Behavioral and Neurochemical Effects of Extended Access to Stimulant Self-Administration in Rats

Abstract

<b>Abstract ID 15027</b> <b>Poster Board 5</b> Approximately 20 million people in the United States are classified as having a substance use disorder. Given the chronicity of this disorder, it is crucial to gain a better understanding of the toxicity associated with prolonged drug use. Regarding stimulants, monoamine releasers (e.g., methamphetamine) rather than monoamine reuptake inhibitors (e.g., cocaine) are typically associated with neuroinflammatory and neurodegenerative effects that are thought to underlie cognitive dysfunction. Interestingly, recent data suggest that MDPV (a synthetic cathinone that functions as a monoamine reuptake inhibitor), has neurotoxic effects; however, the cognitive and neurochemical consequences of MDPV self-administration remain largely unexplored. Furthermore, despite the fact that drug preparations that contain MDPV often also contain caffeine, little is known regarding the toxic effects produced by of co-use of these two stimulants. The current study aims to investigate the degree to which self-administered MDPV and a mixture of MDPV+caffeine can produce deficits in recognition memory relative to methamphetamine and cocaine. Male Sprague-Dawley rats (n=8/group) were allowed 90-min or 12-h access to grain pellets on one lever and infusions of either MDPV (0.032 mg/kg/inf), MDPV+caffeine (0.032 mg/kg/inf + 0.11mg/kg/inf, respectively), methamphetamine (0.1 mg/kg/inf), cocaine (0.32 mg/kg/inf), or saline on the other lever for 5 days per week, for 6 weeks. Novel object recognition was evaluated prior to any drug self-administration history, 3 and 6 weeks after rats had begun self-administering, and once more following a 3-week drug-free period. Rats that had 12-h access to MDPV, MDPV+caffeine, 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 that self-administered cocaine in 12-h sessions. Rats provided 90-min access to a mixture of MDPV+caffeine also exhibited deficits in recognition memory, whereas 90-min access to other reinforcers did not result in recognition memory deficits. Degrees of monoamine depletion largely coincided with recognition memory deficits. These data suggest that unlike cocaine, the prototypical monoamine reuptake inhibitor, MDPV is capable of producing memory deficits often associated with neuroinflammation and/or neurodegeneration. These data also demonstrate that mixtures of MDPV+caffeine produce deficits in recognition memory following both 90-min and 12-h access, suggesting that caffeine might be enhancing toxicity produced by MDPV. Future studies will evaluate markers of neuroinflammation in these rats and explore pharmacological avenues to mitigate stimulant-induced cognitive deficits. Supported by NIH/NIDA [(R01DA039146; GTC), (P20GM121307, R01NS120676; KSM)], and the IRPs of NIDA and NIAAA (KCR).