Methamphetamine (mAMPH) abusers experience several long-term changes in their brains, including abnormalities in basal ganglia dopamine and cortical structure/function, as detected by neural imaging methods. Also, mAMPH abusers perform less well than controls on several measures of cognitive function, including recognition memory and executive functions. Together, these mAMPH-induced brain structural, neurochemical, and cognitive changes may predispose abusers to failure in escaping their compulsive drug use. These mAMPH-induced changes have been modeled in rodents exposed repeatedly to moderate doses of mAMPH in a "binge" pattern, producing long-lasting injury to brain monoamine pathways, diminished cortical function, and impairments in memory and executive function that are strikingly similar to impairments of human mAMPH abusers. Notably, in both humans and rodents, mAMPH-induced damage slowly recovers toward normal values. The current application examines the influence of voluntary exercise in counteracting mAMPH-induced injury and behavioral impairments in rats. Exercise induces long-term brain changes of potential therapeutic value in treatment after neural injury, and voluntary wheel running has been shown by the applicant to counteract the monoaminergic damage induced by binge mAMPH. Here we hypothesize that the angiogenesis stimulated by chronic exercise may promote a neural environment that can either diminish the initial damage cause by mAMPH treatment or accelerate regrowth and plasticity of the damaged monoamine fibers thus producing behavioral recovery. In three specific aims, this application tests a role for voluntar exercise mitigating mAMPH-induced neurochemical and behavioral deficits. First, we propose a time course experiment to determine whether exercise acts as an initial neuroprotectant or enhances recovery after mAMPH-induced neural injury. Second, we propose to determine whether mAMPH-induced cognitive deficits are long-lasting, whether they recover over time in parallel with normalization of monoaminergic markers, and whether wheel running accelerates their recovery. Third, we will examine the effects of both exercise and binge mAMPH administration on the levels of the angiogenic growth factor vascular endothelial growth factor (VEGF) and its primary angiogenic receptor as a possible signaling pathway mediating the beneficial effects of exercise on recovery from mAMPH-induced damage. In addition, we will investigate the ability of exercise in control and mAMPH-treated animals to increase striatal, cortical and hippocampal neurovascular density and whether these increases in vascularization are necessary for exercise-induced amelioration of mAMPH-induced damage and cognitive changes. We anticipate that the results of these experiments, when taken together, will provide the basis for a novel avenue of therapy for mAMPH addiction that can be rapidly translated to use in humans.

Public Health Relevance

Methamphetamine abuse, which is widespread in the U.S., is characterized by brain injury and memory problems. The goal of this proposal is to determine whether voluntary exercise could prevent or enhance recovery from the brain damage caused by repeated methamphetamine use. Voluntary exercise has several positive effects, including its ability to stimulate formation of new blood vessels, and our experiments will test the effects f exercise and the increased density of blood vessels it causes on the brain damage and cognitive impairments caused by methamphetamine.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Exploratory/Developmental Grants (R21)
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Neurobiology of Motivated Behavior Study Section (NMB)
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Pilotte, Nancy S
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University of California Irvine
Other Basic Sciences
Schools of Arts and Sciences
United States
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Alaghband, Yasaman; O'Dell, Steven J; Azarnia, Siavash et al. (2014) Retrieval-induced NMDA receptor-dependent Arc expression in two models of cocaine-cue memory. Neurobiol Learn Mem 116:79-89
Stolyarova, Alexandra; O'Dell, Steve J; Marshall, John F et al. (2014) Positive and negative feedback learning and associated dopamine and serotonin transporter binding after methamphetamine. Behav Brain Res 271:195-202
O'dell, Steven J; Marshall, John F (2014) Running wheel exercise before a binge regimen of methamphetamine does not protect against striatal dopaminergic damage. Synapse 68:419-25