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 lower thresholds for intracranial self-stimulation (ICSS) in rats. In the first experiment, rats were trained to intravenously self-administer MDPV in daily 2 hr sessions for 10 days at doses of 0.05, 0.1, or 0.2 mg/kg/infusion. Rats were then allowed to self-administer MDPV under a progressive ratio (PR) schedule of reinforcement. Next, rats self-administered MDPV for an additional 10 days under short (2 hr/day, ShA) or long (6 hr/day, LgA) access conditions to assess escalation of intake. Aseparate group of rats underwent the same procedures with the exception of self-administering methamphetamine (0.05 mg/kg/infusion) instead of MDPV. In a 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 the 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.

Methylone is a member of the designer drug class known as synthetic cathinones which have become increasingly popular drugs of abuse in recent years. Commonly referred to as “bath salts”, these amphetamine-like compounds are sold as “legal” alternatives to illicit drugs such as cocaine, methamphetamine, and 3,4-methylenedioxymethamphetamine (MDMA, ecstasy). Following their dramatic rise in popularity along with numerous reports of toxicity and death, several of these drugs were classified as Schedule I drugs in the United States in 2012. Despite these bans, these drugs and other new structurally similar analogues continue to be abused. Currently, however, it is unknown whether these compounds possess the potential for compulsive use and addiction. The present study sought to determine the relative abuse liability of methylone by employing intravenous self-administration (IVSA) and intracranial self-stimulation (ICSS) paradigms in rats. We demonstrate that methylone (0.05, 0.1, 0.2, and 0.5 mg/kg/infusion) dose-dependently functions as a reinforcer, and that there is a significant positive relationship between methylone dose and reinforcer efficacy. Furthermore, responding during short access sessions (ShA, 2 hr/day) appeared more robust than previous IVSA studies with MDMA. However, unlike previous findings with abused stimulants such as cocaine or methamphetamine, long access sessions (LgA, 6 hr/day) did not lead to escalated drug intake or increased reinforcer efficacy. Finally, methylone produced a dose-dependent, but statistically non-significant, trend towards reductions in ICSS thresholds. Together these results reveal that methylone may possess an addiction potential similar to or greater than MDMA, yet patterns of self-administration and effects on brain reward function suggest that this drug may have a lower potential for abuse and compulsive use than prototypical psychostimulants.

Synthetic cathinones, frequently referred to as "bath salts", have significant abuse potential, and recent evidence suggests that these novel psychoactive substances can also produce cognitive deficits as well as cytotoxic effects. However, most of these latter findings have been obtained either using high concentrations in vitro or following non-contingent high dose administration in vivo. The present study utilized a model of long-term voluntary binge-like self-administration to determine potential detrimental effects of synthetic cathinones on cognitive function and their known underlying neural circuits, collectively referred to as neurocognitive dysfunction. Male Sprague-Dawley rats were allowed to self-administer the cocaine-like synthetic cathinone 3,4-methylenedioxypyrovalerone (MDPV, 0.03 mg/kg/infusion i.v.) in 96-hr sessions, or saline as a control. A total of five 96-hr sessions were conducted, each separated by 3 days of abstinence in the home cage. Three weeks following the last 96-hr session, animals underwent assessment of cognitive function using spatial object recognition (SOR) and novel object recognition (NOR) tasks, after which brains were harvested and assessed for neurodegeneration using FluoroJade C (FJC). Compared to animals self-administering saline, animals self-administering MDPV demonstrated (1) robust drug intake that escalated over time, (2) deficits in NOR but not SOR, and (3) neurodegeneration in the perirhinal and entorhinal cortices. These results indicate that repeated binge-like intake of MDPV can induce neurocognitive dysfunction. In addition, utilization of rodent models of extended binge-like intake may provide insight into potential mechanisms and/or approaches to prevent or reverse the detrimental effects of abused substances on cognitive and neurobiological functioning. This article is part of the Special Issue entitled 'Designer Drugs and Legal Highs.'

Rationale Methamphetamine (METH) is a highly potent and addictive psychostimulant with severe detrimental effects to the health of users. Currently, METH addiction is treated with a combination of cognitive and behavioral therapies, but these traditional approaches suffer from high relapse rates. Furthermore, there are currently no pharmacological treatment interventions approved by the FDA specifically for the treatment of METH addiction. Objectives Metabotropic glutamate receptor 5 (mGluR5) negative allosteric modulators (NAMs) have shown promise in significantly attenuating drug self-administration and drug-seeking in reinstatement paradigms. However, studies assessing the potential efficacy of mGluR5 NAMs that have been tested in human subjects are lacking. The current study sought to assess the effect of the mGluR5 NAM fenobam on METH-seeking behavior. Methods Rats were trained to self-administer METH (0.05 mg/kg i.v.), and following extinction, tested for effects of fenobam (5, 10 or 15 mg/kg i.p.) on cue- and drug-induced reinstatement of METH-seeking. To determine if fenobam also alters reinstatement of seeking of natural reinforcers, separate groups of rats were trained to self-administer sucrose or food pellets and were tested for the effects of fenobam on cue-induced reinstatement of sucrose- and food-seeking. Results Fenobam attenuated drug- and cue-induced reinstatement of METH-seeking behavior at doses of 10 and 15 mg/kg. Fenobam also attenuated cue-induced reinstatement of sucrose- and food-seeking at all doses tested. Conclusions The mGluR5 NAM fenobam attenuates the reinstatement of METH-seeking behavior, but these effects may be due to non-specific suppression of general appetitive behaviors.