Methamphetamine (MA) is a drug of abuse with pronounced effects on the CNS including psychomotor stimulation and mood elevation. These effects have contributed to its high abuse liability. Furthermore, prolonged use has produced a behavioral pattern resembling paranoid schizophrenia. These behavioral side effects and abuse potential suggest that MA produces long-lasting neurotoxic effects in the CNS. Recent studies have implicated an excitatory amino acid involvement in MA-induced depletions of striatal dopamine (DA) and serotonin (5HT). No studies to date however, have directly measured brain excitatory amino acids such as the excitotoxin, glutamate, during the time course of repeated MA administration. The manner in which MA selectively destroys DA and 5HT neurons is unknown although a dopaminergic mechanism has been proposed. This proposal will examine a potential cortical-subcortical mechanism of enhanced corticostriatal glutamate release and NMDA receptor activation following MA administration. The primary objective of these studies will be to establish that the neurotoxic effects of MA on DA and 5HT neurons in striatum are mediated in part by glutamate. It is posited that the striatal neurotoxicity to repeated MA injections is partially due to a cumulative increase in striatal glutamate release via increased corticostriatal glutamatergic transmission. In vivo microdialysis will be used to simultaneously measure extracellular levels of glutamate and biogenic amines in both the striatum and frontal cortex of awake-behaving rats during the repeated systemic and intracortical administrations of MA. Striatal tissue content of DA and 5HT will be measured one week after the termination of MA treatment as an index of toxicity. Systemic and local perfusions of specific NMDA receptor antagonists will be used to determine the contribution of the NMDA receptor and the brain region(s) involved in mediating the MA-induced changes in striatal glutamate release and neurotoxicity. The modulatory role of the rat adrenal glucocorticoid, corticosterone will also be examined with regard to the mechanism through which MA increases extracellular glutamate. It is hoped that specific information derived from these experiments will provide basic insight into the neural mechanisms responsible for the neurotoxicity to MA and other psychostimulant drugs.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
1R01DA007606-01A1
Application #
2120084
Study Section
Drug Abuse Biomedical Research Review Committee (DABR)
Program Officer
Frankenheim, Jerry
Project Start
1992-07-15
Project End
1995-06-30
Budget Start
1992-07-15
Budget End
1993-06-30
Support Year
1
Fiscal Year
1992
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

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