The incidence of methamphetamine (METH) abuse has risen sharply over the past few years: hence, its neurochemical effects on central monoaminergic neurons warrant investigation. High-dose METH administration to rodents and primates results in short- and long-term deficits in monoaminergic systems. This laboratory reported recently the novel finding that METH administration causes a rapid and reversible decrease in dopamine transporter (DAT) function which is distinct from degeneration of dopamine terminals. Because DAT are essential for clearing dopamine from the extraneuronal environment, this rapid and reversible change in DAT may be a regulatory phenomenon of importance. Hence, the hypothesis will be tested that METH acutely and selectively alters the nature and function of DAT in a reversible manner by achieving the following Specific Aims: A. Assess the selectivity of the METH effect on DAT by: 1) confirming that this phenomenon is not due to dopamine neuronal degeneration; 2) comparing METH actions on DAT with effects on vesicular monoamine and glutamate transporters; and 3) assessing brain regional and species differences in the METH effect on DAT. B. Elucidate the nature of the reversible effect of METH on DAT by investigating whether: 1) METH treatment alters DAT protein structure; 2) dopamine D2 receptors modulate DAT function; 3) de novo protein synthesis is necessary for DAT recovery; and 4) antioxidants restore DAT activity after METH administration. C. Demonstrate functional consequences of METH-affected DAT by assessing the effect of METH-impaired DAT on dopamine reuptake in vivo, and subsequent uptake of METH in vitro. D. Evaluate whether the METH effect on DAT is selective to METH by assessing the response of DAT to: 1) agents that block dopamine reuptake (cocaine, nomifensine), or increase dopamine release (i.e., amphetamine, MDMA, MDE and fenfluramine); and 2) an agent which increases dopamine synthesis (L-dopa). Results of these studies will elucidate the importance of the rapid and reversible METH-induced decrease DAT activity. An understanding of this phenomenon has important implications regarding the mechanism of action of METH and other psychostimulants, as well as for the physiological regulation of dopaminergic systems. Such understanding could help develop better strategies for treating drug abuse and dopamine-related neurological and psychiatric disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
1R29DA011389-01
Application #
2441140
Study Section
Human Development Research Subcommittee (NIDA)
Program Officer
Lin, Geraline
Project Start
1998-02-01
Project End
2002-12-31
Budget Start
1998-02-01
Budget End
1998-12-31
Support Year
1
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of Utah
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
German, Christopher L; Gudheti, Manasa V; Fleckenstein, Annette E et al. (2017) Brain Slice Staining and Preparation for Three-Dimensional Super-Resolution Microscopy. Methods Mol Biol 1663:153-162
Baladi, Michelle G; Nielsen, Shannon M; McIntosh, J Michael et al. (2016) Prior nicotine self-administration attenuates subsequent dopaminergic deficits of methamphetamine in rats: role of nicotinic acetylcholine receptors. Behav Pharmacol 27:422-30
Vieira-Brock, Paula L; McFadden, Lisa M; Nielsen, Shannon M et al. (2015) Nicotine Administration Attenuates Methamphetamine-Induced Novel Object Recognition Deficits. Int J Neuropsychopharmacol 18:
German, Christopher L; Fleckenstein, Annette E; Hanson, Glen R (2014) Bath salts and synthetic cathinones: an emerging designer drug phenomenon. Life Sci 97:2-8
Baladi, Michelle G; Nielsen, Shannon M; Umpierre, Anthony et al. (2014) Prior methylphenidate self-administration alters the subsequent reinforcing effects of methamphetamine in rats. Behav Pharmacol 25:758-65
Baladi, Michelle G; Newman, Amy H; Nielsen, Shannon M et al. (2014) Dopamine D(3) receptors contribute to methamphetamine-induced alterations in dopaminergic neuronal function: role of hyperthermia. Eur J Pharmacol 732:105-10
McFadden, Lisa M; Vieira-Brock, Paula L; Hanson, Glen R et al. (2014) Methamphetamine self-administration attenuates hippocampal serotonergic deficits: role of brain-derived neurotrophic factor. Int J Neuropsychopharmacol 17:1315-20
German, Christopher L; Alburges, Mario E; Hoonakker, Amanda J et al. (2014) Mephedrone alters basal ganglia and limbic dynorphin systems. Synapse 68:634-640
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; Hanson, Glen R; Fleckenstein, Annette E (2013) The effects of methamphetamine self-administration on cortical monoaminergic deficits induced by subsequent high-dose methamphetamine administrations. Synapse 67:875-81

Showing the most recent 10 out of 25 publications