Atypical binding at dopamine and serotonin transporters contribute to the discriminative stimulus effects of mephedrone

DeLarge, Alyssa F.; Erwin, Laura; Winsauer, Peter J.

doi:10.1016/j.neuropharm.2017.04.006

Cited by 15 publications

(11 citation statements)

References 81 publications

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“…Other less selective drugs such as cocaine, a monoamine transporter inhibitor, and methamphetamine and d-amphetamine, monoamine transporter substrate/releasers, produced partial or full substitution in the high and low training dose groups, respectively, with overall similar results to previous studies (Varner et al2013;Berquist II et al2017;DeLarge et al 2017). Although mephedrone shares dopamine, serotonin, and norepinephrine substrate release with methamphetamine and d-amphetamine (e.g., Baumann, et al2012;Kehr et al 2011;Hadlock et al2011), methamphetamine and d-amphetamine are considered more prototypical dopamine releasers (Matsumoto et al2014) and produce discriminative stimulus effects predominantly through dopaminergic mechanisms (for review see Berquist II and Fantegrossi 2018).…”

Section: Discussionsupporting

confidence: 86%

Effects of dopaminergic and serotonergic compounds in rats trained to discriminate a high and a low training dose of the synthetic cathinone mephedrone

et al. 2019

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Rationale-The underlying pharmacological mechanisms of mephedrone, especially as related to interactions with different neurotransmitter systems, are a critical area of study as mephedrone continues to be abused. Objective-Direct-acting 5-HT 2A/2C receptor agonists and antagonists and D 1-3 receptor antagonists were examined in two groups of rats trained to discriminate mephedrone. A high dose of mephedrone was trained to extend previous results with traditional monoamine transporter inhibitors and substrate releasers. A very low dose of mephedrone was trained to preferentially capture serotonergic activity and to minimize the influence of rate-decreasing effects on substitution patterns. Selective 5-HT 2A/2C and D 1-3 receptor antagonists were examined in both groups. Methods-Male, Sprague-Dawley rats were trained to discriminate either a low dose of 0.5 mg/kg mephedrone (N=24) or a high dose of 3.2 mg/kg mephedrone (N= 11) from saline. Results-In the low training-dose group, mephedrone, MDMA, methamphetamine, damphetamine, cocaine, and enantiomers of mephedrone substituted for mephedrone; mCPP partially substituted overall for mephedrone; and, DOI, WAY163909, and morphine failed to substitute for mephedrone. In the high training-dose group, only mephedrone and MDMA substituted for mephedrone. Sulpiride produced a small antagonism of the low training dose of mephedrone while SCH23390, SB242084, and ketanserin altered response rates. Conclusions-A lower training dose of mephedrone produces a discriminative stimulus fully mimicked by MDMA, methamphetamine, cocaine, and d-amphetamine whereas a higher training a This project was conducted in partial fulfillment of the doctorate degree in Pharmaceutical Sciences at Temple University for Iman Saber.

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Section: Discussionsupporting

confidence: 86%

Effects of dopaminergic and serotonergic compounds in rats trained to discriminate a high and a low training dose of the synthetic cathinone mephedrone

et al. 2019

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“…In addition, previous studies in which rats were trained to discriminate 3.2 mg/kg 4-MMC from saline, substitution tests with cocaine, MDPV, d -amphetamine, and methamphetamine produced only partial substitution and rate-decreasing effects (Varner et al . 2013; DeLarge et al . 2017).…”

Section: Discussionmentioning

confidence: 99%

“…2013; Gatch et al . 2013; Harvey and Baker, 2016; Milewski et al 2017; DeLarge et al 2017), and three of these studies used 4-MMC as the training drug (Varner et al 2013; Milewski et al 2017; DeLarge et al 2017). The results of these initial studies indicate 4-MMC produces interoceptive stimulus effects similar to those of MDMA, cocaine, methamphetamine, and fenfluramine, and the extent of stimulus substitution depends on the drug used as the training stimulus.…”

Section: Introductionmentioning

confidence: 99%

Evaluation of training dose in male Sprague-Dawley rats trained to discriminate 4-methylmethcathinone

2017

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Rationale Although the synthetic cathinone 4-methylmethcathinone (4-MMC, mephedrone) has been a subject of intensive research investigation, the pharmacological mechanisms involved in its interoceptive stimulus effects have yet to be fully characterized. Objective The present study employed drug discrimination methods in rats to compare the interoceptive stimulus properties of two different training doses of 4-MMC to other substances with similar pharmacological actions. Methods Sixteen male Sprague-Dawley rats were trained to discriminate either 1.0 mg/kg (N=8) or 3.0 mg/kg (N=8) 4-MMC from saline. Substitution tests were conducted with drugs that increase extracellular monoamine levels (d-amphetamine, (+)-methamphetamine, 4-MMC, MDMA, MDPV, and (−)-cocaine), a serotonin releaser (+)-fenfluramine, and a serotonergic (5-HT2A) hallucinogen (+)-LSD. Results Stimulus control was established in fewer sessions in the subjects trained with 3.0 mg/kg compared to those trained with 1.0 mg/kg 4-MMC. Cocaine, MDMA, and d-amphetamine produced full substitution in the 1.0 mg/kg 4-MMC-trained rats at doses that did not decrease response rate. However, doses of test drugs that engendered >80% 4-MMC-lever selection concurrently produced rate-decreasing effects in rats trained to discriminate 3.0 mg/kg 4-MMC. Conclusions These findings further characterize the interoceptive stimulus effects of 4-MMC and indicate that these effects vary little with training dose, however qualitative differences in substitutability of test drugs were observed between training groups. This study expands existing knowledge regarding the psychopharmacology of 4-MMC and the potential neurochemical substrates contributing to its subjective effects.

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“…Indeed, amphetamine, methamphetamine, methylphenidate, and cathinone are virtually inactive at SERT; only cocaine, MDMA, MDEA, and mephedrone show high potency as inhibitors mainly as competitive substrates (Table 2). Mephedrone is relatively nonselective as a substrate, and interestingly, in a behavioral study in rats, only cocaine fully substituted for the discriminative stimulus effects of mephedrone 46 …”

Section: Monoamine Transportersmentioning

confidence: 99%

Pharmacology of Drugs Used as Stimulants

Docherty

Alsufyani

2021

The Journal of Clinical Pharma

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Psychostimulant, cardiovascular, and temperature actions of stimulants involve adrenergic (norepinephrine), dopaminergic (dopamine), and serotonergic (serotonin) pathways. Stimulants such as amphetamine, 3,4‐methylenedioxymethamphetamine (MDMA), or mephedrone can act on the neuronal membrane monoamine transporters NET, DAT, and SERT and/or the vesicular monoamine transporter 2 to inhibit reuptake of neurotransmitter or cause release by reverse transport. Stimulants may have additional effects involving pre‐ and postsynaptic/junctional receptors for norepinephrine, dopamine, and serotonin and other receptors. As a result, stimulants may have a wide range of possible actions. Agents with cocaine or MDMA‐like actions can induce serious and potentially fatal adverse events via thermodysregulatory, cardiovascular, or other mechanisms. MDMA‐like stimulants may cause hyperthermia that can be life threathening. Recreational users of stimulants should be aware of the dangers of hyperthermia in a rave/club environment.

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Atypical binding at dopamine and serotonin transporters contribute to the discriminative stimulus effects of mephedrone

Cited by 15 publications

References 81 publications

Effects of dopaminergic and serotonergic compounds in rats trained to discriminate a high and a low training dose of the synthetic cathinone mephedrone

Effects of dopaminergic and serotonergic compounds in rats trained to discriminate a high and a low training dose of the synthetic cathinone mephedrone

Evaluation of training dose in male Sprague-Dawley rats trained to discriminate 4-methylmethcathinone

Pharmacology of Drugs Used as Stimulants

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