Synthetic cathinones are novel psychoactive substances used for their euphorigenic and psychostimulant properties, but carry a significant risk of inducing adverse psychiatric complications, systemic toxicity, and patterns of abuse and dependence. We recently demonstrated that the synthetic cathinone 3,4- methylenedioxypyrovalerone (MDPV), a potent and long-lasting monoamine reuptake inhibitor, is readily self- administered by rodents under limited access conditions. However, synthetic cathinone users frequently engage in repeated binge-like patterns of drug intake across several consecutive days, which have not yet been modeled in rodents to determine potential detrimental effects on cognition and brain function. To address this, we recently conducted preliminary studies in which rats were allowed to self-administer MDPV or saline for 96 consecutive hrs (4 days), followed by 72 hrs (3 days) of abstinence in the home cage. This procedure was repeated to allow for a total of 5 weeks of prolonged drug self-administration alternating with periods of abstinence. Next, animals underwent assessment of cognitive function using object placement and recognition tasks, followed by analysis of brain tissue for potential evidence of neurodegeneration, neuroinflammation, or oxidative stress. Animals self- administering MDPV displayed high levels of drug intake (>100 mg/kg per 96-hr session), and compared to animals self-administering saline, showed performance deficits in object recognition but not object placement. We also observed evidence of MDPV-induced neurodegeneration, neuroinflammation, and oxidative stress in the recognition memory circuit. However, additional studies are needed to further examine the dose and sex- dependency of these effects, whether they extend to measures of cognitive flexibility, and to investigate potential underlying mechanisms and approaches for mitigating these effects. The overarching hypothesis of the studies proposed in this application is that MDPV-induced neurocognitive dysfunction is highly influenced by sex, dose, and neuroinflammatory mechanisms. To test this hypothesis, we propose three independent yet inter-related aims.
In Specific Aim 1, we will examine the influence of sex and dose on MDPV-induced neurocognitive dysfunction.
In Specific Aim 2, we will examine the effects of repeated binge-like MDPV intake on cognitive flexibility. Finally, in Specific Aim 3, we will pharmacologically investigate potential mechanisms (neuroinflammation or oxidative stress) underlying MDPV-induced neurocognitive dysfunction. Together, these studies will assist in the development of therapeutic interventions to counteract the detrimental effects of synthetic cathinones on cognition and brain function.
/ PUBLIC HEALTH RELEVANCE The goals of the studies outlined in this proposal are to explore mechanisms underlying the deleterious effects of synthetic cathinones on cognition and brain function, as well as potential strategies for ameliorating or reversing these effects. These studies will provide novel information that will guide the development of therapeutic approaches for improving neurocognitive function in people who abuse this new class of synthetic drugs, which will ultimately reduce the medical, socioeconomic and legal costs of these drugs to society. The proposed studies may also provide valuable information on possible strategies to counteractive the detrimental neurocognitive effects of traditional psychostimulants such as cocaine and methamphetamine.
| Simmons, Steven J; Leyrer-Jackson, Jonna M; Oliver, Chicora F et al. (2018) DARK Classics in Chemical Neuroscience: Cathinone-Derived Psychostimulants. ACS Chem Neurosci 9:2379-2394 |
| Namba, Mark D; Tomek, Seven E; Olive, M Foster et al. (2018) The Winding Road to Relapse: Forging a New Understanding of Cue-Induced Reinstatement Models and Their Associated Neural Mechanisms. Front Behav Neurosci 12:17 |
| Sewalia, Kaveish; Watterson, Lucas R; Hryciw, Alyssa et al. (2018) Neurocognitive dysfunction following repeated binge-like self-administration of the synthetic cathinone 3,4-methylenedioxypyrovalerone (MDPV). Neuropharmacology 134:36-45 |
