Relative reinforcing effects of second-generation synthetic cathinones: Acquisition of self-administration and fixed ratio dose-response curves in rats

Abstract

"Bath salts" preparations contain synthetic cathinones which interact with monoamine transporters and function as either monoamine uptake inhibitors or releasers. 3,4-Methylenedioxypyrovalerone (MDPV), 3,4-methylenedioxymethcathinone (methylone), and 4-methylmethcathinone (mephedrone) were three of the most common cathinones (i.e., "first-generation" cathinones); however, after the US Drug Enforcement Administration placed them under Schedule I regulations, they were replaced with structurally related cathinones that were not subject to regulations (i.e., "second-generation" cathinones). Although the reinforcing effects of some second-generation cathinones have been described (e.g., α-pyrrolidinopentiophenone [α-PVP]), little is known about how structural modifications, particularly those involving the methylenedioxy moiety and α-alkyl side chain, impact the abuse liability of other second-generation cathinones (e.g., α-pyrrolidinopropiophenone [α-PPP], 3,4-methylenedioxy-α-pyrrolidinobutiophenone [MDPBP], and 3,4-methylenedioxy-α-pyrrolidinopropiophenone [MDPPP]). The present study used male Sprague-Dawley rats (n = 12 per drug) to directly compare: (1) the acquisition of responding for α-PVP (0.032 mg/kg/inf), α-PPP (0.32 mg/kg/inf), MDPBP (0.1 mg/kg/inf), and MDPPP (0.32 mg/kg/inf) under a fixed ratio (FR) 1 schedule of reinforcement; and (2) full dose-response curves for each drug to maintain responding under an FR5 schedule of reinforcement. The average number of days (∼4 days) and percentage (100%) of rats that acquired self-administration was similar for each drug. The observed rank order potency to maintain responding under an FR5 schedule of reinforcement (α-PVP ≈ MDPBP>α-PPP > MDPPP) is consistent with their potencies to inhibit dopamine uptake. These are the first studies to report on the reinforcing effects of the unregulated second-generation cathinones MDPBP, MDPPP, and α-PPP and indicate all three compounds are readily self-administered, suggesting each possesses high potential for abuse. This article is part of the Special Issue entitled 'Designer Drugs and Legal Highs.'

Binge-like acquisition of α-pyrrolidinopentiophenone (α-PVP) self-administration in female rats

“…This study confirms that α-PVP is a highly effective reinforcer in female rats, just as has been previously shown in male rats (Aarde et al 2015a; Gannon et al 2017a). The potency and efficacy of α-PVP and the related drug MDPV (Figure 8) were similar in intravenous self-administration (IVSA) in female rats, just as in male rats (Aarde et al, 2015a).…”

“…These compounds are highly effective and potent (e.g. in comparison with methamphetamine or methylone) reinforcers in male rats when assessed with the intravenous self-administration (IVSA) model (Aarde et al 2013; Schindler et al 2016; Watterson et al 2014), and MDPV and α-PVP have been shown to be approximately equipotent when directly compared under a Progressive Ratio schedule of reinforcement in IVSA (Aarde et al 2015a; Gannon et al 2017a). A binge-like acquisition pattern of MDPV IVSA has been previously reported for male rats (Aarde et al 2015b) in a study which also contrasted the effect of concurrent access to an activity wheel.…”

The abuse-related effects of pyrrolidine-containing cathinones are related to their potency and selectivity to inhibit the dopamine transporter

“…[2][3][4][5][6][7]), a growing number of synthetic cathinones have been reported to increase locomotor activity, produce cocaine-, methamphetamine-, or 3,4-methylenedioxymethamphetaminelike discriminative stimulus effects, and maintain intravenous self-administration (e.g., refs. [10][11][12][13][14][15][16][17][18][19]). For instance, we have recently shown that rats will acquire self-administration of the pyrrolidine-containing cathinones MDPV, MDPBP, MDPPP, α-PVP, and α-PPP at rates comparable to those observed with cocaine and that the potencies of these drugs to maintain responding under a fixed ratio (FR) 5 schedule of reinforcement are highly correlated with their potencies to inhibit uptake at DAT and NET but not SERT [13,16].…”

Binge-like Acquisition of α-pyrrolidinopentiophenone (α-PVP) Self-Administration in Female Rats

“…These compounds are highly effective and potent (e.g. in comparison with methamphetamine or methylone) reinforcers in male rats when assessed with the intravenous self-administration (IVSA) model Schindler et al 2016;Watterson et al 2014), and MDPV and α-PVP have been shown to be approximately equipotent when directly compared under a Progressive Ratio schedule of reinforcement in IVSA (Aarde et al 2015a; Gannon et al 2017a). A binge-like acquisition pattern of MDPV IVSA has been previously reported for male rats (Aarde et al 2015b) in a study which also contrasted the effect of concurrent access to an activity wheel.…”