Reinforcing and neurochemical effects of the “bath salts” constituents 3,4-methylenedioxypyrovalerone (MDPV) and 3,4-methylenedioxy-N-methylcathinone (methylone) in male rats

Abstract

Rationale 3,4-Methylenedioxypyrovalerone (MDPV) and 3,4-methylenedioxy-N-methylcathinone (methylone) are synthetic drugs found in so-called “bath salts” products. Both drugs exert their effects by interacting with monoamine transporter proteins. MDPV is a potent uptake blocker at transporters for dopamine and norepinephrine while methylone is a non-selective releaser at transporters for dopamine, norepinephrine and serotonin (5-HT). Objectives We hypothesized that prominent 5-HT-releasing actions of methylone would render this drug less reinforcing than MDPV. Methods To test this hypothesis, we compared behavioral effects of MDPV and methylone using intravenous (i.v.) self-administration on a fixed-ratio 1 schedule in male rats. Additionally, neurochemical effects of the drugs were examined using in vivo microdialysis in nucleus accumbens, in a separate cohort of rats. Results MDPV self-administration (0.03 mg/kg/inj) was acquired rapidly, and reached 40 infusions per session, similar to the effects of cocaine (0.5 mg/kg/inj), by the end of training. By contrast, methylone self-administration (0.3 & 0.5 mg/kg/inj) was acquired slowly, and response rates only reached 20 infusions per session by the end of training. In dose substitution studies, MDPV and cocaine displayed typical inverted U-shaped dose-effect functions, but methylone did not. In vivo microdialysis revealed that i.v. MDPV (0.1 and 0.3 mg/kg) increased extracellular dopamine while i.v. methylone (1 and 3 mg/kg) increased extracellular dopamine and 5-HT. Conclusions Our findings support the hypothesis that elevations in extracellular 5-HT in the brain can dampen positive reinforcing effects of cathinone-type drugs. Nevertheless, MDPV and methylone are both self-administered by rats suggesting these drugs possess significant abuse liability in humans.

Pharmacokinetic Profiles and Pharmacodynamic Effects for Methylone and Its Metabolites in Rats

“…Consistent with previous work (Baumann et al, 2012;Schindler et al, 2016), we found that methylone produced dose-related elevations in extracellular dopamine and 5-HT in rat nucleus accumbens, with larger effects on extracellular 5-HT. Importantly, the iv doses of methylone tested here in microdialysis experiments are in the range of those self-administered by rats (Schindler et al, 2016;Vandewater et al, 2015;Watterson et al, 2012). Administration of MDC increased dopamine and 5-HT as well, but weakly compared with methylone.…”

“…In vivo studies in rats demonstrate that methylone increases extracellular concentrations of dopamine and 5-HT in the brain, with greater effects on 5-HT (Baumann et al, 2012;Schindler et al, 2016). The mechanism of action for methylone resembles that of MDMA, which is not surprising considering methylone is the β-keto analog of MDMA.…”

Role of hypocretin/orexin receptor blockade on drug-taking and ultrasonic vocalizations (USVs) associated with low-effort self-administration of cathinone-derived 3,4-methylenedioxypyrovalerone (MDPV) in rats

“…Specifically, MDPV blocks cellular uptake of dopamine (DA) and norepinephrine (NE) by binding to presynaptic transporters (Baumann et al 2013). Preclinical studies find that MDPV elevates locomotor activity, primes reward threshold during intracranial self-stimulation, induces place preference, and is readily self-administered intravenously (Bonano et al 2014; Nguyen et al 2016; Schindler et al 2016; Simmons et al 2016; Watterson et al 2014). At high doses, “bizarre behaviors” can be observed in rats following acute injection of synthetic cathinone drugs including sporadic jumping while facing away from chamber wall, retropulsion and flattened body posture (Marusich et al 2014).…”

Effects of orally self-administered bath salt constituent 3,4-methylenedioxypyrovalerone (MDPV) in mice

“…Thus, it seems plausible that formation of these same phase I metabolites could also impact the reinforcing effects of MDPV, suggesting that route of administration may be an important factor to consider when evaluating the abuse liability of this compound. Intravenous self-administration of MDPV has been described in rats (e.g., Watterson et al, 2012; Aarde et al, 2013, 2015a, 2015b; Schindler et al, 2016; Gannon et al, 2017), however there is a paucity of information related to the abuse-related effects of orally administered MDPV. The aims of the current study were therefore (1) to determine whether concentrations of MDPV would elicit locomotor stimulant effects, (2) to determine whether MDPV is preferentially chosen over alternative fluids in a 2-bottle choice paradigm, (3) to use conditioned place preference (CPP) to determine whether voluntary consumption of a preferred MDPV concentration with locomotor stimulant effects would also induce appetitive stimulus effects, and (4) to determine whether any observed appetitive stimulus effects are similar to those observed following IP administration of MDPV.…”