Comparative Behavioral Pharmacology of Three Pyrrolidine-Containing Synthetic Cathinone Derivatives

Gatch, Michael B.; Dolan, Sean B.; Forster, Michael J.

doi:10.1124/jpet.115.223586

Cited by 67 publications

(81 citation statements)

References 32 publications

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“…Although both compounds stimulated locomotor activity with comparable efficacy across the two routes of administration, activity levels at each vapor concentration were similar whereas activity levels exhibited greater dose-dependence with injections, which was especially notable for α-PVP. In agreement with past research using injected METH and α-PVP (Cherng et al, 2007; Gatch et al, 2015; Schindler et al, 2002; Shimosato and Ohkuma, 2000; Zakharova et al, 2009), vapor exposure to both compounds also produced CPP.…”

Section: 0 Discussionsupporting

confidence: 91%

“…These behavioral effects have been previously reported with other classic stimulants and synthetic cathinones in male mice (Aarde et al, 2015; Gatch et al, 2015; Marusich et al, 2012, 2014). Vaporized METH and α-PVP produced a similar profile of stimulant-like overt effects.…”

Section: 0 Discussionsupporting

confidence: 84%

“…Since CPP has been demonstrated with injected METH and α-PVP (Cherng et al, 2007; Gatch et al, 2015; Schindler et al, 2002; Shimosato and Ohkuma, 2000; Zakharova et al, 2009), vapor exposure was the only route of administration used in this assay. A new cohort of male mice were randomly assigned to 24.0 mg/ml METH vapor, 72 mg/ml α-PVP vapor, or PG/VG vehicle groups (n=8 per group).…”

Section: 0 Methodsmentioning

confidence: 99%

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Pharmacological effects of methamphetamine and alpha-PVP vapor and injection

et al. 2016

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Vaporizing drugs in e-cigarettes is becoming a common method of administration for synthetic cathinones and classical stimulants. Heating during vaporization can expose the user to a cocktail of parent compound and thermolytic degradants, which could lead to different toxicological and pharmacological effects compared to ingesting the parent compound alone via injection or nasal inhalation. This study examined the in vivo toxicological and pharmacological effects of vaporized and injected methamphetamine (METH) and α-pyrrolidinopentiophenone (α-PVP). Male and female ICR mice were administered METH or α-PVP through vapor or i.p. injection. Dose-effect curves were determined for locomotor activity and a functional observational battery (FOB). METH and α-PVP vapor were also evaluated for place preference in male mice. Vapor exposure and injection led to more similarities than differences in toxicological and pharmacological effects. In the FOB, both routes of administration produced typical stimulant effects, and injection also increased some bizarre behaviors (e.g. licking, teeth chattering, darting). Both METH and α-PVP vapor exposure produced conditioned place preference. The two routes of administration had comparable efficacy in locomotor activation, with vapor producing longer lasting effects than injection. Females showed greater METH-induced locomotor activity, and greater incidence of a few somatic signs in the FOB than males. These results explore the toxicology of stimulant vapor inhalation in mice using an e-cigarette device. Despite the current technological and methodological difficulties, studying drug vapor promises to allow determination of toxicological effects of thermolytic products and flavor additives.

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Section: 0 Discussionsupporting

confidence: 91%

Section: 0 Discussionsupporting

confidence: 84%

Section: 0 Methodsmentioning

confidence: 99%

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Pharmacological effects of methamphetamine and alpha-PVP vapor and injection

et al. 2016

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“…The pure transporter inhibitor activity of this group may be due to the n-pyrrolidino substituent, as Sandtner et al (2016) observed that interactions with critical aspartate residues of DAT and SERT are necessary for substrate activity, and secondary or tertiary substitution on nitrogen inhibits interaction with these residues. The high selectivity for hDAT over hSERT suggests that these compounds may have high abuse liability, consistent with the ability of a-PBP and a-PVP to fully substitute for discriminative stimulus effects of both cocaine and METH and to produce conditioned place preference (Gatch et al, 2015a). In contrast, 4-MePPP fully substitutes only for METH, does not produce conditioned place preference, and in the current study had less selectivity for hDAT, all of which suggest a lower abuse liability as compared with other a-pyrrolidinophenones characterized here.…”

Section: Discussionmentioning

confidence: 94%

Structure-Activity Relationships of Substituted Cathinones, with Transporter Binding, Uptake, and Release

Eshleman

Wolfrum

Reed

et al. 2016

J Pharmacol Exp Ther

114

187

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Synthetic cathinones are components of "bath salts" and have physical and psychologic side effects, including hypertension, paranoia, and hallucinations. Here, we report interactions of 20 "bath salt" components with human dopamine, serotonin, and norepinephrine transporters [human dopamine transporter (hDAT), human serotonin transporter (hSERT), and human norepinephrine transporter (hNET), respectively] heterologously expressed in human embryonic kidney 293 cells. Transporter inhibitors had nanomolar to micromolar affinities (K i values) at radioligand binding sites, with relative affinities of hDAT.hNET.hSERT for a-pyrrolidinopropiophenone (a-PPP), a-pyrrolidinobutiophenone, a-pyrrolidinohexiophenone, 1-phenyl-2-(1-pyrrolidinyl)-1-heptanone, 3,4-methylenedioxy-a-pyrrolidinopropiophenone, 3,4-methylenedioxy-a-pyrrolidinobutiophenone, 4-methyl-a-pyrrolidinopropiophenone, a-pyrrolidinovalerophenone, 4-methoxy-a-pyrrolidinovalerophenone, a-pyrrolidinopentiothiophenone (alpha-PVT), and a-methylaminovalerophenone, and hDAT.hSERT.hNET for methylenedioxypentedrone. Increasing the a-carbon chain length increased the affinity and potency of the a-pyrrolidinophenones. Uptake inhibitors had relative potencies of hDAT.hNET.hSERT except a-PPP and a-PVT, which had highest potencies at hNET. They did not induce [3 H]neurotransmitter release. Substrates can enter presynaptic neurons via transporters, and the substrates methamphetamine and 3,4-methylenedioxymethylamphetamine are neurotoxic. We determined that 3-fluoro-, 4-bromo-, 4-chloromethcathinone, and 4-fluoroamphetamine were substrates at all three transporters; 5,6-methylenedioxy-2-aminoindane (MDAI) and 4-methylethcathinone (4-MEC) were substrates primarily at hSERT and hNET; and 3,4-methylenedioxy-Nethylcathinone (ethylone) and 5-methoxy-methylone were substrates only at hSERT and induced [ 3 H]neurotransmitter release. Significant correlations between potencies for inhibition of uptake and for inducing release were observed for these and additional substrates. The excellent correlation of efficacy at stimulating release versus K i /IC 50 ratios suggested thresholds of binding/uptake ratios above which compounds were likely to be substrates. Based on their potencies at hDAT, most of these compounds have potential for abuse and addiction. 4-Bromomethcathinone, 4-MEC, 5-methoxy-methylone, ethylone, and MDAI, which have higher potencies at hSERT than hDAT, may have empathogen psychoactivity.

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“…In addition, the cathinone flephedrone (Gatch et al, 2013), the sympathomimetic dimethylamylamine (Dolan & Gatch, 2015), and the phenethylamine hallucinogens 2C-D and DOC (Eshleman et al, 2014) produced a profile similar to that of MDAI and MDMA: depressant effects followed by rebound stimulant effects. In contrast, a wide range of psychostimulants produce locomotor stimulation, often in an-inverted U-shaped function, such that increasing doses produce increases in locomotor activity, with the highest doses producing marked decreases in locomotor activity (Carroll et al, 2009; Gatch et al, 2013; 2015a; 2015b; Katz, 2001). When tested in the same manner, most hallucinogens produce dose-dependent depression of locomotor activity (Eshleman et al, 2014; Gatch et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

Locomotor, discriminative stimulus, and place conditioning effects of MDAI in rodents

Gatch

Dolan

Forster

2016

Behavioural Pharmacology

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5,6-Methylenedioxy-2-aminoindane (MDAI) has become a common substitute for (±)-3,4-methylenedioxymethamphetamine (MDMA) in Ecstasy. MDAI is known to produce MDMA-like discriminative stimulus effects, but it is not known whether MDAI has psychostimulant or hallucinogen-like effects. MDAI was tested for locomotor stimulant effects in mice and subsequently for discriminative stimulus effects in rats trained to discriminate cocaine (10 mg/kg, i.p.), methamphetamine (1 mg/kg, i.p.), ±MDMA (1.5 mg/kg, i.p.), or (−)-2,5-dimethoxy-4-methylamphetamine hydrochloride (DOM) (0.5 mg/kg, i.p.) from saline. The ability of MDAI to produce conditioned place preference was also tested in mice. MDAI (3 to 30 mg/kg) depressed locomotor activity from 10 to 60 min. A rebound stimulant effect was observed at 1 to 3.5 hr following 30 mg/kg. Lethality occurred in 8/8 mice following 100 mg/kg MDAI. Similarly, MDMA depressed locomotor activity immediately following administration of 0.25 mg/kg and stimulant effects were observed 50–70 min following administration of 0.5 and 1 mg/kg. MDAI fully substituted for the discriminative stimulus effects of MDMA (2.5 mg/kg), DOM (5 mg/kg) and cocaine (7.5 mg/kg), but produced only 73% methamphetamine-appropriate responding at a dose that suppressed responding (7.5 mg/kg). MDAI produced tremors at 10 mg/kg in one methamphetamine-trained rat. MDAI produced conditioned place preference from 0.3 to 10 mg/kg. The effects of MDAI on locomotor activity and drug discrimination were similar to those produced by MDMA, having both psychostimulant- and hallucinogen-like effects, so MDAI may have similar abuse potential as MDMA.

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Comparative Behavioral Pharmacology of Three Pyrrolidine-Containing Synthetic Cathinone Derivatives

Cited by 67 publications

References 32 publications

Pharmacological effects of methamphetamine and alpha-PVP vapor and injection

Pharmacological effects of methamphetamine and alpha-PVP vapor and injection

Structure-Activity Relationships of Substituted Cathinones, with Transporter Binding, Uptake, and Release

Locomotor, discriminative stimulus, and place conditioning effects of MDAI in rodents

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