The long-term consequences of methamphetamine (METH) abuse include a persistent, partial loss of monoamine systems in the brain, particularly the dopamine innervation of the striatum. Despite the apparent relative sparing of function at smaller sizes of dopamine depletion, several lines of evidence suggest that there is a significant impact of such partial dopamine loss on central nervous system function. Both abstinent METH abusers with documented decreases in dopamine uptake sites in striatum and patients early in the course of Parkinson's disease show deficits on cognitive tasks. Studies in animals with partial monoamine depletions have revealed deficits in learning and memory functions dependent on striatal, hippocampal, and cortical function, and recent data from our laboratory suggest that such deficits may be associated with impaired activation of the effector immediate early gene arc. Partial dopamine depletions also are associated with decreased dopamine concentrations evoked by electrical stimulation mimicking phasic dopamine signaling. Finally, partial monoamine depletions are associated with changes in measures of the function of striatonigral (direct pathway) efferent neurons of striatum. Taken together, these data suggest that partial dopamine depletions of striatum selectively alter striatonigral neuron function and, consequently, basal ganglia- dependent learning and memory function by impairing phasic dopamine neurotransmission. This hypothesis will be examined by 1) further characterizing the impact of METH-induced neurotoxicity on basal ganglia-mediated learning and memory processes;2) determining whether METH-induced neurotoxicity is associated with degradation of dopamine transients and whether activating phasic dopamine transmission will selectively enhance striatonigral neuron function;and 3) examining the impact of METH-induced neurotoxicity on arc induction and cytoplasmic distribution as well as on the involvement of striatal Arc in learning and memory. Completion of these experiments will provide improved understanding of the molecular, cellular, and behavioral impact of METH-induced neurotoxicity to central dopamine systems on basal ganglia function. Such understanding will be critical to allow for the development of targeted strategies to therapeutically manage the long-term effects of such stimulant abuse.

Public Health Relevance

It is now established that methamphetamine (METH) abuse leads to long-lasting decreases in the dopamine innervation of the caudate-putamen in humans, as well as other species. The goal of this project is to further determine the impact of METH- induced neurotoxicity on basal ganglia function and basal ganglia-mediated learning and memory processes and to assess whether changes in phasic dopamine neurotransmission underlie the long-term effects of METH on basal ganglia function and behavior.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-IFCN-H (02))
Program Officer
Frankenheim, Jerry
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Utah
Schools of Pharmacy
Salt Lake City
United States
Zip Code
Covey, Dan P; Bunner, Kendra D; Schuweiler, Douglas R et al. (2016) Amphetamine elevates nucleus accumbens dopamine via an action potential-dependent mechanism that is modulated by endocannabinoids. Eur J Neurosci 43:1661-73
Furlong, Teri M; Leavitt, Lee S; Keefe, Kristen A et al. (2016) Methamphetamine-, d-Amphetamine-, and p-Chloroamphetamine-Induced Neurotoxicity Differentially Effect Impulsive Responding on the Stop-Signal Task in Rats. Neurotox Res 29:569-82
Robinson, John D; Howard, Christopher D; Pastuzyn, Elissa D et al. (2014) Methamphetamine-induced neurotoxicity disrupts pharmacologically evoked dopamine transients in the dorsomedial and dorsolateral striatum. Neurotox Res 26:152-67
Pastuzyn, Elissa D; Keefe, Kristen A (2014) Changes in neural circuitry regulating response-reversal learning and Arc-mediated consolidation of learning in rats with methamphetamine-induced partial monoamine loss. Neuropsychopharmacology 39:963-72
Covey, Dan P; Roitman, Mitchell F; Garris, Paul A (2014) Illicit dopamine transients: reconciling actions of abused drugs. Trends Neurosci 37:200-10
Howard, Christopher D; Pastuzyn, Elissa D; Barker-Haliski, Melissa L et al. (2013) Phasic-like stimulation of the medial forebrain bundle augments striatal gene expression despite methamphetamine-induced partial dopamine denervation. J Neurochem 125:555-65
Howard, Christopher D; Daberkow, David P; Ramsson, Eric S et al. (2013) Methamphetamine-induced neurotoxicity disrupts naturally occurring phasic dopamine signaling. Eur J Neurosci 38:2078-88
Son, Jong-Hyun; Kuhn, James; Keefe, Kristen A (2013) Perseverative behavior in rats with methamphetamine-induced neurotoxicity. Neuropharmacology 67:95-103
Daberkow, D P; Brown, H D; Bunner, K D et al. (2013) Amphetamine paradoxically augments exocytotic dopamine release and phasic dopamine signals. J Neurosci 33:452-63
Barker-Haliski, M L; Pastuzyn, E D; Keefe, K A (2012) Expression of the core exon-junction complex factor eukaryotic initiation factor 4A3 is increased during spatial exploration and striatally-mediated learning. Neuroscience 226:51-61

Showing the most recent 10 out of 16 publications