The adverse effects of methamphetamine (METH) are of international and national concern (SAMSHA, 2010;UNODC, 2010). It is now clear the METH has toxic effects on the human brain. Animal studies have provided valuable information on the neurotoxic mechanisms and consequences of METH but the precise means by which METH causes brain damage remain unclear It is commonly and logically assumed that its neurotoxic effects are derived from its direct action on the brain. However, largely ignored are the myriad peripheral effects that might contribute to METH neurotoxicity. A likely peripheral source of these effects is the liver. It is known that the liver is a direct target of METH and man other drugs of abuse but no consideration has been given to whether liver or other peripheral organ damage is related to METH neurotoxicity. However, a well known consequence of acute liver damage is the neuropsychiatric syndrome, hepatic encephalopathy (HE). The key mediator of HE is hyperammonemia. Ammonia (NH3) causes neuronal damage through mechanisms strikingly similar to excitotoxicity and oxidative stress that have been implicated in METH-induced neurotoxicity. Specifically, NH3 increases glutamate (GLU) release, activates NMDA receptors, and down- regulates the GLU transporter, while inhibiting glutamine synthetase (condensation of GLU) and increasing superoxide radical and nitric oxide formation. This proposal will examine a new concept related to the neurotoxicity of METH by identifying a peripherally derived, novel mediator of METH-induced neurotoxicity based on exciting preliminary evidence implicating peripheral NH3 in the neurotoxic effects of METH. The long term goal is to identify the determinants of METH neurotoxicity to assess the risk to human health of repeated METH exposures. The objective is to elucidate the mechanisms by which METH causes damage to dopamine (DA) terminals. The central hypothesis is that METH causes a hyperammonemic state that triggers interdependent and convergent alterations in GLU homeostasis, excitotoxicity, and oxidative stress to GLUergic and DAergic regulatory proteins. These changes in turn, promote a feed-forward process that culminates in the classical METH neurotoxicity.
Specific Aim 1 will identify NH3 as a mediator of METH-induced damage to DA terminals while Specific Aim 2 will elucidate the excitotoxic/glutamatergic mechanisms underlying the effects of NH3 in METH- induced damage to DA.
Specific Aim 3 will build upon the other aims and determine if NH3 contributes to oxidative stress to DA terminals through a dysregulation of GLU transmission. Overall, the findings should have a positive impact because the identification of peripheral NH3 as a small molecule mediator of METH can lead to feasible therapeutic strategies for the treatment of METH overdose and neurotoxicity while fundamentally advancing the field of drug-induced brain damage in general. The proposal highlights the broader significance of peripheral organ toxicity in mediating neurological consequences.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA007606-22
Application #
8477153
Study Section
Special Emphasis Panel (ZRG1-IFCN-H (02))
Program Officer
Pilotte, Nancy S
Project Start
1992-07-15
Project End
2017-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
22
Fiscal Year
2013
Total Cost
$303,435
Indirect Cost
$95,703
Name
University of Toledo
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
807418939
City
Toledo
State
OH
Country
United States
Zip Code
43614
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
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) Behavioral impairments and serotonin reductions in rats after chronic L-dopa. Psychopharmacology (Berl) 232:3203-13
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
Natarajan, Reka; Northrop, Nicole A; Yamamoto, Bryan K (2015) Protracted effects of chronic stress on serotonin-dependent thermoregulation. Stress 18:668-76
Stansley, Branden J; Yamamoto, Bryan K (2014) Chronic L-dopa decreases serotonin neurons in a subregion of the dorsal raphe nucleus. J Pharmacol Exp Ther 351:440-7
Halpin, Laura E; Northrop, Nicole A; Yamamoto, Bryan K (2014) Ammonia mediates methamphetamine-induced increases in glutamate and excitotoxicity. Neuropsychopharmacology 39:1031-8
Poddar, Nitesh K; Zano, Stephen; Natarajan, Reka et al. (2014) Enhanced brain distribution of modified aspartoacylase. Mol Genet Metab 113:219-24
Halpin, Laura E; Collins, Stuart A; Yamamoto, Bryan K (2014) Neurotoxicity of methamphetamine and 3,4-methylenedioxymethamphetamine. Life Sci 97:37-44
Northrop, Nicole A; Yamamoto, Bryan K (2013) Cyclooxygenase activity contributes to the monoaminergic damage caused by serial exposure to stress and methamphetamine. Neuropharmacology 72:96-105

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