title: Chronic wheel running reduces maladaptive patterns of methamphetamine intake: regulation by attenuation of methamphetamine-induced neuronal nitric oxide synthase.
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 Another set of WR rats were withdrawn (WRw) or continued (WRc) to have access to running wheels in their home cages during self-administration days.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.
authors: Skaggs School of Pharmaceutical Sciences, University of California San Diego, La Jolla, CA, USA.
authors: Alexander J
authors: AJ
authors: Engelmann
authors: Mark B
authors: MB
authors: Aparicio
authors: Airee
authors: A
authors: Kim
authors: Jeffery C
authors: JC
authors: Sobieraj
authors: Clara J
authors: CJ
authors: Yuan
authors: Yanabel
authors: Y
authors: Grant
authors: Chitra D
authors: CD
authors: Mandyam
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001973:Bromodeoxyuridine / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D000697:Central Nervous System Stimulants / Q000633:toxicity*; D004195:Disease Models, Animal; D006624:Hippocampus / Q000473:pathology*; D019394:Ki-67 Antigen / Q000378:metabolism; D008297:Male; D008694:Methamphetamine / Q000633:toxicity*; D058953:Neural Stem Cells / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000201:enzymology*; D020258:Neurotoxicity Syndromes / Q000209:etiology*; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D016761:Oncogene Proteins v-fos / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012201:Reward; D012420:Running / Q000502:physiology; D012646:Self Administration; D013997:Time Factors
chemical_list: D000697:Central Nervous System Stimulants; D019394:Ki-67 Antigen; D016761:Oncogene Proteins v-fos; D008694:Methamphetamine; D019001:Nitric Oxide Synthase; D053148:Caspase 3; D001973:Bromodeoxyuridine