High doses of METH produce long-term consequences indicative of neurotoxicity as revealed by cognitive deficits in humans and long-term decreases in markers of dopamine (DA) and 5HT neurotransmission in humans and animals. Our studies during the previous funding period and findings by others revealed that high levels of striatal glutamate (GLU) play an important role in METH toxicity. Nevertheless, there is no evidence of how striatal GLU transmission is increased by METH and if this produces excitotoxic damage. Moreoever, despite the neurochemical similarities between METH, environmental stress, and drug abuse, it is unknown if and how stress might enhance the excitotoxic effects of METH. The hippocampus is also vulnerable to the toxic effects of METH and is particularly sensitive to stress and excitotoxic insult due the dense composition of GLU neurons and glucocorticoid receptors in this region. Despite numerous studies demonstrating that the hippocampus is involved in cognition and human METH abusers exhibit cognitive deficits, it is surprising that little is known about how METH damages the hippocampus or how stress affects the excitotoxic effects of METH. The proposed project is a novel extension of our prior studies and will elucidate the neurochemical determinants and consequences of GLU-mediated excitotoxicity to the striatum and hippocampus and how they are affected by prior exposure to chronic unpredictable stress. The overarching hypothesis that will be tested by the proposed specific aims is that excitotoxicity in the striatum is produced by METH, augmented by prior exposure to chronic stress, and mediated differentially by D1 and D2 receptors. Excitotoxicity will be paralleled by increased presynaptic storage and extracellular concentrations of striatal GLU resulting in oxidative stress to the vesicular monoamine transporter (VMAT2) and the mitochondrial electron transport chain to culminate in proteasomal inhibition and spectrin proteolysis. In addition, a stress-induced enhancement of GLU transmission in the hippocampus will be similarly evidenced by increased synaptic and extracellular GLU and consequently, decreased cellular bioenergetics, decreased proteasomal activation, and spectrin proteolysis.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
3R01DA007606-18S1
Application #
7940307
Study Section
Neurobiology of Motivated Behavior Study Section (NMB)
Program Officer
Frankenheim, Jerry
Project Start
1992-07-15
Project End
2012-04-30
Budget Start
2009-09-30
Budget End
2010-04-30
Support Year
18
Fiscal Year
2009
Total Cost
$150,000
Indirect Cost
Name
University of Toledo
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
807418939
City
Toledo
State
OH
Country
United States
Zip Code
43614
Blaker, Amanda L; Yamamoto, Bryan K (2018) Methamphetamine-Induced Brain Injury and Alcohol Drinking. J Neuroimmune Pharmacol 13:53-63
Natarajan, Reka; Northrop, Nicole; Yamamoto, Bryan (2017) Fluorescein Isothiocyanate (FITC)-Dextran Extravasation as a Measure of Blood-Brain Barrier Permeability. Curr Protoc Neurosci 79:9.58.1-9.58.15
Natarajan, Reka; Forrester, Laura; Chiaia, Nicolas L et al. (2017) Chronic-Stress-Induced Behavioral Changes Associated with Subregion-Selective Serotonin Cell Death in the Dorsal Raphe. J Neurosci 37:6214-6223
Northrop, Nicole A; Halpin, Laura E; Yamamoto, Bryan K (2016) Peripheral ammonia and blood brain barrier structure and function after methamphetamine. Neuropharmacology 107:18-26
Rappeneau, Virginie; Blaker, Amanda; Petro, Jeff R et al. (2016) Disruption of the Glutamate-Glutamine Cycle Involving Astrocytes in an Animal Model of Depression for Males and Females. Front Behav Neurosci 10:231
Huff, Courtney L; Morano, Rachel L; Herman, James P et al. (2016) MDMA decreases glutamic acid decarboxylase (GAD) 67-immunoreactive neurons in the hippocampus and increases seizure susceptibility: Role for glutamate. Neurotoxicology 57:282-290
Collins, Stuart A; Huff, Courtney; Chiaia, Nicolas et al. (2016) 3,4-methylenedioxymethamphetamine increases excitability in the dentate gyrus: role of 5HT2A receptor-induced PGE2 signaling. J Neurochem 136:1074-84
Stansley, Branden J; Yamamoto, Bryan K (2015) L-Dopa and Brain Serotonin System Dysfunction. Toxics 3:75-88
Natarajan, Reka; Northrop, Nicole A; Yamamoto, Bryan K (2015) Protracted effects of chronic stress on serotonin-dependent thermoregulation. Stress 18:668-76
Collins, Stuart A; Gudelsky, Gary A; Yamamoto, Bryan K (2015) MDMA-induced loss of parvalbumin interneurons within the dentate gyrus is mediated by 5HT2A and NMDA receptors. Eur J Pharmacol 761:95-100

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