Potent rewarding and reinforcing effects of the synthetic cathinone 3,4-methylenedioxypyrovalerone (MDPV)

Abstract

Reports of abuse and toxic effects of synthetic cathinones, frequently sold as 'bath salts' or 'legal highs', have increased dramatically in recent years. One of the most widely used synthetic cathinones is 3,4-methylenedioxypyrovalerone (MDPV). The current study evaluated the abuse potential of MDPV by assessing its ability to support intravenous self-administration and to lower thresholds for intracranial self-stimulation (ICSS) in rats. In the first experiment, the rats were trained to intravenously self-administer MDPV in daily 2-hour sessions for 10 days at doses of 0.05, 0.1 or 0.2 mg/kg per infusion. The rats were then allowed to self-administer MDPV under a progressive ratio (PR) schedule of reinforcement. Next, the rats self-administered MDPV for an additional 10 days under short access (ShA; 2 hours/day) or long access (LgA; 6 hours/day) conditions to assess escalation of intake. A separate group of rats underwent the same procedures, with the exception of self-administering methamphetamine (0.05 mg/kg per infusion) instead of MDPV. In the second experiment, the effects of MDPV on ICSS thresholds following acute administration (0.1, 0.5, 1 and 2 mg/kg, i.p.) were assessed. MDPV maintained self-administration across all doses tested. A positive relationship between MDPV dose and breakpoints for reinforcement under PR conditions was observed. LgA conditions led to escalation of drug intake at 0.1 and 0.2 mg/kg doses, and rats self-administering methamphetamine showed similar patterns of escalation. Finally, MDPV significantly lowered ICSS thresholds at all doses tested. Together, these findings indicate that MDPV has reinforcing properties and activates brain reward circuitry, suggesting a potential for abuse and addiction in humans.

Keywords: 3; 4-methylenedioxypyrovalerone; abuse liability; bath salt; extended access; intracranial self-stimulation; intravenous self-administration; synthetic cathinone.

Figure 1

Intravenous self-administration of MPDV. Data presented are active and inactive lever presses across the first ten days of IVSA procedures for the (a) 0.05, (b) 0.1, and (c) 0.2 mg/kg/infusion groups (n = 9 for each group). * indicates p <0.05 between active and inactive lever presses. (d) Total number of infusions during 2 hr daily access sessions across the first ten days of IVSA and for each dose of MDPV tested.

Figure 2

Total number of infusions earned during PR responding for the 0.05, 0.1, and 0.2 mg/kg/infusion doses of MDPV (n = 9 for each group) as well as a separate group of rats self-administering methamphetamine at a dose of 0.05 mg/kg/infusion (n=9). The total number of infusions earned during the PR session is plotted along the left y-axis. As a reference, the total number of active lever presses completed during the test is plotted along the right y-axis. * indicates p<0.05 vs. the 0.05 mg/kg dose of MDPV. # indicates p <0.05 vs. the 0.1 mg/kg dose of MDPV.

Figure 3

Total number of infusions obtained during ShA, LgA, and the first 2 hr of LgA sessions across the final ten days of IVSA procedures for the (a) 0.05, (b) 0.1, and (c) 0.2 mg/kg/infusion MDPV groups (n = 5 for each LgA group), as well as rats self-administering methamphetamine at a dose of 0.05 mg/kg/infusion (d, n=9). * indicates p < 0.05 for sessions in which the number of total infusions obtained during LgA was significantly greater than total infusions obtained during ShA. # indicates p<0.05 for total number of infusions obtained during LgA sessions vs. Day 1 of LgA. + indicates p<0.05 for total number of infusions obtained during the first 2 hr of LgA sessions vs. Day 1 of LgA (first 2 hr).

Figure 4

Effects of vehicle and MDPV (0.1, 0.5, 1 and 2 mg/kg i.p.) on thresholds for ICSS (n = 5). * indicates p < 0.05 vs. vehicle.