Although psychostimulant drug abuse poses several potential health risks, the chronic abuse of amphetamines carries the danger of permanent brain injury. In animals, repeated administration of methamphetamine during the course of a single day produces long lasting damage to striatal dopamine and forebrain serotonin terminals. In addition, this drug produces a degeneration of pyramidal and stellate cells in the rat somatosensory cortex. Moreover, the degeneration of somatosensory cortical neurons appears to represent only the most visible form of methamphetamine's long term deleterious effects on cerebral cortex. Recent findings indicate that exposure to methamphetamine in animals reduces the immediate early gene responses of neurons in widespread cortical areas to dopaminergic agents, even long after the methamphetamine exposure. These findings agree with results from human methamphetamine abusers, indicating long lasting functional abnormalities in the cerebral cortex of abstinent addicts. The mechanisms underlying the long term suppression of cortical cell response are of particular interest because prior research concerning long term effects of methamphetamine has focused almost exclusively on mechanisms of injury to dopamine and serotonin terminals. The hypothesis underlying this application is that the long term reductions in cortical immediate early gene response of animals given methamphetamine relate to diminished basal ganglia gating of cortical function.
Four specific aims are proposed to test this hypothesis: (i) to test the role of dopamine D1 and D2 receptors in the methamphetamine induced reductions in basal ganglia gating of cortical function;(ii) to establish the role of the striatum in the actions of dopamine in gating of cortical function;(iii) to determine whether methamphetamine affects the density or function of G proteins that couple dopamine with specific second messengers;and (iv) to investigate the effects of methamphetamine on signal transduction pathways leading to reduced cortical function. In aggregate, these experiments should provide a body of novel evidence concerning how methamphetamine addiction can alter cortical functions.

Public Health Relevance

Approximately 12 million Americans age 12 and older have tried methamphetamine. Methamphetamine abusers often show memory and other cognitive problems. Using rats, we are studying how the brain damage caused by methamphetamine abuse occurs and might cause memory problems. Our goal is to discover information useful in preventing or repairing this cognitive decline.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
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Neurobiology of Motivated Behavior Study Section (NMB)
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Frankenheim, Jerry
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University of California Irvine
Other Basic Sciences
Schools of Arts and Sciences
United States
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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
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
Kosheleff, Alisa R; Grimes, Millie; O'Dell, Steve J et al. (2012) Work aversion and associated changes in dopamine and serotonin transporter after methamphetamine exposure in rats. Psychopharmacology (Berl) 219:411-20
O'Dell, Steven J; Galvez, Bryan A; Ball, Alexander J et al. (2012) Running wheel exercise ameliorates methamphetamine-induced damage to dopamine and serotonin terminals. Synapse 66:71-80
Gross, N B; Duncker, P C; Marshall, J F (2011) Cortical ionotropic glutamate receptor antagonism protects against methamphetamine-induced striatal neurotoxicity. Neuroscience 199:272-83
Gross, Noah B; Duncker, Patrick C; Marshall, John F (2011) Striatal dopamine D1 and D2 receptors: widespread influences on methamphetamine-induced dopamine and serotonin neurotoxicity. Synapse 65:1144-55
O'Dell, Steven J; Feinberg, Leila M; Marshall, John F (2011) A neurotoxic regimen of methamphetamine impairs novelty recognition as measured by a social odor-based task. Behav Brain Res 216:396-401
Izquierdo, Alicia; Belcher, Annabelle M; Scott, Lori et al. (2010) Reversal-specific learning impairments after a binge regimen of methamphetamine in rats: possible involvement of striatal dopamine. Neuropsychopharmacology 35:505-14
Boikess, Steven R; O'Dell, Steven J; Marshall, John F (2010) A sensitizing D-amphetamine dose regimen induces long-lasting spinophilin and VGLUT1 protein upregulation in the rat diencephalon. Neurosci Lett 469:49-54

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