The long term goal of the proposed research continues to be to generate guiding principles for interpretation of the role of telencephalic opioid peptides in brain and behavioral mechanisms. Efforts toward this understanding involve the characterization of convulsant and psychoactive drug effects on the gene expression of identified opioid peptidergic pathways in the limbic cortex and basal ganglia. The proposed experiments concern the effects of the psychostimulants, cocaine and amphetamine, on the expression of the opioid peptide, dynorphin, and the immediate early gene, fos (and related antigens), in the dorsal and ventral striatum, prefrontal cortex, and hippocampal formation of rats. Low, medium, and high dose regimens of cocaine and amphetamine are proposed that induce behavioral sensitization (increased locomotor activity and/or stereotypy) in rats over time. Rats receiving dose regimens that induce sensitization will be behaviorally rated and euthanized, immediately or after varying' periods of withdrawal and/or challenge, for immunocytochemistry or in situ hybridization of dynorphin and fos immunoreactivity and mRNA. A second series of experiments will assess the contribution of serotonergic and glutamatergic afferents to dynorphin and fos regulation in dorsal and ventral striatum of normal and psychostimulant-treated rats. Specific lesions of these pathways and pharmacologically selective agonists and antagonists will be used to unmask glutamatergic and serotonergic mediation of cocaine's and amphetamine's effects. Third, rats receiving dose regimens of cocaine and lidocaine that induce convulsions will be rated for seizure severity and histochemically processed for neuron-specific markers, such as dynorphin, enkephalin, fos, and protein kinase C isoforms, already demonstrated to respond to various types of seizure activity in the hippocampal formation and limbic cortex. Selective glutamatergic antagonists will be used in an attempt to block the seizures and their neurochemical sequelae. With the combined use of immunochemical and molecular neurobiological tools, these studies should contribute to the definition of the neurobiological substrates of chronic psychostimulant actions and simultaneously elicit further information about the regulation of telencephalic opioid peptide and immediate early gene expression.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
2R01DA003982-09
Application #
3208895
Study Section
Special Emphasis Panel (SRCD (17))
Project Start
1988-05-01
Project End
1995-12-31
Budget Start
1992-01-01
Budget End
1992-12-31
Support Year
9
Fiscal Year
1992
Total Cost
Indirect Cost
Name
East Carolina University
Department
Type
Schools of Medicine
DUNS #
City
Greenville
State
NC
Country
United States
Zip Code
27858
Schmidt, Heath D; McGinty, Jacqueline F; West, Anne E et al. (2013) Epigenetics and psychostimulant addiction. Cold Spring Harb Perspect Med 3:a012047
Schwendt, Marek; Sigmon, Stacey A; McGinty, Jacqueline F (2012) RGS4 overexpression in the rat dorsal striatum modulates mGluR5- and amphetamine-mediated behavior and signaling. Psychopharmacology (Berl) 221:621-35
Shi, Xiangdang; McGinty, Jacqueline F (2011) D1 and D2 dopamine receptors differentially mediate the activation of phosphoproteins in the striatum of amphetamine-sensitized rats. Psychopharmacology (Berl) 214:653-63
McGinty, Jacqueline F; Bache, Alexandra J; Coleman, Nortorious T et al. (2011) The Role of BDNF/TrkB Signaling in Acute Amphetamine-Induced Locomotor Activity and Opioid Peptide Gene Expression in the Rat Dorsal Striatum. Front Syst Neurosci 5:60
Schwendt, M; McGinty, J F (2010) Amphetamine up-regulates activator of G-protein signaling 1 mRNA and protein levels in rat frontal cortex: the role of dopamine and glucocorticoid receptors. Neuroscience 168:96-107
Saylor, Alicia J; McGinty, Jacqueline F (2010) An intrastriatal brain-derived neurotrophic factor infusion restores striatal gene expression in Bdnf heterozygous mice. Brain Struct Funct 215:97-104
McGinty, Jacqueline F; Whitfield Jr, Timothy W; Berglind, William J (2010) Brain-derived neurotrophic factor and cocaine addiction. Brain Res 1314:183-93
Saylor, A J; McGinty, J F (2008) Amphetamine-induced locomotion and gene expression are altered in BDNF heterozygous mice. Genes Brain Behav 7:906-14
McGinty, Jacqueline F; Shi, Xiangdang D; Schwendt, Marek et al. (2008) Regulation of psychostimulant-induced signaling and gene expression in the striatum. J Neurochem 104:1440-9
Boger, Heather A; Middaugh, Lawrence D; Patrick, Kennerly S et al. (2007) Long-term consequences of methamphetamine exposure in young adults are exacerbated in glial cell line-derived neurotrophic factor heterozygous mice. J Neurosci 27:8816-25

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