Because abuse and associated problems of the phenylethylamine drugs, such as methamphetamine (METH), continue to be a major concern in the United States and throughout the world, it is critical to under- stand the short- and long-term consequences resulting from abusing these psychostimulants. Of particular relevance to this project is the elucidation of the role of monoamine transporters to the acute andchronic effects of phenylethylamines. We recently demonstrated that METH treatments rapidly and profoundly reduce the activity of vesicular monoamine transporters-2 (VMAT-2) in striatal purified vesicles. This VMAT- 2 Acute Transporter Response (VATR) has at least two distinct components: one (1st component) that occurs after a single METH administration, and the other (2nd component) apparently only after multiple METH adminstrations that lead to neurotoxicity. Based on these observations, we hypothesize that """"""""Expression of a 2nd, but not the 1st, component of the VATR is linked to occurrence of phenylethylamine- induced monoamine neurotoxicity."""""""" This hypothesis will be tested by achieving the following Specific Aims: A. Determine and compare the features of the components of the METH-induced striatal VATR. We will study and contrast the full complement of basic dose, temporal, kinetic, anatomical, and mechanistic features of the VATR after a single (nontoxic) and multiple (neurotoxic) METH administrations. B. Elucidate the funtional significance of the VATR components. This will be accomplished by determining if the VATR components interfere with vesicular monoamine sequestration and releasing functions. C. Determine the effects on VATR expression of diverse phenylethylamines (i.e., amphetamine, MDMA, fenfluramine, and ephedrine), with monoamine neurotoxcity profiles distinct from METH. This will identify how the VATR components link with the various effects on monoamine systems and different expressions of monoamine toxicity associated with these distinct phenylethylamine analogs.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA004222-24
Application #
7794851
Study Section
Special Emphasis Panel (ZRG1-IFCN-C (03))
Program Officer
Lin, Geraline
Project Start
1986-09-01
Project End
2013-02-28
Budget Start
2010-03-01
Budget End
2013-02-28
Support Year
24
Fiscal Year
2010
Total Cost
$211,258
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
Vieira-Brock, Paula L; Andrenyak, David M; Nielsen, Shannon M et al. (2013) Age-related differences in the disposition of nicotine and metabolites in rat brain and plasma. Nicotine Tob Res 15:1839-48
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
McFadden, Lisa M; Hunt, Madison M; Vieira-Brock, Paula L et al. (2012) Prior methamphetamine self-administration attenuates serotonergic deficits induced by subsequent high-dose methamphetamine administrations. Drug Alcohol Depend 126:87-94
German, Christopher L; Hanson, Glen R; Fleckenstein, Annette E (2012) Amphetamine and methamphetamine reduce striatal dopamine transporter function without concurrent dopamine transporter relocalization. J Neurochem 123:288-97
Hanson, G R; Hoonakker, A J; Alburges, M E et al. (2012) Response of limbic neurotensin systems to methamphetamine self-administration. Neuroscience 203:99-107
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
Frankel, Paul S; Hoonakker, Amanda J; Alburges, Mario E et al. (2011) Effect of methamphetamine self-administration on neurotensin systems of the basal ganglia. J Pharmacol Exp Ther 336:809-15
Vieira-Brock, Paula L; Miller, Eleanor I; Nielsen, Shannon M et al. (2011) Simultaneous quantification of nicotine and metabolites in rat brain by liquid chromatography-tandem mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci 879:3465-74
Hadlock, Gregory C; Webb, Katy M; McFadden, Lisa M et al. (2011) 4-Methylmethcathinone (mephedrone): neuropharmacological effects of a designer stimulant of abuse. J Pharmacol Exp Ther 339:530-6

Showing the most recent 10 out of 101 publications