Impact of Extended Access Methamphetamine, Cocaine, and MDPV Self‐administration on Recognition Memory in Rats

Abstract

Over 18 million people in the United States alone are classified as having an untreated substance use disorder. Given that substance use disorders are chronic by nature, with significant negative impacts on quality of life, it is crucial to gain a better understanding of the consequences of prolonged use in an effort to prevent or reverse deficits in afflicted individuals. Regarding stimulants, monoamine releasers (e.g., methamphetamine) rather than monoamine uptake inhibitors (e.g., cocaine) are associated with greater degrees of neurodegeneration and neuroinflammation, often linked to deficits in memory, psychosis, and loss of impulse control. Interestingly, recent data suggest that MDPV, a synthetic cathinone and monoamine uptake inhibitor, has neurotoxic effects; however, the neurocognitive consequences of MDPV self-administration remain largely unexplored. The current study aimed to directly compare the neurocognitive impacts (deficits in novel object recognition assay [NOR]) in rats (n=8/group) with short- (90-min) or extended- (12-h) access to MDPV (0.032 mg/kg/inf), methamphetamine (0.1 mg/kg/inf), or cocaine (0.32 mg/kg/inf) self-administration; grain pellets were also available throughout the sessions for responding on the alternate lever. Self-administration sessions were conducted five days per week to allow for other behaviors to be evaluated in a drug-free state. NOR was conducted four times, once prior to any drug self-administration history, after 3 and 6 weeks of drug self-administration, and once more following a 3-week drug-free period. To conduct NOR, 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, one of the previously explored objects along with a novel 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. Rats that had extended access to MDPV or methamphetamine exhibited time-dependent deficits in the novel object recognition assay relative to rats given access to saline. No deficits were observed in rats with extended access to cocaine. Furthermore, rats showed no deficits in recognition memory following short access to any reinforcer. The total exploration time of objects remained comparable among all groups. These data suggest that unlike cocaine, the prototypical monoamine uptake inhibitor, MDPV is capable of producing memory deficits often associated with neuroinflammation and/or neurodegeneration. Future studies will evaluate markers of neurodegeneration and neuroinflammation in these rats and explore pharmacological avenues to mitigate stimulant-induced neurocognitive deficits.