The incidence of methamphetamine (METH) abuse is alarmingly high, and METH abuse and addiction remains a critical societal problem due in part to its disturbing consequent effects such as violent behavior and psychosis. Thus, elucidating the basis of such dangerous behaviors and developing strategies to manage these adverse consequences is important. Of particular interest to our lab are the effects of METH-induced increases in extracellular dopamine (DA) on the functioning of striatal efferent pathways such as the striatonigral projection. During the past funding period we observed that DA release induced by a high dose of METH did not appear to activate the striatonigral pathway as previously thought. Although a high dose of METH increased tissue levels of the neuropeptides associated with the striatonigral pathway (substance P [SP] and neurotensin [NT]) and increased expression of their precursor mRNAs, it surprisingly did not increase extracellular levels of the neuropeptides in the terminal fields of these nigral projections. Conversely, the low dose of METH tended to decrease tissue levels of SP and NT, did not alter expression of the precursor mRNAs, and significantly elevated the extracellular levels of the neuropeptides in the terminal fields. These data therefore lead to the hypothesis that the functional output of the striatonigral pathway is increased by low doses of METH and unaffected by administration of high doses of METH. This hypothesis will be tested by accomplishing the following Specific Aims: A) Establishing the effect of low and high doses of METH on the functional output of the striatonigral pathway. B) Resolving the mechanism underlying the differential effect of low and high doses of METH on the activity of the striatonigral pathway. C) Determining the behavioral consequences of the differential effects of low and high doses of METH on the striatonigral pathway. Elucidating the impact of low vs. high doses of METH on the striatonigral projection will be critical for determining the mechanisms responsible for the differential dose-dependent effects of METH and for improving therapeutics for METH-related problems, as well as for other basal ganglia-related disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA009407-10
Application #
6805284
Study Section
Integrative, Functional and Cognitive Neuroscience 8 (IFCN)
Program Officer
Lin, Geraline
Project Start
1995-04-01
Project End
2008-06-30
Budget Start
2004-07-01
Budget End
2005-06-30
Support Year
10
Fiscal Year
2004
Total Cost
$299,000
Indirect Cost
Name
University of Utah
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
009095365
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
McFadden, Lisa M; Stout, Kristen A; Vieira-Brock, Paula L et al. (2012) Methamphetamine self-administration acutely decreases monoaminergic transporter function. Synapse 66:240-5
McFadden, Lisa M; Hadlock, Greg C; Allen, Scott C et al. (2012) Methamphetamine self-administration causes persistent striatal dopaminergic alterations and mitigates the deficits caused by a subsequent methamphetamine exposure. J Pharmacol Exp Ther 340:295-303
Hadlock, Gregory C; Nelson, Chad C; Baucum 2nd, Anthony J et al. (2011) Ex vivo identification of protein-protein interactions involving the dopamine transporter. J Neurosci Methods 196:303-7
Alburges, Mario E; Hoonakker, Amanda J; Horner, Kristen A et al. (2011) Methylphenidate alters basal ganglia neurotensin systems through dopaminergic mechanisms: a comparison with cocaine treatment. J Neurochem 117:470-8
Alburges, Mario E; Frankel, Paul S; Hoonakker, Amanda J et al. (2009) Responses of limbic and extrapyramidal substance P systems to nicotine treatment. Psychopharmacology (Berl) 201:517-27
Frankel, Paul S; Alburges, Mario E; Bush, Lloyd et al. (2008) Striatal and ventral pallidum dynorphin concentrations are markedly increased in human chronic cocaine users. Neuropharmacology 55:41-6
Frankel, Paul S; Hoonakker, Amanda J; Hanson, Glen R (2008) Differential response of neurotensin to methamphetamine self-administration. Ann N Y Acad Sci 1139:112-7
Frankel, Paul S; Hoonakker, Amanda J; Danaceau, Jonathan P et al. (2007) Mechanism of an exaggerated locomotor response to a low-dose challenge of methamphetamine. Pharmacol Biochem Behav 86:511-5
Frankel, Paul S; Alburges, Mario E; Bush, Lloyd et al. (2007) Brain levels of neuropeptides in human chronic methamphetamine users. Neuropharmacology 53:447-54
Alburges, Mario E; Hoonakker, Amanda J; Hanson, Glen R (2007) Nicotinic and dopamine D2 receptors mediate nicotine-induced changes in ventral tegmental area neurotensin system. Eur J Pharmacol 573:124-32

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