This application seeks renewal of research support for five years to study the sites and mechanisms of action of psychomotor stimulant drugs, including amphetamine and cocaine. Experiments are proposed to determine the mechanisms underlying alterations in catecholaminergic and non-catecholaminergic neuronal terminal excitability, including an analysis of the influence of cocaine on catecholaminergic terminal excitability and whether changes in terminal excitability of dopaminergic neurons in the rat brain occur in the chronically implanted, behaving animal. An attempt will be made to collect converging evidence regarding the identity and postsynaptic target of dopaminergic synapses made in neostriatum and to assess the relation of dopaminergic synapses made in neostriatum to its compartmentalization into the dopaminergic islandic or striosomal and matrix compartments. Further experiments are proposed to assess the consequences of amphetamine administration on neuronal activity in neostriatal targets such as pars reticulata of substantia nigra and globus pallidus. Finally, we will continue to assess the anatomical and pathological consequences of amphetamine and cocaine administration on the rat brain using tyrosine hydroxylase immunocytochemistry, the Fink-Heimer method for identifying degeneration in caudate nucleus and cerebral cortex, and biochemical analysis of potential monoamine depletions from these sites.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Method to Extend Research in Time (MERIT) Award (R37)
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Drug Abuse Biomedical Research Review Committee (DABR)
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University of California San Diego
Schools of Medicine
La Jolla
United States
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Kuczenski, Ronald; Everall, Ian P; Crews, Leslie et al. (2007) Escalating dose-multiple binge methamphetamine exposure results in degeneration of the neocortex and limbic system in the rat. Exp Neurol 207:42-51
Clark, Robert E; Kuczenski, Ronald; Segal, David S (2007) Escalating dose, multiple binge methamphetamine regimen does not impair recognition memory in rats. Synapse 61:515-22
Shilling, Paul D; Kuczenski, Ronald; Segal, David S et al. (2006) Differential regulation of immediate-early gene expression in the prefrontal cortex of rats with a high vs low behavioral response to methamphetamine. Neuropsychopharmacology 31:2359-67
O'Neil, Meghan L; Kuczenski, Ronald; Segal, David S et al. (2006) Escalating dose pretreatment induces pharmacodynamic and not pharmacokinetic tolerance to a subsequent high-dose methamphetamine binge. Synapse 60:465-73
Segal, David S; Kuczenski, Ronald (2006) Human methamphetamine pharmacokinetics simulated in the rat: single daily intravenous administration reveals elements of sensitization and tolerance. Neuropsychopharmacology 31:941-55
Segal, David S; Kuczenski, Ronald; O'Neil, Meghan L et al. (2005) Prolonged exposure of rats to intravenous methamphetamine: behavioral and neurochemical characterization. Psychopharmacology (Berl) 180:501-12
Kuczenski, Ronald; Segal, David S (2005) Stimulant actions in rodents: implications for attention-deficit/hyperactivity disorder treatment and potential substance abuse. Biol Psychiatry 57:1391-6
Segal, David S; Kuczenski, Ronald; O'Neil, Meghan L et al. (2003) Escalating dose methamphetamine pretreatment alters the behavioral and neurochemical profiles associated with exposure to a high-dose methamphetamine binge. Neuropsychopharmacology 28:1730-40
Capani, F; Deerinck, T J; Ellisman, M H et al. (2001) Phalloidin-eosin followed by photo-oxidation: a novel method for localizing F-actin at the light and electron microscopic levels. J Histochem Cytochem 49:1351-61
Capani, F; Ellisman, M H; Martone, M E (2001) Filamentous actin is concentrated in specific subpopulations of neuronal and glial structures in rat central nervous system. Brain Res 923:1-11

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