Effects of synthetic cathinone 3,4‐methylenedioxypyrovalerone (MDPV) on impulsivity and vulnerability to psychostimulant abuse using delay discounting in rats

In recent years, novel synthetic drugs frequently touted as ‘legal stimulants’ or ‘research chemicals’ have been marketed online and sold in head shops. One of the larger categories, known as “bath salts,” typically contain synthetic cathinone analogues (SCs) – including 3,4‐methylenedioxypyrovalerone (MDPV) – which are presumed to possess potent psychostimulant actions similar to those of methamphetamine and cocaine. Recent studies have indicated that the psychotropic effects of MDPV are elicited by selective and potent passive reuptake inhibition at catecholamine transporters. Despite numerous reports of morbidity and mortality, coupled with sensationalized media reports detailing bizarre behavior, little is known about these drugs beyond surveillance and limited case reports. While scarce, these reports indicate that while the SCs increase synaptic dopamine and norepinephrine like traditional psychostimulants, their clinical effects may differ at higher doses. Additionally, no literature is available on the safety and efficacy of SCs following chronic administration. Scientific evidence suggests that dopamine plays an integral role in the regulation of risky behaviors, such as drug abuse, by altering levels of impulsivity. Further, impulsivity has been found to exist not only as a consequence of risky behavior, but as a cause. In this regard, the goal of these studies was two‐fold: to identify potential risk factors for SCs abuse and administration, and to investigate how SC administration may further compound and amplify these risk factors through interaction with the dopamine neurobiological system. Two sets of 12 rats were examined using different delay‐discounting tasks (DDTs) to profile drug‐naïve animals into high‐ and low‐impulsivity groups, which could inform abuse liability risk. Both assays allowed rats to choose between small (3 sec access) but immediate, or large (9 sec access) but delayed presentations of a milk solution. Additionally, in both DDTs the large choice delay was altered based on the choices rats made in previous blocks. The first DDT was used to separate animals into groups by their long choice delay recorded at a stable indifference point, while the second DDT used a mean adjusted delay procedure to increase the ability to separate animals into impulsive populations. In the first DDT, stable indifference points were obtained, allowing selection of distinct populations of high‐ and low‐impulsivity animals. Half of each population then received a saline regimen consisting of 4 total injections, one every 2 hours, while the other half received an identical regimen of 3 mg/kg MDPV. Following a 5 day wash out period , animals were re‐assessed in the DDT to determine any changes in impulsivity. No systemic effects on impulsivity were observed. Animals were then euthanized, brains were collected and sectioned, and analyzed for expression of dopamine transporter (DAT) and D2‐like receptor proteins using Western blot techniques. In the second DDT, animals will once again be separated into high‐ and low‐impulsive populations, then be trained to intravenously self‐administer MDPV. We hypothesize that trait impulsivity will be correlated with acquisition of MDPV self‐administration and reinforcing strength under a progressive ratio schedule, and that a history of MDPV self‐administration will increase impulsivity in all subjects. Support or Funding Information These studies supported by R01 DA039195, National Institute on Drug Abuse (NIDA).