Effects of methcathinone and 3-Cl-methcathinone (PAL-434) in cocaine discrimination or self-administration in rhesus monkeys

Kohut, Stephen J.; Fivel, Peter A.; Blough, Bruce E.; Rothman, Richard B.; Mello, Nancy K.

doi:10.1017/s146114571300059x

Cited by 15 publications

(19 citation statements)

References 49 publications

(57 reference statements)

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“…These findings agree with a recent study demonstrating that a-PVP fully substitutes for the discriminative Behavioral Pharmacology of Synthetic Cathinones stimulus effects of methamphetamine (Naylor et al, 2015) and previous reports that other cathinone compounds fully substitute for the discriminative stimulus effects of cocaine, amphetamine, and methamphetamine (Dal Cason et al, 1997;Schechter 1997;Bondareva et al, 2002;Gatch et al, 2013Gatch et al, , 2015Kohut et al, 2013). a-PVP produced a much flatter dose-effect curve in the cocaine-trained rats than in the methamphetamine-trained rats.…”

Section: Discussionsupporting

confidence: 92%

Comparative Behavioral Pharmacology of Three Pyrrolidine-Containing Synthetic Cathinone Derivatives

Gatch

Dolan

Forster

2015

J Pharmacol Exp Ther

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Synthetic cathinones, often sold as "bath salts," are a popular class of recreational drugs used as quasi-legal alternatives to cocaine, methamphetamine, and methylenedioxymethamphetamine. The increased prevalence and health consequences of synthetic cathinone use has prompted regulatory agencies to control a number of these compounds; however, a broad class of analogous compounds known as the second-generation cathinones has been brought to the market to take the place of the banned synthetic cathinone derivatives. The current study aims to characterize the behavioral pharmacology of three pyrrolidinylated secondgeneration cathinones: 4-methyl-a-pyrrolidinopropiophenone (4ʹ-MePPP), a-pyrrolidinopropiobutiophenone (a-PBP), and a-pyrrolidinopentiophenone (a-PVP). Locomotor activity was tested in mice over an 8-hour period. The discriminative stimulus effects of these compounds were tested in rats trained to discriminate either cocaine or methamphetamine. The rewarding effects of these drugs were assessed in mice using conditioned place preference. Both a-PBP and a-PVP produced long-lasting increases in locomotor activity across a wide range of doses, whereas 4ʹ-MePPP produced locomotor stimulation only at 30 mg/kg. Both a-PBP and a-PVP fully substituted for the discriminative stimulus effects of both cocaine and methamphetamine, whereas 4ʹ-MePPP substituted fully for the discriminative stimulus effects of methamphetamine only. Both a-PBP and a-PVP produced conditioned place preference in an inverted U-shaped dose effect, whereas 4ʹ-MePPP did not produce conditioned place preference. These findings suggest that a-PBP and a-PVP are likely to be recreationally used and have potential for addiction and abuse, but 4ʹ-MePPP may not.

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Section: Discussionsupporting

confidence: 92%

Comparative Behavioral Pharmacology of Three Pyrrolidine-Containing Synthetic Cathinone Derivatives

Gatch

Dolan

Forster

2015

J Pharmacol Exp Ther

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“…Methcathinone has been shown to fully substitute in both methamphetamine- and cocaine-trained subjects (Bondareva et al 2002; Kohut et al 2013; Schechter 1997a), and cocaine fully substitutes in S(−)-methcathinone-trained rats (Young and Glennon 1998). However, there have been no previous reports on the discriminative stimulus effects of pentedrone, pentylone, 4-MEC, or 3-FMC.…”

Section: Discussionmentioning

confidence: 99%

“…Methcathinone acts at monoamine transporters where it produces release of DA and NET, and less potently, 5-HT (Cozzi et al 2013; Eshleman et al 2013; Glennon et al 1987). It produces discriminative stimulus effects comparable to that of other psychostimulants, fully substituting for amphetamine (Glennon et al 1987; Schechter 1997b) and cocaine (Kohut et al 2013; Li et al 2006; Schechter 1997a). Similarly, methamphetamine, amphetamine, and cocaine substitute in methcathinone-trained rats (Young and Glennon 1998).…”

Section: Introductionmentioning

confidence: 98%

Discriminative and locomotor effects of five synthetic cathinones in rats and mice

2014

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Rationale Synthetic cathinones continue to be sold as “legal” alternatives to methamphetamine or cocaine. As these marginally legal compounds become controlled, suppliers move to other, unregulated compounds. Objectives The purpose of these experiments was to determine whether several temporarily controlled cathinone compounds, which are currently abused on the street, stimulate motor activity and have discriminative stimulus effects similar to cocaine and/or methamphetamine. Methods Methcathinone, pentedrone, pentylone, 3-fluoromethcathinone (3-FMC), and 4-methylethcathinone (4-MEC) were tested for locomotor stimulant effects in mice and subsequently for substitution in rats trained to discriminate cocaine (10 mg/kg, i.p.) or methamphetamine (1 mg/kg, i.p.) from saline. Results Methcathinone, pentedrone, and pentylone produced locomotor stimulant effects which lasted up to 6 hours. In addition, pentylone produced convulsions and lethality at 100 mg/kg. 4-MEC produced locomotor stimulant effects which lasted up to 2 hours. Methcathinone, pentedrone, pentylone, 3-FMC, and 4-MEC each produced discriminative stimulus effects similar to those of cocaine and methamphetamine. Conclusions All of the tested compounds produce discriminative stimulus effects similar to either those of cocaine, methamphetamine or both, which suggests that these compounds are likely to have similar abuse liability to cocaine and/or methamphetamine. Pentylone may be more dangerous on the street, as it produced adverse effects at doses that produced maximal stimulant-like effects.

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“…Five adult male rhesus macaques were trained to discriminate intramuscular (IM) injections of cocaine (0.4 mg/kg) from saline (see Kohut et al 2013a). Briefly, training sessions consisted of 1 to 3 cycles, and each cycle consisted of a 15 min time-out period followed by a 5 min response period.…”

Section: Methodsmentioning

confidence: 99%

“…Relatively non-selective releasers of dopamine (DA) and norepinephrine (NE), such as d-amphetamine or d-methamphetamine (d-MA) have been especially promising in both preclinical and clinical studies (reviewed in Herin et al 2010); however, their own abuse liability (reflected in Schedule II/III under the Controlled Substances Act) and other unwanted effects (e.g., increased cardiovascular response, disruptions to circadian rhythm) likely preclude their clinical application. A lack of behavioral selectivity also has been observed in laboratory studies in nonhuman primates: doses of nonselective DA/NE releasers that decreased cocaine self-administration, e.g., d-amphetamine, typically produced nonspecific and disruptive behavioral effects early in treatment and have well-recognized abuse liability (Negus and Mello 2003; Negus et al 2007; Negus et al 2009; Czoty et al 2010b; Czoty et al 2010a; Kohut et al 2013a). Habituation to some but not all the disruptive effects of these drugs (and not to their abuse liability) occurs over the course of prolonged exposure.…”

Section: Introductionmentioning

confidence: 96%

Effects of l-methamphetamine treatment on cocaine- and food-maintained behavior in rhesus monkeys

2015

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Rationale Monoamine releasers with prominent dopaminergic actions, e.g., d-methamphetamine (d-MA), significantly reduce cocaine use and craving in clinical and preclinical laboratory studies. However, d-MA and related drugs also display high abuse potential, which limits their acceptability as agonist replacement medications for the management of Cocaine Use Disorder. Objectives The l-isomer of methamphetamine (l-MA), unlike d-MA, has preferential noradrenergic actions and is used medicinally with low, if any, abuse liability. The present study was conducted to determine whether l-MA could serve as an agonist replacement medication by both mimicking interoceptive effects of cocaine and decreasing intravenous (IV) cocaine self-administration. Methods Separate groups (N=4-5) of rhesus monkeys were studied to determine whether l-MA could (1) substitute for cocaine in subjects that discriminated intramuscular (IM) cocaine (0.4 mg/kg) from saline and, (2) decrease IV cocaine self-administration under a second-order FR2(VR16:S) schedule of reinforcement. Results l-MA, like d-MA but with approximately 5-fold lesser potency, substituted for cocaine in drug discrimination experiments in a dose-dependent manner. In IV self-administration studies, 5-10 day treatments with continuously infused l-MA (0.032-0.32 mg/kg/hr, IV) dose-dependently decreased cocaine-maintained responding; the highest dosage reduced cocaine intake to levels of saline self-administration without appreciable effects on food-maintained responding. Conclusions These results indicate that l-MA both shares discriminative-stimulus effects with cocaine and reduces cocaine self-administration in a behaviorally selective manner. l-MA and other compounds with a similar pharmacological profile deserve further evaluation for the management of Cocaine Use Disorder.

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Effects of methcathinone and 3-Cl-methcathinone (PAL-434) in cocaine discrimination or self-administration in rhesus monkeys

Cited by 15 publications

References 49 publications

Comparative Behavioral Pharmacology of Three Pyrrolidine-Containing Synthetic Cathinone Derivatives

Comparative Behavioral Pharmacology of Three Pyrrolidine-Containing Synthetic Cathinone Derivatives

Discriminative and locomotor effects of five synthetic cathinones in rats and mice

Effects of l-methamphetamine treatment on cocaine- and food-maintained behavior in rhesus monkeys

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