Stereoselective Effects of Abused "Bath Salt" Constituent 3,4-Methylenedioxypyrovalerone in Mice: Drug Discrimination, Locomotor Activity, and Thermoregulation

Gannon, Brenda M.; Williamson, Adrian; Suzuki, Masaki; Rice, Kenner C.; Fantegrossi, William E.

doi:10.1124/jpet.115.229500

Cited by 70 publications

(67 citation statements)

References 23 publications

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“…However, despite engendering significantly different MDPV intakes, we did not observe dose-dependent differences in locomotor stimulant effects following oral consumption of these MDPV solutions. This is consistent with our previous findings using intraperitoneal injections (Fantegrossi et al, 2013; Gannon et al, 2016) where we also observed a relatively “flat” dose-effect function for MDPV-induced hyperactivity in the cool (~20°C) ambient temperature of the telemetry laboratory. Similarly, chronic (10 day) access to the 0.30 mg/mL MDPV solution in a forced-choice setting engendered significant locomotor stimulant effects across the access period, but no systematic upward or downward trends in locomotor activity were observed despite escalation of intake resulting in approximately a 2-fold higher MDPV dose on the last three days of the access period than on the first day.…”

Section: 0 Discussionsupporting

confidence: 93%

“…In vivo studies of rodents trained to discriminate methamphetamine or cocaine have reported that MDPV substitutes for both psychostimulants (Gatch et al, 2013; Collins et al, 2016; Gannon et al, 2016). Similarly, we previously trained mice to discriminate MDPV from saline and reported that 3,4-methylenedioxymethamphetamine and methamphetamine generalize to MDPV (Fantegrossi et al, 2013).…”

Section: 0 Introductionmentioning

confidence: 99%

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Effects of orally self-administered bath salt constituent 3,4-methylenedioxypyrovalerone (MDPV) in mice

Gannon

Russell

Modi

et al. 2017

Drug and Alcohol Dependence

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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 1.00 mg/mL MDPV solutions versus 0.10 mg/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 (0.30 mg/mL), using water as a control, and compared with results from intraperitoneally-administered MDPV. Consumption of MDPV solutions (0.03 – 1.00 mg/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 – 0.30 mg/mL) were almost exclusively preferred, and treatment with the catecholamine synthesis inhibitor αMPT decreased MDPV choice. Consumption of MDPV concentrations (0.1 – 1.0 mg/mL) stimulated locomotor activity. Chronic (10 day) access to 0.30 mg/mL MDPV resulted in escalated consumption, but locomotor effects did not systematically change across the access period. Finally, consumption of 0.30 mg/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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Section: 0 Discussionsupporting

confidence: 93%

Section: 0 Introductionmentioning

confidence: 99%

Effects of orally self-administered bath salt constituent 3,4-methylenedioxypyrovalerone (MDPV) in mice

Gannon

Russell

Modi

et al. 2017

Drug and Alcohol Dependence

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“…These data indicate the PK properties of MDPV enantiomers are not further complicated by in vivo racemization. Nevertheless, since the pharmacological effects are more potently due to ( S )-MDPV (Gannon et al, 2016; Kolanos et al, 2015), it would be important for investigators to know the chiral purity of both ( R )- and ( S )-MDPV stock reagents before use in experiments.…”

Section: Discussionmentioning

confidence: 99%

“…( S )-MDPV has profound pharmacological activity, while ( R )-MDPV is less potent in mice and rats (Gannon et al, 2016; Kolanos et al, 2015). In human users, ( R,S )-MDPV is often self-administered for a rapid onset of action by intravenous, inhalation, or insufflation routes, or by the oral route which has a slower onset of action and susceptibility to gut and first pass metabolism (Froberg et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

The pharmacokinetics of racemic MDPV and its (R) and (S) enantiomers in female and male rats

Hambuchen

Hendrickson

Gunnell

et al. 2017

Drug and Alcohol Dependence

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Background These studies investigated the serum pharmacokinetic (PK) profile of racemic (3,4)-methylenedioxypyrovalerone [(R,S)-MDPV)] and its (R)- and (S)-enantiomers in female and male Sprague Dawley rats. Methods Intravenous (R,S)-MDPV (3 and 5.6 mg/kg) and single enantiomer of (R)- and (S)-MDPV (1.5 mg/kg) were administered to both sexes for PK studies. Intraperitoneal (ip) bioavailability was determined at 3 mg/kg (R,S)-MDPV. Locomotor activity studies were conducted after ip treatment with saline and 0.3–5.6 mg/kg of (R,S)-MDPV. Results PK values after iv (R,S)-MDPV showed a significant (p<0.05) sex-dependent differences in the volume of distribution at steady state (Vdss) for (R)- and (R,S)-MDPV at both (R,S)-MDPV doses. The female S/R enantiomeric ratios for area under the concentration time curve (AUCinf) and clearance were significantly lower and higher, respectively, than values determined in males. Importantly, there was no evidence of in vivo inversion of (R)-MDPV or (S)-MDPV to its antipode. There were, however, significant sex-dependent differences in volume of distribution after administration of the (R)-enantiomer. Bioavailability studies of ip (R,S)-MDPV showed greater variability and significantly greater bioavailability in male rats. Accordingly, there was a significantly greater maximal distance traveled measurement in male rats at a 3.0 mg/kg dose. Conclusion PK sex differences in (R,S)-MDPV and enantiomers were most apparent in volume of distribution, which could be caused by differences in drug blood and tissue protein binding. The increased magnitude and variance in ip bioavailability in male compared to female rats could lead to sex-dependent differences in the pharmacological action caused by active enantiomer (S)-MDPV.

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“…A growing body of research supports the legal restriction of these substances, as their pharmacology and abuse liability are comparable to other abused psychostimulants (Cameron et al, 2013; Baumann et al, 2012). However, only a few published studies have examined the interoceptive effects of MDPV or mephedrone using animal models of drug discrimination (Gannon et al, 2016; Fantegrossi et al, 2013; Gatch et al, 2013; Varner et al, 2013). To date, no published studies have examined the specific receptor mechanisms contributing to the interoceptive stimulus effects of these substances.…”

Section: Introductionmentioning

confidence: 99%

Effects of D1 and D2 receptor antagonists on the discriminative stimulus effects of methylendioxypyrovalerone and mephedrone in male Sprague-Dawley rats trained to discriminate d-amphetamine

Harvey

Burroughs

Baker

2017

Behavioural Pharmacology

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Psychopharmacology research has amassed substantial evidence for similarities between synthetic cathinones and other commonly abused psychostimulants. Few studies have utilized drug discrimination methods to investigate synthetic cathinones, and the precise neurochemical substrates underlying their interoceptive effects have not been examined. The present study assessed the involvement of D1 and D2 dopaminergic receptors in the stimulus effects of MDPV and mephedrone in rats trained to discriminate d-amphetamine. Eight male Sprague-Dawley rats were trained to discriminate 0.5 mg/kg d-amphetamine (AMPH) from saline. Dose-response curves were then generated with AMPH (0.0 – 1.0 mg/kg), MDPV (0.0 – 1.0 mg/kg), and mephedrone (MEPH) (0.0 – 2.0 mg/kg). Subsequently, Sch 39166 (0.3 mg/kg) and haloperidol (0.5 mg/kg) were administered in combination with select doses of MDPV and MEPH. Both MDPV and MEPH produced full substitution for AMPH. Sch 39166 produced a downward shift in the MDPV and MEPH dose response curves and haloperidol produced similar results with MDPV. These preliminary findings indicate MDPV and MEPH produce interoceptive stimuli that are similar to those produced by d-amphetamine and that D1 and D2 dopamine receptors contribute to these effects. Additional studies are warranted to investigate the contribution of other receptor mechanisms involved in the interoceptive stimuli produced by synthetic cathinones.

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Stereoselective Effects of Abused "Bath Salt" Constituent 3,4-Methylenedioxypyrovalerone in Mice: Drug Discrimination, Locomotor Activity, and Thermoregulation

Cited by 70 publications

References 23 publications

Effects of orally self-administered bath salt constituent 3,4-methylenedioxypyrovalerone (MDPV) in mice

Effects of orally self-administered bath salt constituent 3,4-methylenedioxypyrovalerone (MDPV) in mice

The pharmacokinetics of racemic MDPV and its (R) and (S) enantiomers in female and male rats

Effects of D1 and D2 receptor antagonists on the discriminative stimulus effects of methylendioxypyrovalerone and mephedrone in male Sprague-Dawley rats trained to discriminate d-amphetamine

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