Methamphetamine (METH) is a drug of abuse with pronounced effects on the CNS including psychomotor activation and mood elevation. These effects have contributed to its high abuse liability. Furthermore, prolonged used has produced a behavioral pattern resembling paranoid schizophrenia. These behavioral side effects and abuse potential suggest that METH produces long-lasting neurotoxic effects in the CNS. However, the exact mechanisms by which METH damages dopamine neurons are unknown. Excitatory amino acids such as glutamate have been implicated in the METH-induced depletions of dopamine. The primary objective of this proposal is to elucidate the factors underlying METH toxicity and focuses on the glutamate-dependent mechanisms and responses mediating the toxic effects of METH to striatal dopamine neurons. Pharmacological manipulations of glutamate transmission and in vivo measures of extracellular concentrations of dopamine and glutamate using microdialysis will be employed. In addition, the cellular responses to METH and glutamate-induced neurotoxicity will be assessed by measuring spectrin breakdown, hydroxyl radical formation, and lipid peroxidation. The first series of experiments will evaluate whether alterations in extracellular glutamate concentrations affect METH-induced striatal dopamine depletIons. The second specific aim will be to disrupt corticostriatal glutamatergic transmission by lesioning the ventral thalamic nuclei. The effects of these lesions on METH induced increases in striatal extra cellular glutamate concentrations and its long term effects on striatal dopamine content and tyrosine hydroxylase immunoreactivity will be determined. The third and fourth specific aims will determine the cytotoxic consequences of the increased extracellular concentrations of dopamine and glutamate by measuring the degree of spectrin proteolysis, the production of hydroxyl free radicals and their attendant neurotoxic effects indicated by lipid peroxidation.
The final aim will be to evaluate the effects of repeated stress episodes and repeated administrations of low doses of METH or corticosterone on the subsequent neurotoxic effects of METH to dopamine neurons in forebrain regions. Overall, these experiments have significant clinical implications for the influence of toxic excitatory amino acids, environmental stressors, and/or prior drug exposure as determinants and consequences of drug-induced neurotoxicity. Since stress has a strong influence on the susceptibility to self administer amphetamine, these studies are also relevant to the consequences of prior exposure to neurotoxic doses of METH on drug seeking behavior and the reactivity to stressful events.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA007606-08
Application #
2897875
Study Section
Special Emphasis Panel (SRCD (52))
Program Officer
Frankenheim, Jerry
Project Start
1992-07-15
Project End
2000-05-31
Budget Start
1999-06-01
Budget End
2000-05-31
Support Year
8
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Case Western Reserve University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
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
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
Das, Sujan C; Yamamoto, Bryan K; Hristov, Alexandar M et al. (2015) Ceftriaxone attenuates ethanol drinking and restores extracellular glutamate concentration through normalization of GLT-1 in nucleus accumbens of male alcohol-preferring rats. Neuropharmacology 97:67-74
Stansley, Branden J; Yamamoto, Bryan K (2015) Behavioral impairments and serotonin reductions in rats after chronic L-dopa. Psychopharmacology (Berl) 232:3203-13

Showing the most recent 10 out of 70 publications