Reinforcing Effects of the Synthetic Cathinone α-Pyrrolidinopropiophenone (α-PPP) in a Repeated Extended Access Binge Paradigm

Abstract

Synthetic cathinones are designer psychostimulants that are derivatives of the natural alkaloid cathinone, and produce effects similar to more traditional illicit stimulants such as cocaine and methamphetamine. The pyrovalerone cathinones methylenedioxypyrovalerone (MDPV) and α-pyrrolidinopropiophenone (α-PPP) exert their effects via inhibition of presynaptic dopamine and norepinephrine reuptake transporters. While the reinforcing effects of MDPV in rodents are well-established, very few studies have examined self-administration patterns of α-PPP. Users of synthetic cathinones often engage in repeated binge episodes of drug intake that last several days. We therefore sought to determine the reinforcing effects of three doses of α-PPP (0.05, 0.1 and 0.32 mg/kg/infusion) under conditions of prolonged binge-like access conditions, with three 96-h periods of drug access interspersed with 72 h of abstinence. MDPV (0.05 mg/kg/infusion) was used as a comparison drug. Our results show that both MDPV and the high (0.32 mg/kg/infusion) dose of α-PPP are readily self-administered at high levels across all three extended access periods, whereas lower doses of α-PPP produce variable and less robust levels of self-administration. These results indicate that higher doses of α-PPP have reinforcing effects under conditions of extended access, suggesting the potential for abuse and a need for consideration in drug control policies.

Effects of repeated binge intake of the pyrovalerone cathinone derivative 3,4-methylenedioxypyrovalerone on prefrontal cytokine levels in rats – a preliminary study

“…We observed robust intravenous self-administration of MDPV in each of the three 96 h binge-like intake periods in both males and females, similar to our previous findings using this paradigm (Sewalia et al, 2018;Nagy et al, 2020), as well findings from various laboratories under more limited access conditions (i.e., 1-6 h/day) (Aarde et al, 2013;Watterson et al, 2014;Aarde et al, 2015;Gannon et al, 2017;Doyle et al, 2021;Abbott et al, 2022). As expected, saline self-administration was minimal across all sessions.…”

“…Rats were allowed to spontaneously acquire self-administration of MDPV or saline in 96 h sessions. A dose of 0.05 mg/kg/infusion for MDPV was selected based on our prior studies where we have observed reliable self-administration in rats under both daily limited access and 96 h binge-like access conditions (Watterson et al, 2014;Sewalia et al, 2018;Nagy et al, 2020). After the first 96 h session, animals were returned to the home cage for 72 h of abstinence, and this procedure was repeated twice, so that each animal underwent a total of three 96 h self-administration sessions, each separated by 72 h of abstinence in the home cage.…”

Distinguishing the behavioral potencies of α-pyrrolidino-phenone cathinone stimulants

“…The copyright holder for this preprint this version posted December 15, 2020. ; https://doi.org/10.1101/2020.12.14.422779 doi: bioRxiv preprint Nagy et al, 2020) as well as in assays of dopamine transporter inhibition (Gannon et al, 2018;Kolanos et al, 2015). Nevertheless, α-PPP is clearly an effective stimulant since it reduced wheel running and increased spontaneous locomotor behavior in female rats.…”

“…Although similar potency at the DAT suggests a similar profile of acute effects of α-PHP and α-PVP, a limited study from this lab has shown that α-PHP is slightly more effective than α-PVP as a reinforcer in a self-administration (Javadi-Paydar et al, 2018b). In recent studies, rats selfadministered similar numbers of infusions of α-PPP (0.1-0.32 mg/kg/infusion) and MDPV (0.05 mg/kg/infusion) in a 96 hour binge IVSA paradigm (Nagy et al, 2020), and α-PPP generated a rightshifted dose-response curve compared with MDPV or α-PVP in a 2 hr IVSA paradigm (Gannon et al, 2018). In both cases this suggests a lower potency of α-PPP relative to α-PVP, in vivo, as it is in vitro (Gannon et al, 2018;Kolanos et al, 2015).…”

Early Life Stress Promotes Heroin Seeking But Does Not Alter the Excitability of Insular Pyramidal Cells Targeting the Nucleus Accumbens

“…All self-administration procedures were conducted in Med Associates operant conditioning chambers as described elsewhere ( Nagy et al, 2020 ). Animals were allowed to self-administer heroin (0.06 mg/kg/inf) via nosepoke on an FR1 reinforcement schedule in 3 hr daily sessions.…”