Cocaine-like discriminative stimulus effects of amphetamine, cathinone, methamphetamine, and their 3,4-methylenedioxy analogs in male rhesus monkeys

Abstract

Rationale Synthetic cathinones have emerged as the newest class of abused monoamine transporter substrates. Structurally, these compounds are all beta-ketone amphetamine (cathinone) analogs. Whether synthetic cathinone analogs produce differential behavioral effects from their amphetamine analog counterparts has not been systematically examined. Preclinical drug discrimination procedures have been useful for determining the structure activity relationships (SAR) of abused drugs; however, direct comparisons between amphetamine and cathinone analogs are lacking and, in particular, in nonhuman primate models. Objectives The study aim was to determine the potency and time course of (±)-amphetamine, (±)-cathinone, (±)-methamphetamine, and their 3,4-methylenedioxy analogs (±)-MDA, (±)-MDC, and (±)-MDMA, respectively to produce cocaine-like discriminative stimulus effects. If cathinone analogs have similar behavioral pharmacological properties to their amphetamine counterparts, then we would predict similar potencies and efficacies to produce cocaine-like discriminative stimulus effects. Methods Male rhesus monkeys (n=4) were trained to discriminate intramuscular cocaine (0.32 mg/kg) from saline in a two-key food-reinforced discrimination procedure. Results Racemic amphetamine, cathinone, and methamphetamine produced dose-dependent and full, ≥90% cocaine-appropriate responding, in all monkeys. Addition of 3,4-methylenedioxy moiety attenuated both the potency and efficacy of amphetamine (MDA), cathinone (MDC), and methamphetamine (MDMA) to produce full cocaine-like effects. Moreover, the cocaine-like effects of amphetamine and cathinone were attenuated to a greater extent than methamphetamine or previously published methcathinone (Smith et al. 2016). Conclusion The presence of an N-methyl group blunted both the potency and efficacy shift of the 3,4-methylenedioxy addition for both amphetamine and cathinone analogs.

Discriminative-Stimulus Effects of Synthetic Cathinones in Squirrel Monkeys

“…Unlike MA in MDMA-trained subjects, MDMA failed to produce any drug-appropriate effects in MA-trained subjects in the present experiments. These findings contrast with those in recent cocaine-discrimination studies in which MDMA produced complete substitution for cocaine in 3 of 4 monkeys ( Smith et al, 2017a ). The reason for such differing results with MA and cocaine are unclear but may reflect differences in indirect mechanisms and selectivity of neurochemical action (DA-preferring monoamine releaser vs nonselective monoamine transport blocker, respectively).…”

“…Although there has been considerable work describing the discriminative-stimulus effects of cathinones in MA-trained or MDMA-trained rodents, comparable studies have not yet been conducted to determine whether a similar range of MA-like and MDMA-like effects occur in a primate species. Smith et al (2017a , 2017b ) report that several cathinones—including α-PVP, MDPV, MCAT, and methylone, but not mephedrone—fully substitute for cocaine (0.32 mg/kg) in male rhesus monkeys. However, MDMA also fully substituted for cocaine in 3 of the 4 monkeys, suggesting that its discriminative-stimulus effects did not differ greatly from those of cocaine ( Smith et al, 2017a ).…”

“… Smith et al (2017a , 2017b ) report that several cathinones—including α-PVP, MDPV, MCAT, and methylone, but not mephedrone—fully substitute for cocaine (0.32 mg/kg) in male rhesus monkeys. However, MDMA also fully substituted for cocaine in 3 of the 4 monkeys, suggesting that its discriminative-stimulus effects did not differ greatly from those of cocaine ( Smith et al, 2017a ). The present experiments were conducted to further investigate the discriminative-stimulus effects of selected synthetic cathinones considered to be dopamine-preferring (α-PVP, MDPV, MCAT) or serotonin-preferring (methylone, mephedrone) by directly comparing their discriminative stimulus effects in different groups of squirrel monkeys trained to discriminate either MA or MDMA from saline.…”

Locomotor activity and discriminative stimulus effects of a novel series of synthetic cathinone analogs in mice and rats

“…Similarly, there is a possibility that addition of a methylenedioxy ring may reduce efficacy, as 3,4-methylenedioxy analogs of cathinone, amphetamine and methamphetamine had less potency and efficacy in monkeys trained to discriminate cocaine (Smith et al 2017). This agrees with the finding that α-PBP produced full substitution in cocaine-trained rats (Gatch et al, 2105a), but its 3,4-methylenedioxy analog failed to fully substitute for cocaine in the present study.…”

Single Exposure to the Cathinones MDPV and α-PVP Alters Molecular Markers of Neuroplasticity in the Adult Mouse Brain

“…Among the several synthetic cathinones existing on the clandestine market, we focused our attention on the methylenedioxy derivative of pyrovalerone MDPV (3,4-methylenedioxypyrovalerone) and its closely related derivative α-PVP ((1-Phenyl-2-(pyrrolidin-1-yl)pentan-1-one), also known as “flakka” or “gravel”) [ 26 , 27 , 28 , 29 , 30 ]. While synthetic cathinones exhibit features typical of amphetamines-like compounds, MDPV and α-PVP more closely resemble cocaine-like compounds [ 31 ] as they primarily block the dopamine transporter (DAT) and the norepinephrine transporter (NET), whereas, at variance from cocaine [ 32 , 33 ], these two compounds do not seem to block the serotonin transporter (SERT) [ 34 , 35 , 36 , 37 , 38 ]. Further, MDPV and α-PVP show reinforcing properties higher than cocaine and their abuse liability is positively correlated with their ability to block the DAT [ 39 ].…”