Cocaine-like discriminative stimulus effects of alpha-pyrrolidinovalerophenone, methcathinone and their 3,4-methylenedioxy or 4-methyl analogs in rhesus monkeys

Abstract

Synthetic cathinones are beta-ketone amphetamine analogs that have emerged as a heterogeneous class of abused compounds that function as either monoamine transporter substrates or inhibitors. Preclinical drug discrimination procedures are useful for interrogating structure-activity relationships (SAR) of abuse-related drug effects; however, in vivo SAR comparisons between synthetic cathinones with different mechanisms of action are lacking. The aim of the present study was to determine whether the cocaine-like discriminative stimulus effects of the monoamine transporter inhibitor alpha-pyrrolidinovalerophenone (alpha-PVP) and the monoamine transporter substrate methcathinone were differentially sensitive to 3,4-methylenedioxy and 4-methyl substitutions. 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. Potency and timecourse of cocaine-like discriminative stimulus effects were determined for (±)-alpha-PVP, (±)-methcathinone, and their 3,4-methylenedioxy or 4-methyl analogs. Alpha-PVP and methcathinone produced dose- and time-dependent cocaine-like effects. A 3,4-methylenedioxy addition to either alpha-PVP (MDPV) or methcathinone (MDMC; methylone) did not alter the potency or efficacy to produce cocaine-like effects, but did prolong the time course. A 4-methyl addition to alpha-PVP (4MPVP; pyrovalerone) did not alter the potency or efficacy to produce cocaine-like effects, but did prolong the time course. In contrast, addition of a 4-methyl moiety to methcathinone (4MMC; mephedrone) significantly attenuated efficacy to produce cocaine-like effects. Overall, these results suggest different structural requirements for cocaine-like discriminative stimulus effects of monoamine transporter inhibitor and substrate synthetic cathinone analogs. Given that 4MMC is more hydrophobic than MDMC, these results suggest hydrophobicity may be an important determinant for limiting monoamine transporter substrate abuse-related behavioral effects.

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

“…We hypothesized that the cocaine-like discriminative stimulus effects of amphetamine and cathinone would be attenuated by a 3,4-methylenedioxy addition. Furthermore, we hypothesized the cocaine-like discriminative stimulus effects of methamphetamine would not be altered by a 3,4-methylenedioxy addition, similar to our previous methcathinone and MDMC results (Smith et al 2016). …”

“…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). …”

“…All monkeys had a cocaine discrimination experimental history (Banks 2014; Banks et al 2013; Banks et al 2015; Smith et al 2016) and were maintained on a diet of biscuits (Lab Diet High Protein Monkey Biscuits, PMI Feeds, Inc., St. Louis, MO) and fresh fruit provided after the behavioral session. Experimental sessions were conducted in the monkey’s home chamber and water was available throughout behavioral sessions.…”

“…For comparison, we also determined the effects of a 3,4-methylenedioxy addition on the cocaine-like effects of methamphetamine (3,4-methylenedioxymethamphetamine; MDMA). We have previously published (±)-methcathinone and (±)-3,4-methylenedioxymethcathinone (MDMC) results in these same monkeys under the same cocaine discrimination procedure (Smith et al 2016). These previously published results suggested a 3,4-methylenedioxy addition to methcathinone did not significantly alter the potency or efficacy of methcathinone to produce cocaine-like effects, but did prolong the time course.…”

Reinforcing effects of abused ‘bath salts’ constituents 3,4-methylenedioxypyrovalerone and α-pyrrolidinopentiophenone and their enantiomers

“…Both compounds have been classified by the Drug Enforcement Administration as Schedule I compounds (Drug Enforcement Administration, 2014). Similar to other stimulant drugs of abuse, MDPV and α-PVP have been shown to stimulate locomotor activity, produce cocaine-like discriminative stimulus effects, facilitate intracranial self-stimulation, and are readily self-administered (e.g., Fantegrossi et al, 2013; Watterson et al, 2014a; 2014b; Aarde et al, 2015; Kolanos et al, 2015; Gannon et al, 2016; 2017; Collins et al, 2016; Smith et al, 2016). …”