ABSTRACT
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.