatment with the catecholamine synthesis inhibitor αMPT decreased MDPV choice. Consumption of MDPV concentrations (0.1-1.0mg/mL) stimulated locomotor activity. Chronic (10day) access to 0.30mg/mL MDPV resulted in escalated consumption, but locomotor effects did not systematically change across the access period. Finally, consumption of 0.30mg/mL MDPV elicited CPP with a magnitude similar to the preference observed following intraperitoneal administration of MDPV. Consistent with human abuse patterns, oral MDPV has reinforcing effects in the mouse which are most likely related to its psychostimulant-like pharmacological profile.
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3,4-Methylenedioxypyrovalerone (MDPV) Induces Cytotoxic Effects on Human Dopaminergic SH-SY5Y Cells
Journal of Drug and Alcohol Research, 2016Co-Authors: Hector Rosas-hernandez, Kenner C Rice, Brenda M. Gannon, William E. Fantegrossi, Elvis Cuevas, Susan M. Lantz, Syed Z. Imam, Merle G. Paule, Syed F. AliAbstract:Background. Synthetic cathinones are a rapidly growing group of psychostimulant drugs usually referred to as "bath salts" and have been used as an alternative to classic amphetamine-like drugs, with 3,4-Methylenedioxypyrovalerone (MDPV) being one of the most prevalent constituents. Consistent with the effects of other psychostimulants, MDPV may induce neurotoxicity by altering monoamine systems in the brain or by inducing neuronal apoptosis. Purpose. The aim of this study was to evaluate the effects of MDPV on the human dopaminergic cell line SH-SY5Y. Experimental design. After 24-hour exposure to MDPV (100µ Mt o 2.5 mM), cytotoxicity, cellular proliferation, and apoptosis were evaluated, whereas reactive oxygen species (ROS) production was evaluated at 2 h, 4 h, 6 h, 22 h, and 24 h. Results. MDPV increased ROS production after 1 h, 4 h, and 6 h of exposure in all but the highest concentration; a moderate increase was observed at 22 h and 24 h. Only high concentrations of the drug decreased cellular proliferation and induced apoptosis and necrosis. Conclusion. MDPV induces dopaminergic toxicity by decreasing cellular proliferation and by increasing apoptosis and necrosis. The production of ROS may play a role in the early response to the drug.
Michael H. Baumann - One of the best experts on this subject based on the ideXlab platform.
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Atypical dopamine efflux caused by 3,4-Methylenedioxypyrovalerone (MDPV) via the human dopamine transporter
Journal of chemical neuroanatomy, 2017Co-Authors: Aparna Shekar, Michael H. Baumann, Nicholas V. Cozzi, Simon D. Brandt, Jenny I. Aguilar, Greta Galli, Arnold E. Ruoho, Heinrich J.g. Matthies, Aurelio GalliAbstract:Abstract Synthetic cathinones are similar in chemical structure to amphetamines, and their behavioral effects are associated with enhanced dopaminergic signaling. The past ten years of research on the common constituent of bath salts, MDPV (the synthetic cathinone 3,4-Methylenedioxypyrovalerone), has aided the understanding of how synthetic cathinones act at the dopamine (DA) transporter (DAT). Several groups have described the ability of MDPV to block the DAT with high-affinity. In this study, we demonstrate for the first time a new mode of action of MDPV, namely its ability to promote DAT-mediated DA efflux. Using single cell amperometric assays, we determined that low concentrations of MDPV (1 nM) can cause reverse transport of DA via DAT. Notably, administration of MDPV leads to hyperlocomotion in Drosophila melanogaster. These data describe further how MDPV acts at the DAT, possibly paving the way for novel treatment strategies for individuals who abuse bath salts.
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Pharmacological mechanisms underlying the cardiovascular effects of the "bath salt" constituent 3,4-Methylenedioxypyrovalerone (MDPV).
British journal of pharmacology, 2016Co-Authors: Charles W. Schindler, Masaki Suzuki, Kenner C Rice, Eric B. Thorndike, Michael H. BaumannAbstract: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 blood pressure (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) increased BP and HR in a dose-dependent manner. The S(+) enantiomer (0.3–3.0 mg/kg) of MDPV produced similar effects, while the R(-) enantiomer (0.3–3.0 mg/kg) 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) antagonized the increases in BP and HR produced by 1 mg/kg MDPV. The α-adrenergic antagonist prazosin (0.3 mg/kg) attenuated the increase in BP following MDPV, while the β-adrenergic antagonists propranolol (1 mg/kg) and atenolol (1 and 3 mg/kg) attenuated the HR increases. Conclusions and Implications The S(+) enantiomer appears to mediate MDPV's cardiovascular effects, while the metabolites of MDPV do not alter BP or HR significantly. MDPV produces increases in BP and HR through activation of central sympathetic outflow. Mixed-action α/β-receptor blockers may be useful as treatments in counteracting the adverse cardiovascular effects of MDPV.
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Neuropharmacology of 3,4-Methylenedioxypyrovalerone (MDPV), Its Metabolites, and Related Analogs
Current topics in behavioral neurosciences, 2016Co-Authors: Michael H. Baumann, Kenner C Rice, Kurt R. Lehner, Mohammad O. Bukhari, Sebastien Anizan, Marta Concheiro, Marilyn A. HuestisAbstract:3,4-Methylenedioxypyrovalerone (MDPV) is a psychoactive component of so-called bath salts products that has caused serious medical consequences in humans. In this chapter, we review the neuropharmacology of MDPV and related analogs, and supplement the discussion with new results from our preclinical experiments. MDPV acts as a potent uptake inhibitor at plasma membrane transporters for dopamine (DAT) and norepinephrine (NET) in nervous tissue. The MDPV formulation in bath salts is a racemic mixture, and the S isomer is much more potent than the R isomer at blocking DAT and producing abuse-related effects. Elevations in brain extracellular dopamine produced by MDPV are likely to underlie its locomotor stimulant and addictive properties. MDPV displays rapid pharmacokinetics when injected into rats (0.5–2.0 mg/kg), with peak plasma concentrations achieved by 10–20 min and declining quickly thereafter. MDPV is metabolized to 3,4-dihydroxypyrovalerone (3,4-catechol-PV) and 4-hydroxy-3-methoxypyrovalerone (4-OH-3-MeO-PV) in vivo, but motor activation produced by the drug is positively correlated with plasma concentrations of parent drug and not its metabolites. 3,4-Catechol-PV is a potent uptake blocker at DAT in vitro but has little activity after administration in vivo. 4-OH-3-MeO-PV is the main MDPV metabolite but is weak at DAT and NET. MDPV analogs, such as α-pyrrolidinovalerophenone (α-PVP), display similar ability to inhibit DAT and increase extracellular dopamine concentrations. Taken together, these findings demonstrate that MDPV and its analogs represent a unique class of transporter inhibitors with a high propensity for abuse and addiction.
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Reinforcing and neurochemical effects of the “bath salts” constituents 3,4-Methylenedioxypyrovalerone (MDPV) and 3,4-methylenedioxy-N-methylcathinone (methylone) in male rats
Psychopharmacology, 2015Co-Authors: Charles W. Schindler, Nicholas V. Cozzi, Eric B. Thorndike, Steven R. Goldberg, Kurt R. Lehner, Simon D. Brandt, Michael H. BaumannAbstract: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).
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powerful cocaine like actions of 3 4 Methylenedioxypyrovalerone mdpv a principal constituent of psychoactive bath salts products
Neuropsychopharmacology, 2013Co-Authors: Michael H. Baumann, Eric B. Thorndike, Steven R. Goldberg, Kurt R. Lehner, John S Partilla, Alexander F Hoffman, Marion Holy, Richard B Rothman, Carl R Lupica, Harald H SitteAbstract:Powerful Cocaine-Like Actions of 3,4-Methylenedioxypyrovalerone (MDPV), a Principal Constituent of Psychoactive ‘Bath Salts’ Products
Richard A Glennon - One of the best experts on this subject based on the ideXlab platform.
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neurobiology of 3 4 Methylenedioxypyrovalerone mdpv and α pyrrolidinovalerophenone α pvp
Brain Research Bulletin, 2016Co-Authors: Richard A Glennon, Richard YoungAbstract:Synthetic cathinones are analogs of cathinone or β-ketoamphetamine - the major psychostimulant component of the shrub Catha edulis or khat. Cathinone analogs - though not termed as such - have been known for >100 years, but confusing chemical nomenclature often made the topic difficult to appreciate. In addition, many of the early analogs were prepared as synthetic precursors for the development of various other agents, and relatively few were pharmacologically evaluated. Cathinone is a close structural relative of amphetamine. Today, certain cathinone derivatives, synthetic cathinones, are known to produce central stimulant actions and represent a "new" class of drugs of abuse. Depending upon the nature of their terminal amine, α substituent, and aryl substituents, they seem to produce their effects via release or reuptake of various neurotansmitters including dopamine norepinephreine and/or serotonin. Two of the newest and most prominent members of the class are MDPV and its parent α-PVP ("flakka"). Both have been encountered on their own and in what might be constituents of what has been termed by a variety of names including psychoactive "bath salts". Here, we describe the nomenclature of synthetic cathinones, the mechanism(s) of action of MDPV and α-PVP, and their structure-activity relationships. In order to assist in forensic studies, and to identify novel substances requiring future pharmacological evaluation, the metabolism of these agents is also described. Finally, the preclinical behavioral actions of these two agents in a variety of behavioral assays, including rodent locomotor assays, self-administration studies, intracranial self-stimulation, conditioned place preference, and drug discrimination, is summarized. The results of these studies with MDPV and α-PVP are consistent with their acting as potent cocaine-like central stimulants with abuse liability.
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bath salts mephedrone and Methylenedioxypyrovalerone as emerging illicit drugs that will need targeted therapeutic intervention
Advances in pharmacology (San Diego), 2014Co-Authors: Richard A GlennonAbstract:Abstract The term “synthetic cathinones” is fairly new, but, although the abuse of synthetic cathinones is a recent problem, research on cathinone analogs dates back > 100 years. One structural element cathinone analogs have in common is an α-aminophenone moiety. Introduction of amine and/or aryl substituents affords a large number of agents. Today, > 40 synthetic cathinones have been identified on the clandestine market and many have multiple “street names.” Many cathinone analogs, although not referred to as such until the late 1970s, were initially prepared as intermediates in the synthesis of ephedrine analogs. The cathinones do not represent a pharmacologically or mechanistically homogeneous class of agents. Currently abused synthetic cathinones are derived from earlier agents and seem to produce their actions primarily via the dopamine, norepinephrine, and/or serotonin transporter; that is, they either release and/or inhibit the reuptake of one or more of these neurotransmitters. The actions of these agents can resemble those of central stimulants such as methamphetamine, cocaine, and/or empathogens such as 1-(3,4-methylenedioxyphenyl)-2-aminopropane (Ecstasy) and/or produce other effects. Side effects are primarily of a neurological and/or cardiovascular nature. The use of the “and/or” term is emphasized because synthetic cathinones represent a broad class of agents that produce a variety of actions; the agents cannot be viewed as being pharmacologically equivalent. Until valid structure–activity relationships are formulated for each behavioral/mechanistic action, individual synthetic cathinones remain to be evaluated on a case-by-case basis. Treatment of synthetic cathinone intoxication requires more “basic science” research. At this time, treatment is mostly palliative.
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"Deconstruction" of the abused synthetic cathinone Methylenedioxypyrovalerone (MDPV) and an examination of effects at the human dopamine transporter.
ACS chemical neuroscience, 2013Co-Authors: Renata Kolanos, Louis J De Felice, Ernesto Solis, Farhana Sakloth, Richard A GlennonAbstract:Synthetic cathinones, β-keto analogues of amphetamine (or, more correctly, of phenylalkylamines), represent a new and growing class of abused substances. Several such analogues have been demonstrated to act as dopamine (DA) releasing agents. Methylenedioxypyrovalerone (MDPV) was the first synthetic cathinone shown to act as a cocaine-like DA reuptake inhibitor. MDPV and seven deconstructed analogues were examined to determine which of MDPV’s structural features account(s) for uptake inhibition. In voltage-clamped (−60 mV) Xenopus oocytes transfected with the human DA transporter (hDAT), all analogues elicited inhibitor-like behavior shown as hDAT-mediated outward currents. Using hDAT-expressing mammalian cells we determined the affinities of MDPV and its analogues to inhibit uptake of [3H]DA by hDAT that varied over a broad range (IC50 values ca. 135 to >25 000 nM). The methylenedioxy group of MDPV made a minimal contribution to affinity, the carbonyl group and a tertiary amine are more important, and the...
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bath salts components mephedrone and Methylenedioxypyrovalerone mdpv act synergistically at the human dopamine transporter
British Journal of Pharmacology, 2013Co-Authors: Krasnodara N Cameron, Renata Kolanos, Richard A Glennon, Ernesto Solis, Louis J De FeliceAbstract:Background and Purpose Bath salts is the street name for drug combinations that contain synthetic cathinone analogues, among them possibly mephedrone (MEPH) and certainly Methylenedioxypyrovalerone (MDPV). In animal studies, cathinone and certain cathinone analogues release dopamine (DA), similar to the action of amphetamine (AMPH) and methamphetamine (METH). AMPH and METH act on the human DA transporter (hDAT); thus, we investigated MEPH and MDPV acting at hDAT. Experimental Approach We recorded electrical currents mediated by hDAT expressed in Xenopus laevis oocytes and exposed to: DA, METH, a known hDAT stimulant and DA releaser, MEPH, MDPV, MEPH + MDPV, or cocaine, a known hDAT inhibitor. Key Results DA, METH and MEPH induce an inward current (depolarizing) when the oocyte is held near the resting potential (–60 mV), therefore acting as excitatory hDAT substrates. Structurally analogous MDPV induces an outward (hyperpolarizing) current similar to cocaine, therefore acting as an inhibitory non-substrate blocker. Conclusions and Implications Two components of bath salts, MEPH and MDPV, produce opposite effects at hDAT that are comparable with METH and cocaine, respectively. In our assay, MEPH is nearly as potent as METH; however, MDPV is much more potent than cocaine and its effect is longer lasting. When applied in combination, MEPH exhibits faster kinetics than MDPV, viz., the MEPH depolarizing current occurs seconds before the slower MDPV hyperpolarizing current. Bath salts containing MEPH (or a similar drug) and MDPV might then be expected initially to release DA and subsequently prevent its reuptake via hDAT. Such combined action possibly underlies some of the reported effects of bath salts abuse.
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mephedrone and Methylenedioxypyrovalerone mdpv major constituents of bath salts produce opposite effects at the human dopamine transporter
Psychopharmacology, 2013Co-Authors: Krasnodara N Cameron, Renata Kolanos, Rakesh Verkariya, Louis J De Felice, Richard A GlennonAbstract:Rationale Psychoactive “bath salts” represent a relatively new drug of abuse combination that was placed in Schedule I in October 2011. Two common ingredients of bath salts include the cathinone analogs: mephedrone and Methylenedioxypyrovalerone (MDPV). The mechanism of action of these synthetic cathinone analogs has not been well investigated.
Scott M. Rawls - One of the best experts on this subject based on the ideXlab platform.
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Methylenedioxypyrovalerone mdpv impairs working memory and alters patterns of dopamine signaling in mesocorticolimbic substrates
Neuroscience Research, 2020Co-Authors: David L Bernstein, Sunil U. Nayak, Scott M. Rawls, Chicora F. Oliver, Slava RomAbstract:Knowledge remains limited about how chronic cathinone exposure impacts dopamine systems in brain reward circuits. In the present study, a binge-like MDPV exposure that impaired novel object recognition (NOR) dysregulated dopamine markers in mesocorticolimbic substrates of rats, with especially profound effects on D1 and D2 receptor's and VMAT gene expression. Our data suggested that dopamine receptivity was reduced in the NAc but increased in the PFC and dopamine-producing VTA. The MDPV-induced impairment of NOR was prevented by a D1 receptor antagonist, suggesting that chronic MDPV exposure produces site-specific dysregulation of dopamine markers in the mesocorticolimbic circuit and memory deficits in the NOR test that are influenced by D1 receptors.
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DARK Classics in Chemical Neuroscience: Cathinone-Derived Psychostimulants.
ACS chemical neuroscience, 2018Co-Authors: Steven J. Simmons, Callum Hicks, Scott M. Rawls, Jonna M. Leyrer-jackson, Chicora F. Oliver, John W. Muschamp, M. Foster OliveAbstract:Cathinone is a plant alkaloid found in khat leaves of perennial shrubs grown in East Africa. Similar to cocaine, cathinone elicits psychostimulant effects which are in part attributed to its amphetamine-like structure. Around 2010, home laboratories began altering the parent structure of cathinone to synthesize derivatives with mechanisms of action, potencies, and pharmacokinetics permitting high abuse potential and toxicity. These “synthetic cathinones” include 4-methylmethcathinone (mephedrone), 3,4-Methylenedioxypyrovalerone (MDPV), and the empathogenic agent 3,4-methylenedioxymethcathinone (methylone) which collectively gained international popularity following aggressive online marketing as well as availability in various retail outlets. Case reports made clear the health risks associated with these agents and, in 2012, the Drug Enforcement Agency of the United States placed a series of synthetic cathinones on Schedule I under emergency order. Mechanistically, cathinone and synthetic derivatives work...
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Dopamine D1-Like Receptor Agonist and D2-Like Receptor Antagonist (-)-Stepholidine Reduces Reinstatement of Drug-Seeking Behavior for 3,4-Methylenedioxypyrovalerone (MDPV) in Rats.
ACS Chemical Neuroscience, 2018Co-Authors: Callum Hicks, Sunil U. Nayak, Yohanka Caro, Scott M. Rawls, Allen B Reitz, Garry R Smith, Linnet Ramos, Peng Huang, Lee Yuan Liu-chenAbstract:Psychostimulant reinforcement is mediated by stimulation of both dopamine (DA) D1-like and D2-like receptors, suggesting that pharmacotherapy agents with a dual DA receptor mechanism may be useful for managing psychostimulant abuse. (−)-Stepholidine (L-SPD) is a Chinese herbal extract that functions as a D1-like receptor agonist and D2-like receptor antagonist. L-SPD has been shown to attenuate the reinforcing effects of heroin; however, its effects on the synthetic cathinone 3,4-Methylenedioxypyrovalerone (MDPV) have not been examined. The current study determined the effects of L-SPD on reinstatement of MDPV-seeking behavior in the drug intravenous self-administration (IVSA) and conditioned place preference (CPP) paradigms. To determine whether the effects of L-SPD were specific to psychostimulant reinforcement, we also examined its effects on sucrose-seeking behavior. Using a locomotor activity assay, we tested the locomotor effects of L-SPD, as well as its effects on MDPV-induced hyperactivity. The re...
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dopamine d1 like receptor agonist and d2 like receptor antagonist stepholidine reduces reinstatement of drug seeking behavior for 3 4 Methylenedioxypyrovalerone mdpv in rats
ACS Chemical Neuroscience, 2018Co-Authors: Callum Hicks, Sunil U. Nayak, Yohanka Caro, Scott M. Rawls, Allen B Reitz, Garry R Smith, Linnet Ramos, Peng Huang, Leeyuan LiuchenAbstract:Psychostimulant reinforcement is mediated by stimulation of both dopamine (DA) D1-like and D2-like receptors, suggesting that pharmacotherapy agents with a dual DA receptor mechanism may be useful for managing psychostimulant abuse. (−)-Stepholidine (L-SPD) is a Chinese herbal extract that functions as a D1-like receptor agonist and D2-like receptor antagonist. L-SPD has been shown to attenuate the reinforcing effects of heroin; however, its effects on the synthetic cathinone 3,4-Methylenedioxypyrovalerone (MDPV) have not been examined. The current study determined the effects of L-SPD on reinstatement of MDPV-seeking behavior in the drug intravenous self-administration (IVSA) and conditioned place preference (CPP) paradigms. To determine whether the effects of L-SPD were specific to psychostimulant reinforcement, we also examined its effects on sucrose-seeking behavior. Using a locomotor activity assay, we tested the locomotor effects of L-SPD, as well as its effects on MDPV-induced hyperactivity. The re...
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Glutamate carboxypeptidase II (GCPII) inhibitor 2-PMPA reduces rewarding effects of the synthetic cathinone MDPV in rats: a role for N-acetylaspartylglutamate (NAAG).
Psychopharmacology, 2017Co-Authors: Callum Hicks, Sunil U. Nayak, Allen B Reitz, Garry R Smith, Ryan A. Gregg, Lee Anne Cannella, Giana J. Schena, Christopher S. Tallarida, Scott M. RawlsAbstract:Rationale Metabotropic glutamate 2 and 3 (mGluR2/3) receptors are implicated in drug addiction as they limit excessive glutamate release during relapse. N-acetylaspartylglutamate (NAAG) is an endogenous mGluR2/3 agonist that is inactivated by the glutamate carboxypeptidase II (GCPII) enzyme. GCPII inhibitors, and NAAG itself, attenuate cocaine-seeking behaviors. However, their effects on the synthetic cathinone 3,4-Methylenedioxypyrovalerone (MDPV) have not been examined.