Comparing rewarding and reinforcing properties between ‘bath salt’ 3,4‐methylenedioxypyrovalerone (MDPV) and cocaine using ultrasonic vocalizations in rats

Abstract

Abuse of synthetic psychostimulants like synthetic cathinones has risen in recent years. 3,4-Methylenedioxypyrovalerone (MDPV) is one such synthetic cathinone that demonstrates a mechanism of action similar to cocaine. Compared to cocaine, MDPV is more potent at blocking dopamine and norepinephrine reuptake and is readily self-administered by rodents. The present study compared the rewarding and reinforcing properties of MDPV and cocaine using systemic injection dose-response and self-administration models. Fifty kilohertz ultrasonic vocalizations (USVs) were recorded as an index of positive affect throughout experiments. In Experiment 1, MDPV and cocaine dose-dependently elicited 50-kHz USVs upon systemic injection, but MDPV increased USVs at greater rates and with greater persistence relative to cocaine. In Experiment 2, latency to begin MDPV self-administration was shorter than latency to begin cocaine self-administration, and self-administered MDPV elicited greater and more persistent rates of 50-kHz USVs versus cocaine. MDPV-elicited 50-kHz USVs were sustained over the course of drug load-up whereas cocaine-elicited USVs waned following initial infusions. Notably, we observed a robust presence of context-elicited 50-kHz USVs from both MDPV and cocaine self-administering rats. Collectively, these data suggest that MDPV has powerfully rewarding and reinforcing effects relative to cocaine at one-tenth doses. Consistent with prior work, we additionally interpret these data in supporting that MDPV has significant abuse risk based on its potency and subjectively positive effects. Future studies will be needed to better refine therapeutic strategies targeted at reducing the rewarding effects of cathinone analogs in efforts to ultimately reduce abuse liability.

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

“…Our prior report shows that self-administered MDPV—which potently elevates extracellular DA levels in ventral striatum (Baumann et al 2013)—evokes 50-kHz USVs only during initial drug infusions (Simmons et al 2016). Here, we report a 30-min assessment of pre-lever USVs elicited by exposure to a context paired with MDPV self-administration.…”

“…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).…”

“…Additionally, we showed that suvorexant suppresses cocaine-elicited 50-kHz ultrasonic vocalizations (USVs)—a measure that may reflect a suppression of positive subjective response to cocaine—relative to vehicle pre-treatment levels. 50-kHz USVs are readily and robustly observed following cocaine self-administration as well as during exposure to a cocaine-paired context (Barker et al 2014; Maier et al 2010; Simmons et al 2016) but can also be observed from aggressed male rats (Thomas et al 1983) and following electrical footshock (Taylor et al 2017). …”

7,8-Dihydroxyflavone blocks the development of behavioral sensitization to MDPV, but not to cocaine: Differential role of the BDNF-TrkB pathway

“…Animal studies indicate that MDPV is 10-50-fold more potent as a dopamine transporter (DAT) blocker than cocaine [3,4]. Moreover, it has also been demonstrated that MDPV exerts powerful psychostimulant, rewarding and reinforcing effects related to cocaine at one tenth-doses [5], pointing to a high abuse liability and thus a presumable upward consumption of this substance in the next years, probably favored by its affordable cost. Therefore, new findings about MDPV and its relationship with addiction are of special interest.…”

Effects of ceftriaxone on conditioned nicotine reward in rats

“…In addition to nicotine addiction, the efficacy of β-lactam pharmacotherapies have been tested in models of psychostimulant addictions, including to cocaine and synthetic cathinones, which are designer stimulant drugs that behave in mechanistically and subjectively comparable manners as cocaine (Baumann et al 2013; Fischer et al 2013; Kim et al 2016; Simmons et al 2016). Our study supports an impressive body of literature that is leading to clinical study of tolerated and non-addictive antibiotic adjunct therapies for substance use disorders including nicotine addiction.…”