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Chronic wheel running reduces maladaptive patterns of methamphetamine intake: regulation by attenuation of methamphetamine-induced neuronal nitric oxide synthase

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Abstract

We investigated whether prior exposure to chronic wheel running (WR) alters maladaptive patterns of excessive and escalating methamphetamine intake under extended access conditions, and intravenous methamphetamine self-administration-induced neurotoxicity. Adult rats were given access to WR or no wheel (sedentary) in their home cage for 6 weeks. A set of WR rats were injected with 5-bromo-2′-deoxyuridine (BrdU) to determine WR-induced changes in proliferation (2-h old) and survival (28-day old) of hippocampal progenitors. Another set of WR rats were withdrawn (WRw) or continued (WRc) to have access to running wheels in their home cages during self-administration days. Following self-administration [6 h/day], rats were tested on the progressive ratio (PR) schedule. Following PR, BrdU was injected to determine levels of proliferating progenitors (2-h old). WRc rats self-administered significantly less methamphetamine than sedentary rats during acquisition and escalation sessions, and demonstrated reduced motivation for methamphetamine seeking. Methamphetamine reduced daily running activity of WRc rats compared with that of pre-methamphetamine days. WRw rats self-administered significantly more methamphetamine than sedentary rats during acquisition, an effect that was not observed during escalation and PR sessions. WR-induced beneficial effects on methamphetamine self-administration were not attributable to neuroplasticity effects in the hippocampus and medial prefrontal cortex, but were attributable to WR-induced inhibition of methamphetamine-induced increases in the number of neuronal nitric oxide synthase expressing neurons and apoptosis in the nucleus accumbens shell. Our results demonstrate that WR prevents methamphetamine-induced damage to forebrain neurons to provide a beneficial effect on drug-taking behavior. Importantly, WR-induced neuroprotective effects are transient and continued WR activity is necessary to prevent compulsive methamphetamine intake.

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Acknowledgments

The study was supported by funds from the National Institute on Drug Abuse (DA022473 to CDM), and Skaggs School of Pharmacy and Pharmaceutical Sciences (Skaggs Scholarship to AJE and MBA). We acknowledge the excellent technical assistance of Cameron McKay from The Scripps Research Institute SURF program, Patrick Recinto from Skaggs School of Pharmacy and Pharmaceutical Sciences, Matthew Soleiman from the independent study program at the University of California, San Diego and Jan Kirby Zabala, Siddharth Iyengar, Wednesday Bushong from the Life Sciences Summer Internship Program at The Scripps Research Institute for assistance with immunohistochemistry. We appreciate the technical support of Dr. Sunmee Wee for intravenous surgeries, Elena Crawford for immunohistochemical analysis and Robert Lintz for operant behavior software support. The authors thank Drs. Scott Edwards, George Koob, Michael Taffe and Sunmee Wee for critical reading of the manuscript and helpful discussions. The publication number 21790 is from The Scripps Research Institute.

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The authors report no biomedical financial interests or potential conflict of interest.

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Correspondence to Chitra D. Mandyam.

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A. J. Engelmann and M. B. Aparicio equally contributed to this work.

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Engelmann, A.J., Aparicio, M.B., Kim, A. et al. Chronic wheel running reduces maladaptive patterns of methamphetamine intake: regulation by attenuation of methamphetamine-induced neuronal nitric oxide synthase. Brain Struct Funct 219, 657–672 (2014). https://doi.org/10.1007/s00429-013-0525-7

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  • DOI: https://doi.org/10.1007/s00429-013-0525-7

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