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, Eric; Burroughs, Rachel L.; Baker, Lisa E.

doi:10.1097/fbp.0000000000000328

Cited by 15 publications

(16 citation statements)

References 16 publications

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“…Many cathinones fully substitute for the discriminative stimulus effects of MDMA; however, several do not. [45][46][47][48] Recently, it has been reported that chemical structure plays a role, such that compounds with no substitutions on the phenyl ring, pyrrolidinyl cathinones, and compounds with long alpha side chains produce less MDMA-appropriate responding, 13,49 which is in agreement with other studies indicating that the alpha side chain length 38 and 4-substitutions 37,49 predict activity of cathinones.…”

Section: Drug Discriminationsupporting

confidence: 87%

Behavioral effects of four novel synthetic cathinone analogs in rodents

et al. 2020

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A new generation of novel cathinone compounds has been developed as stimulant substitutes to avoid drug control laws and detection of use by blood tests. Dipentylone, N‐ethylhexedrone, 4‐chloroethcathinone (4‐CEC), and 4′‐methyl‐α‐pyrrolidinohexiophenone (MPHP) were tested for in vivo psychostimulant‐like effects to assess their abuse liability. Locomotor activity was assessed in an open‐field assay using Swiss–Webster mice to screen for locomotor stimulant effects and to identify behaviorally‐active dose ranges, times of peak effect, and durations of action. Discriminative stimulus effects were assessed in separate groups of Sprague–Dawley rats trained to discriminate cocaine or methamphetamine from vehicle. Dipentylone, N‐ethylhexedrone, 4‐CEC, and MPHP dose‐dependently increased locomotor activity. Dipentylone, N‐ethylhexedrone, and MPHP produced maximal stimulant effects similar to cocaine and methamphetamine. 4‐CEC was less efficacious, producing peak stimulant effects of about 74% of that of methamphetamine. The compounds were less potent than methamphetamine and approximately equipotent with cocaine. The doses of cocaine, methamphetamine, dipentylone, and 4‐CEC that produced peak effects lasted 2 to 3 h, the peak dose of N‐ethylhexedrone lasted 4 h, and the peak dose of MPHP lasted 6 h. All four compounds fully substituted for the discriminative stimulus effects of methamphetamine and cocaine, although full substitution by 4‐CEC occurred at doses that substantially decreased response rate. Only 4‐CEC fully substituted for MDMA. These data provide evidence that the novel cathinone compounds dipentylone, N‐ethylhexedrone, 4‐CEC, and MPHP demonstrate potential for abuse as psychostimulants, given their ability to stimulate locomotor activity and their substitution for the discriminative stimulus effects of methamphetamine and cocaine.

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Section: Drug Discriminationsupporting

confidence: 87%

Behavioral effects of four novel synthetic cathinone analogs in rodents

et al. 2020

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“…It is interesting to note that MDPV fully substituted in rhesus monkeys trained to discriminate cocaine (Smith et al, 2017) and in amphetamine-trained rats (Harvey et al, 2017), but not in MDMA-trained rats (Harvey and Baker, 2016) or in mephedrone-trained rats (DeLarge et al, 2017). This finding suggests that at least some cathinones may produce strong psychostimulant effects, but may not have MDMA-like effects.…”

Section: Introductionmentioning

confidence: 99%

Methylenedioxymethamphetamine-like discriminative stimulus effects of pyrrolidinyl cathinones in rats

Gatch

Forster

2020

J Psychopharmacol

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Background: Synthetic cathinone derivatives are used as alternatives both for stimulant drugs such as cocaine and methamphetamine and for club drugs such as 3,4-methylenedioxymethamphetamine (MDMA), but little is known about their MDMA-like subjective effects. Methods In order to determine their similarity to MDMA, the discriminative stimulus effects of 10 pyrrolidinyl cathinones (α-pyrrolidinopropiophenone, 4′-methyl-α-pyrrolidinopropiophenone (4′-MePPP), α-pyrrolidinobutiophenone, 3′,4′-methylenedioxy-α-pyrrolidinobutyrophenone (MD-PBP), α-pyrrolidinovalerophenone, 3,4-methylenedioxy-pyrovalerone (MDPV), α-pyrrolidinopentiothiophenone, napthylpyrovalerone (naphyrone), α-pyrrolidinohexiophenone, and 4′-methyl-α-pyrrolidinohexiophenone (4′-MePHP)) were assessed in Sprague–Dawley rats trained to discriminate 1.5 mg/kg racemic ±-MDMA from vehicle. Results: Compounds with no substitutions on the phenyl ring and the thiophene produced 44–67% MDMA-appropriate responding. In contrast, the substituted pyrrolidinyl cathinones produced a range of MDMA-appropriate responding dependent upon the length of the alpha side chain. 4′-MePPP, with a single carbon on the alpha position, produced 99.8% MDMA-appropriate responding, MD-PBP (two carbons) produced 83%, naphyrone (three carbons) produced 71%, MDPV (three carbons) produced, 66%, and 4′-MePHP (four carbons) produced 47%. Conclusions: Many cathinone compounds have discriminative stimulus effects similar to those of MDMA. However, the pyrrolidine substitution appears to reduce serotonergic effects, with a commensurate decrease in MDMA-like effects. Substitutions on the phenyl ring appear to be able to restore MDMA-like responding, but only in compounds with short alpha side chains. These findings agree with earlier findings of increasing dopaminergic effects and stronger reinforcing effects with increasing side chain. Assessment of more compounds is necessary to establish the replicability/robustness of this phenomenon. These findings may be of use in predicting which compounds will have MDMA/club drug-like effects versus psychostimulant-like effects.

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“…Several other studies have evaluated MDPV for substitution in animals trained to discriminate other stimulants. Full substitution was observed with MDPV in rats trained to discriminate d-amphetamine (Harvey et al 2017) or cocaine (Gannon et al 2016;Gatch et al 2013), although only partial substitution was observed with MDPV in rats trained to discriminate MDMA (Harvey and Baker 2016).…”

mentioning

confidence: 99%

Contribution of monoaminergic mechanisms to the discriminative stimulus effects of 3,4-methylenedioxypyrovalerone (MDPV) in Sprague-Dawley rats

Risca

Baker

2018

Psychopharmacology

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Rationale: 3,4-Methylenedioxypyrovalerone (MDPV) is a popular synthetic cathinone reported to have a high abuse potential. Recent preclinical research indicates the psychopharmacology of MDPV is comparable to cocaine. Despite a recent influx of research on the psychopharmacology of MDPV, few studies have employed preclinical drug discrimination methods to discern the neurochemical mechanisms involved in its interoceptive stimulus effects.Objective: The aim of this study was to evaluate a variety of monoaminergic agents for substitution, potentiation or antagonism in rats trained to discriminate MDPV.Methods: Male Sprague-Dawley rats were trained to discriminate 0.5 (Experiment 1) or 1 mg/kg MDPV (Experiment 2) from saline under an FR 20 schedule of food reinforcement. In Experiment 1, MDMA, MDA and their respective optical isomers (0.75 -3 mg/kg), cocaine (2.5 -20 mg/kg), GBR 12909 (5-40 mg/kg), and desipramine (3.2-10 mg/kg) were assessed for substitution. GBR 12909 (40 mg/kg) and desipramine (3.2 mg/kg) were subsequently assessed for potentiation of the MDPV cue. In Experiment 2, stimulus antagonism tests were conducted with dopamine antagonists (Sch 23390, haloperidol) and serotonin antagonists (pirenperone, MDL100907, WAY 100635). Results:The MDMA and MDA enantiomers produced divergent results, with virtually no substitution by (−)-MDMA or (−)-MDA, partial substitution with (+)-MDA, and full substitution with (+)-MDMA, as well as full substitution by the racemates, (±)-MDMA and (±)-MDA. Consistent with previous findings, cocaine fully substituted for MDPV. Although no dose of GBR 12909 or desipramine substituted for MDPV, these reuptake inhibitors enhanced the discriminative stimulus effects of lower MDPV doses. Both D1 (Sch 23390) and D2 (haloperidol) DA antagonists attenuated 1 mg/kg MDPV discrimination, whereas none of the 5-HT antagonists assessed altered MDPV discrimination. Conclusions:These findings indicate MDPV's interoceptive stimulus effects are mediated predominantly by dopaminergic actions, although serotonergic and/or noradrenergic modulation of these effects cannot be ruled out. Further investigations into the neurochemical actions involved in

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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

Cited by 15 publications

References 16 publications

Behavioral effects of four novel synthetic cathinone analogs in rodents

Behavioral effects of four novel synthetic cathinone analogs in rodents

Methylenedioxymethamphetamine-like discriminative stimulus effects of pyrrolidinyl cathinones in rats

Contribution of monoaminergic mechanisms to the discriminative stimulus effects of 3,4-methylenedioxypyrovalerone (MDPV) in Sprague-Dawley rats

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