Self-administration of the synthetic cathinone MDPV enhances reward function via a nicotinic receptor dependent mechanism

Abstract

Methylenedioxypyrovalerone (MDPV) is an addictive synthetic drug with severe side effects. Previous studies have shown that MDPV has positive reinforcing properties. However, little is known about the effect of MDPV self-administration on the state of the brain reward system and the neuronal mechanisms by which MDPV mediates its effects. The goal of the present studies was to determine the effect of MDPV self-administration on reward function and the role of cholinergic neurotransmission in the reinforcing effects of MDPV. To study the effect of MDPV self-administration on the brain reward system, rats were prepared with intravenous catheters and intracranial self-stimulation electrodes (ICSS). For 10 days, the reward thresholds were assessed immediately before (23 h post prior session) and after 1 h of MDPV self-administration. The reward thresholds were decreased immediately after MDPV self-administration, which is indicative of a potentiation of brain reward function. The reward thresholds 23 h after MDPV intake gradually increased over time, which is indicative of anhedonia. Pretreatment with the nicotinic acetylcholine receptor (nAChR) antagonist mecamylamine decreased the self-administration of MDPV and completely prevented the decrease in reward thresholds. A control study with palatable chocolate pellets showed that responding for a natural reinforcer does not affect the state of the brain reward system. Furthermore, mecamylamine did not affect responding for food pellets. In conclusion, the self-administration of MDPV potentiates reward function and nAChR blockade prevents the reward enhancing effects of MDPV self-administration. Preventing the MDPV-induced increase in cholinergic neurotransmission might be a safe approach to diminish MDPV abuse.

Methylenedioxymethamphetamine-like discriminative stimulus effects of pyrrolidinyl cathinones in rats

“…Several of the compounds are self-administered, including α-pyrrolidinopropiophenone (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, 2017, 2019; Watterson 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). In studies assessing comparative self-administration of alpha-pyrrolidine cathinones with other drugs of abuse, α-PVP and MDPV are self-administered to a greater degree than cocaine (Collins et al, 2019; Schindler et al, 2016) and the commonly abused non-pyrrolidine cathinone methylone (Gannon, 2018c).…”

Paradoxical changes in brain reward status during oxycodone self-administration in a novel test of the negative reinforcement hypothesis

“…Reward threshold elevations may also depend on the rewarding efficacy of a given drug, in addition to the specific access duration. For example, self-administration of the highly efficacious reinforcer (Aarde, Huang, Creehan, Dickerson & Taffe, 2013; Collins, Sulima, Rice & France, 2019; Watterson et al, 2014) 3,4-methylenedioxypyrovalerone (MDPV) in 1 h sessions elevated reward thresholds across 10 days (Geste, Pompilus, Febo & Bruijnzeel, 2018). In a related vein, the reinforcing efficacy of a unit dose of oxycodone self-administered by rats is enhanced by THC (Nguyen et al, 2019) and we similarly found in this study that THC pretreatment reduced oxycodone intake in a 6 h IVSA session ( Figure 6A ) by attenuating, but not eliminating, the loading dose phase ( Figure 6C ).…”

Cannabidiol Modulates the Motivational and Anxiety-Like Effects of 3,4-Methylenedioxypyrovalerone (MDPV) in Mice

“…Previous studies reported that MDPV works as a reinforcer for intravenous selfadministration in rats (Aarde et al, 2015b(Aarde et al, , 2015a(Aarde et al, , 2013Gannon et al, 2017a;Geste et al, 2018;Schindler et al, 2016;Sewalia et al, 2018;. However, although Fantegrossi et al (2013) demonstrated that mice discriminate between MDPV (0.3 mg/kg i.p.)…”