Administration of methamphetamine to several species of animals results in long-lasting injury of the monoaminergic (dopaminergic and serotonergic) inputs to the striatum. These findings indicate that the health concerns associated with repeated methamphetamine self-administration in human extend beyond those related to the acute sympathomimetic effects of stimulant abuse. In particular, long-lasting injury to striatal dopaminergic nerve terminals may increase the risk of development of motoric disorders, especially in later life. Studies using animals suggest that the methamphetamine-induced neurotoxicity depends upon the release of DA from mesostriatal terminals. In this proposal, a key to studying these transmitter interactions in methamphetamine-induced neurotoxicity lies in the ability to measure the striatal extracellular levels of DA and its metabolites in rats using microdialysis perfusion during the entire period of repeated methamphetamine intoxication. The proposal discusses recent evidence from this laboratory indicating that neurotoxic regimens of methamphetamine treatment induce a dramatic rise in striatal dopamine efflux. Further, the neuroprotective effects of several pharmacological agents, including the noncompetitive N-methyl-D-aspartate antagonist MK-801 and the dopamine antagonists eticlopride and SCH 23390, correspond with the ability of these drugs to attenuate the massive release of DA otherwise seen after neurotoxic regimens of methamphetamine. The current proposal has three objectives: (i) to test further the relationship between DA release by m-AMPH and this stimulant's neurotoxic effects on striatal DA terminals, (ii) to examine the characteristics of striatal dopamine terminals at the time that they are susceptible to massive dopamine overflow by methamphetamine, and (iii) to determine the acute and long-term consequences for sensorimotor function of the dopamine terminal injury induced by methamphetamine.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA008052-02
Application #
2120505
Study Section
Drug Abuse Biomedical Research Review Committee (DABR)
Project Start
1993-04-01
Project End
1996-03-31
Budget Start
1994-04-01
Budget End
1995-03-31
Support Year
2
Fiscal Year
1994
Total Cost
Indirect Cost
Name
University of California Irvine
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
161202122
City
Irvine
State
CA
Country
United States
Zip Code
92697
Eisch, A J; Marshall, J F (1998) Methamphetamine neurotoxicity: dissociation of striatal dopamine terminal damage from parietal cortical cell body injury. Synapse 30:433-45
Eisch, A J; Schmued, L C; Marshall, J F (1998) Characterizing cortical neuron injury with Fluoro-Jade labeling after a neurotoxic regimen of methamphetamine. Synapse 30:329-33
LaHoste, G J; Ruskin, D N; Marshall, J F (1996) Cerebrocortical Fos expression following dopaminergic stimulation: D1/D2 synergism and its breakdown. Brain Res 728:97-104
Vargo, J M; Marshall, J F (1996) Unilateral frontal cortex ablation producing neglect causes time-dependent changes in striatal glutamate receptors. Behav Brain Res 77:189-99
Vargo, J M; Marshall, J F (1996) Frontal cortex ablation reversibly decreases striatal zif/268 and junB expression: temporal correspondence with sensory neglect and its spontaneous recovery. Synapse 22:291-303
Vargo, J M; Bromberg, B B; Best, P J et al. (1995) D1-class dopamine receptor involvement in the behavioral recovery from prefrontal cortical injury. Behav Brain Res 72:39-48
Vargo, J M; Marshall, J F (1995) Time-dependent changes in dopamine agonist-induced striatal Fos immunoreactivity are related to sensory neglect and its recovery after unilateral prefrontal cortex injury. Synapse 20:305-15
O'Dell, S J; Weihmuller, F B; McPherson, R J et al. (1994) Excitotoxic striatal lesions protect against subsequent methamphetamine-induced dopamine depletions. J Pharmacol Exp Ther 269:1319-25
Ruskin, D N; Marshall, J F (1994) Amphetamine- and cocaine-induced fos in the rat striatum depends on D2 dopamine receptor activation. Synapse 18:233-40
Weihmuller, F B; O'Dell, S J; Marshall, J F (1993) L-dopa pretreatment potentiates striatal dopamine overflow and produces dopamine terminal injury after a single methamphetamine injection. Brain Res 623:303-7