Comparison of the behavioral and cardiovascular effects of mephedrone with other drugs of abuse in rats

Varner, Kurt J.; Daigle, Kyle; Weed, Peter F.; Lewis, Peter B.; Mahne, Sarah; Sankaranarayanan, Ananthakrishnan; Winsauer, Peter J.

doi:10.1007/s00213-012-2855-1

Cited by 61 publications

(55 citation statements)

References 36 publications

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“…Mephedrone is known to have similar effects to other psychostimulant drugs (Brunt et al 2012;Varner et al 2012). There are two reported fatalities in the European Union in which mephedrone appears to be the sole cause of death and there are at least another 37 deaths in which mephedrone have been detected in post-mortem samples (Maskell et al 2011).…”

Section: Introductionmentioning

confidence: 99%

Mephedrone pharmacokinetics after intravenous and oral administration in rats: relation to pharmacodynamics

et al. 2013

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Rationale Mephedrone (4-methylmethcathinone) is a still poorly known drug of abuse, alternative to ecstasy or cocaine.Objective The major aims were to investigate the pharmacokinetics and locomotor activity of mephedrone in rats and provide a pharmacokinetic/pharmacodynamic model. MethodsMephedrone was administered to male Sprague-Dawley rats intravenously (10 mg/kg) and orally (30 and 60 mg/kg). Plasma concentrations and metabolites were characterized by LC/MS and LC-MS/MS fragmentation patterns. Locomotor activity was monitored for 180-240 min.Results Mephedrone plasma concentrations after i.v. administration fit to a twocompartment model (α=10.23 h -1 and β=1.86 h -1 ). After oral administration, peak mephedrone concentrations were achieved between 0.5-1 h, and declined to undetectable levels at 9 h. Absolute bioavailability of mephedrone was of about 10% and the percentage of mephedrone protein binding was of 21.59 ± 3.67%. We have identified five Phase I metabolites in rat blood after oral administration. The relationship between brain levels and free plasma concentration was 1.85 ± 0.08.Mephedrone induced a dose-dependent increase in locomotor activity, which lasted up to 2 h. The pharmacokinetic-pharmacodynamic model successfully describes the relationship between mephedrone plasma concentrations and its psychostimulant effect. ConclusionsWe suggest a very important first-pass effect for mephedrone after oral administration and an easy access to the central nervous system. The model described might be useful in the estimation and prediction of the onset, magnitude and time course of mephedrone pharmacodynamics as well as to design new animal models of mephedrone addiction and toxicity.

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Section: Introductionmentioning

confidence: 99%

Mephedrone pharmacokinetics after intravenous and oral administration in rats: relation to pharmacodynamics

et al. 2013

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“…Furthermore, the S (−)MCAT stimulus was potently antagonized by the DA antagonist haloperidol (Young & Glennon, 1998). However, MDMA substituted in rats trained to discriminate mephedrone, but full substitution failed to occur with METH or cocaine; furthermore, the mephedrone stimulus could not be antagonized by pretreatment of the animals with haloperidol (Varner, Daigle, Weed, Lewis, Mahne, Sankaranarayanan et al, 2012). It was recently demonstrated, using mice trained to discriminate MDPV from saline, that substitution occurred following administration of (±)METH and (±)MDMA (Fantegrossi et al, 2013) suggesting similarities amongst the stimulus actions of the three agents.…”

Section: Synthetic Cathinones: Mechanisms Of Action and Behavioral Stmentioning

confidence: 99%

Bath Salts, Mephedrone, and Methylenedioxypyrovalerone as Emerging Illicit Drugs That Will Need Targeted Therapeutic Intervention

Glennon

2014

Advances in Pharmacology

107

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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 (MDMA; 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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“…The present substitution of both MDMA and METH for the cocaine-like monoamine reuptake blocker MDPV would seem to be consistent with these previous findings. A recent study involving discriminative stimulus effects of the cathinone analogue and common 'bath salt' constituent mephedrone in the rat showed that cocaine, MDMA, and METH elicited dose-dependent mephedrone-like responding (Varner et al, 2012), although MDMA was more effective in this regard. These results are also consistent with a psychostimulant-like interoceptive effect of synthetic cathinones, and fit with an early publication investigating amphetamine-like discriminative stimulus effects of several N-alkyl and methylenedioxysubstituted cathinone analogues in the rat (Dal Cason et al, 1997), although this report did suggest that the methylenedioxy analogues were more MDMA-like than amphetaminelike, which is perhaps not surprising.…”

Section: 4-methylenedioxypyrovalerone In Micementioning

confidence: 99%

In vivo Effects of Abused ‘Bath Salt’ Constituent 3,4-methylenedioxypyrovalerone (MDPV) in Mice: Drug Discrimination, Thermoregulation, and Locomotor Activity

Fantegrossi

Gannon

Zimmerman

et al. 2012

Neuropsychopharmacol

138

151

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In recent years, synthetic analogues of naturally occurring cathinone have emerged as psychostimulant-like drugs of abuse in commercial 'bath salt' preparations. 3,4-Methylenedioxypyrovalerone (MDPV) is a common constituent of these illicit products, and its structural similarities to the more well-known drugs of abuse 3,4-methylenedioxymethamphetamine (MDMA), and methamphetamine (METH) suggest that it may have similar in vivo effects to these substances. In these studies, adult male NIH Swiss mice were trained to discriminate 0.3 mg/kg MDPV from saline, and the interoceptive effects of a range of substitution doses of MDPV, MDMA, and METH were then assessed. In separate groups of mice, surgically implanted radiotelemetry probes simultaneously monitored thermoregulatory and locomotor responses to various doses of MDPV and MDMA, as a function of ambient temperature. We found that mice reliably discriminated the MDPV training dose from saline and that cumulative doses of MDPV, MDMA, and METH fully substituted for the MDPV training stimulus. All three drugs had similar ED 50 values in this procedure. Stimulation of motor activity was observed following administration of a wide range of MDPV doses (1-30 mg/kg), and the warm ambient temperature potentiated motor activity and elicited profound stereotypy and self-injurious behavior at 30 mg/kg. In contrast, MDPV-induced hyperthermic effects were observed in only the warm ambient environment. This pattern of effects is in sharp contrast to MDMA, where ambient temperature interacts with thermoregulation, but not locomotor activity. These studies suggest that although the interoceptive effects of MDPV are similar to those of MDMA and METH, direct effects on thermoregulatory processes and locomotor activity are likely mediated by different mechanisms than those of MDMA.

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Comparison of the behavioral and cardiovascular effects of mephedrone with other drugs of abuse in rats

Cited by 61 publications

References 36 publications

Mephedrone pharmacokinetics after intravenous and oral administration in rats: relation to pharmacodynamics

Mephedrone pharmacokinetics after intravenous and oral administration in rats: relation to pharmacodynamics

Bath Salts, Mephedrone, and Methylenedioxypyrovalerone as Emerging Illicit Drugs That Will Need Targeted Therapeutic Intervention

In vivo Effects of Abused ‘Bath Salt’ Constituent 3,4-methylenedioxypyrovalerone (MDPV) in Mice: Drug Discrimination, Thermoregulation, and Locomotor Activity

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