Behavioral economic analysis of the reinforcing effects of “bath salts” mixtures: studies with MDPV, methylone, and caffeine in male Sprague-Dawley rats

Abstract

Rationale: "Bath salts" preparations often contain combinations of synthetic cathinones (e.g., 3,4methylenedioxymethcathinone [methylone], 3,4-methylenedioxypyrovalerone [MDPV]) and caffeine, and evidence suggests that mixtures of synthetic cathinones and caffeine (e.g., MDPV +caffeine or methylone+caffeine) can be more potent and/or effective reinforcers than predicted for an additive interaction. Objective: To use demand curve analyses to compare the reinforcing effectiveness of MDPV and methylone to mixtures of MDPV+caffeine and methylone+caffeine. Methods: Male Sprague-Dawley rats acquired methylone self-administration (0.32 mg/kg/inf) under a fixed ratio (FR) 1 schedule of reinforcement, and generated full dose-response curves for methylone (0.01-1 mg/kg/inf) under an FR5 schedule of reinforcement. Demand curves were then obtained for methylone, MDPV, caffeine, and methylone+caffeine and MDPV+caffeine mixtures by increasing the FR across sessions according to the following series: 3,

Interactions between reinforcement history and drug‐primed reinstatement: Studies with MDPV and mixtures of MDPV and caffeine

“…Although much is known about the pharmacology of single drug entities, relatively little is known about how interactions among psychoactive constituents of abused drug preparations impact their abuse‐related and toxic effects. Previous work suggests caffeine can synergistically enhance the discriminative stimulus 1–3 and reinforcing effects 4,5 of stimulants, such as cocaine and synthetic cathinones. Synthetic cathinones have stimulant properties and act as inhibitors (e.g., 3,4‐methylenedioxypyrovalerone [MDPV]) or substrates (e.g., 3,4‐methylenedioxy‐ N ‐methylcathinone [methylone]) at monoamine transporters.…”

“…In contrast, caffeine, an adenosine receptor antagonist, is a relatively weak reinforcer, maintaining responding at near saline‐like levels 4,13,14 . Yet, addition of caffeine to cocaine appears to enhance the reinforcing effects of cocaine, 15–17 and mixing caffeine with MDPV or methylone produces supra‐additive enhancements in reinforcing potency and effectiveness, respectively 4,5 …”

“…Unsurprising, MDPV shares discriminative stimulus effects with methamphetamine and cocaine 1,19–22 . Mixtures of MDPV and caffeine exhibit supra‐additive interactions in rats trained to discriminate cocaine from saline, 1 suggesting caffeine can enhance not only the reinforcing, 4,5 but also discriminative stimulus effects of MDPV.…”

“…Despite numerous studies describing the reinforcing and discriminative stimulus effects of MDPV, 4,5,12,19–22 little is known about relapse‐related effects of MDPV, 23,24 and nothing is known about how these effects might be altered by common bath salts constituents, such as caffeine. Although MDPV (1 mg/kg) can reinstate responding in the presence or absence of infusion‐paired stimuli, 23 other factors (e.g., priming dose and self‐administration history) that mediate the magnitude of the reinstatement response have yet to be explored.…”

Methylenedioxymethamphetamine-like discriminative stimulus effects of pyrrolidinyl cathinones in rats

“…These compounds largely act as inhibitors of monoamine transporters and, in general, are selective for the dopamine transporter (DAT) over the norepinephrine (NET) or serotonin (SERT) transporters (e.g., Eshleman et al 2017;Gannon et al, 2018a;Meltzer et al, 2006). Several of the compounds are self-administered, including αpyrrolidinopropiophenone (α-PPP; Aarde et al, 2015;Gannon et al, 2018b), 4′-methyl-α-pyrrolidinopropiophenone (4′-MePPP; Huskinson et al, 2017), α-pyrrolidinovalerophenone (α-PVP; Huskinson et al, 2017;Javadi-Paydar et al, 2018), 3,4-methylenedioxy-pyrovalerone (MDPV; Aarde et al, 2013;Gannon et al, 2017Gannon et al, , 2019Watterson et al, 2014), α-pyrrolidinopentiothiophenone (α-PVT; Cheong et al, 2017), and α-pyrrolidinohexiophenone (α-PHP; Javadi-Paydar et al, 2018). MDPV (Atehortua-Martinez et al, 2019;Karlsson et al, 2014;King et al, 2015) and α-PVT (Cheong et al, 2017) produced a conditioned place preference, and MDPV increased intracranial self-stimulation (ICSS; Bonano et al, 2014;Geste et al, 2018;Watterson et al, 2014).…”