Abstract
Methamphetamine affects the hippocampus, a brain region crucial for learning and memory, as well as relapse to drug seeking. Rats self-administered methamphetamine for 1 h twice weekly (intermittent-short-I-ShA), 1 h daily (limited-short-ShA), or 6 h daily (extended-long-LgA) for 22 sessions. After 22 sessions, rats from each access group were withdrawn from self-administration and underwent spatial memory (Y-maze) and working memory (T-maze) tests followed by extinction and reinstatement to methamphetamine seeking or received one intraperitoneal injection of 5-bromo-2′-deoxyuridine (BrdU) to label progenitors in the hippocampal subgranular zone (SGZ) during the synthesis phase. Two-hour-old and 28-day-old surviving BrdU-immunoreactive cells were quantified. I-ShA rats performed better on the Y-maze and had a greater number of 2-h-old SGZ BrdU cells than nondrug controls. LgA rats, but not ShA rats, performed worse on the Y- and T-maze and had a fewer number of 2-h-old SGZ BrdU cells than nondrug and I-ShA rats, suggesting that new hippocampal progenitors, decreased by methamphetamine, were correlated with impairment in the acquisition of new spatial cues. Analyses of addiction-related behaviors after withdrawal and extinction training revealed methamphetamine-primed reinstatement of methamphetamine-seeking behavior in all three groups (I-ShA, ShA, and LgA), and this effect was enhanced in LgA rats compared with I-ShA and ShA rats. Protracted withdrawal from self-administration enhanced the survival of SGZ BrdU cells, and methamphetamine seeking during protracted withdrawal enhanced Fos expression in the dentate gyrus and medial prefrontal cortex in LgA rats to a greater extent than in ShA and I-ShA rats. These results indicate that changes in the levels of the proliferation and survival of hippocampal neural progenitors and neuronal activation of hippocampal granule cells predict the effects of methamphetamine self-administration (limited vs extended access) on cognitive performance and relapse to drug seeking and may contribute to the impairments that perpetuate the addiction cycle.
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Acknowledgements
The study was supported by funds from the National Institute on Drug Abuse (DA022473 to CDM, DA010072 to GFK, and summer research fellowship to AHS), Pearson Center for Alcoholism and Addiction Research to GFK, NIH/Eunice Kennedy Shriver National Institute of Child Health & Human Development (T35HD064385 to PR), and Skaggs School of Pharmacy and Pharmaceutical Sciences (Skaggs Scholarship to CJY). We acknowledge the excellent technical assistance of Roxanne Kotzebue and Cameron Muhlfeld from the independent study program at the University of California, San Diego, and the San Diego State University, respectively, and Siddharth Iyengar and Wednesday Bushong from the Life Sciences Summer Internship Program at The Scripps Research Institute for assistance with immunohistochemistry and the cognitive behavior study. We appreciate the technical support of Elena Crawford and Robert Lintz and the editorial assistance of Michael Arends. The authors report no biomedical financial interests or potential conflict of interest. The publication number 21357 is from The Scripps Research Institute.
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Recinto, P., Samant, A., Chavez, G. et al. Levels of Neural Progenitors in the Hippocampus Predict Memory Impairment and Relapse to Drug Seeking as a Function of Excessive Methamphetamine Self-Administration. Neuropsychopharmacol 37, 1275–1287 (2012). https://doi.org/10.1038/npp.2011.315
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