Neurocognitive Deficits Associated with Methamphetamine, Cocaine, and MDPV Self‐administration in Rats

Abstract

Over 18 million people in the United States alone are classified as having an untreated substance use disorder. Given the chronicity associated with a substance use disorder, it is crucial to gain a better understanding of the toxicity associated with prolonged use in an effort to prevent or reverse deficits in afflicted individuals. In the context of stimulant abuse, monoamine releasers (e.g., methamphetamine) rather than monoamine uptake inhibitors (e.g., cocaine) are typically associated with neurodegeneration and neuroinflammation that have been linked to deficits in memory, psychosis, and loss of impulse control. Interestingly, recent data suggest that the synthetic cathinone MDPV (a monoamine uptake inhibitor) is able to induce neurotoxicity but the neurocognitive consequences of MDPV self‐administration remain largely unexplored. The current study aims to investigate the degree to which self‐administered MDPV can induce deficits in recognition memory compared to more classical stimulants (e.g., methamphetamine and cocaine). Following catheter implantation, male Sprague‐Dawley rats were allowed to respond on a lever for grain pellets in 90‐min sessions for 14 days. Sessions were then extended to 12‐h wherein rats could respond for grain pellets on one lever and an infusion of either 0.032 mg/kg MDPV, 0.1 mg/kg methamphetamine, 0.32 mg/kg cocaine, or saline on the other lever (n=7–8/group). Self‐administration sessions were conducted five days per week to allow for other behaviors to be evaluated in a drug‐free state. The novel object recognition assay was utilized to evaluate hippocampal‐dependent recognition memory prior to the first self‐administration session and reevaluated after thirty self‐administration sessions. To evaluate recognition memory, rats were habituated in the testing arena for 30‐min. 24‐h later, two identical objects were placed in the arena and rats could explore the objects for 5‐min (training). One hour after training, the previously explored object along with a new object were placed in the arena and rats were allowed to explore the objects for 3‐min (testing). Object exploration was defined as the rat’s head being within 2 cm of the object without biting it. MDPV, methamphetamine, cocaine, and grain pellets (in the saline group) all maintained robust levels of self‐administration. Rats that had self‐administered MDPV or methamphetamine exhibited deficits in recognition memory relative to rats given access to saline. No deficits were observed in animals that had previously self‐administered cocaine. The total exploration time of objects remained comparable among all groups. These data suggest that despite being a monoamine uptake inhibitor, MDPV is able to induce deficits in memory that are likely caused by neuroinflammation and/or neurotoxicity. Future studies will evaluate markers of neurodegeneration and neuroinflammation in these animals and explore pharmacological avenues to mitigate stimulant‐induced neurocognitive deficits.Support or Funding InformationSupported by NIH grant R01DA039146 and the NIH IRPs of NIDA and NIAAA.