High-dose methamphetamine acutely activates the striatonigral pathway to increase striatal glutamate and mediate long-term dopamine toxicity.
Methamphetamine (METH) has been shown to increase the extracellular concentrations of both dopamine (DA) and glutamate (GLU) in the striatum. Dopamine, glutamate, or their combined effects have been hypothesized to mediate striatal DA nerve terminal damage. Although it is known that METH releases DA via reverse transport, it is not known how METH increases the release of GLU. We hypothesized that METH increases GLU indirectly via activation of the basal ganglia output pathways. METH increased striatonigral GABAergic transmission, as evidenced by increased striatal GAD65 mRNA expression and extracellular GABA concentrations in substantia nigra pars reticulata (SNr). The METH-induced increase in nigral extracellular GABA concentrations was D1 receptor-dependent because intranigral perfusion of the D1 DA antagonist SCH23390 (10 microm) attenuated the METH-induced increase in GABA release in the SNr. Additionally, METH decreased extracellular GABA concentrations in the ventromedial thalamus (VM). Intranigral perfusion of the GABA-A receptor antagonist, bicuculline (10 microm), blocked the METH-induced decrease in extracellular GABA in the VM and the METH-induced increase in striatal GLU. Intranigral perfusion of either a DA D1 or GABA-A receptor antagonist during the systemic administrations of METH attenuated the striatal DA depletions when measured 1 week later. These results show that METH enhances D1-mediated striatonigral GABAergic transmission (1), which in turn activates GABA-A receptors in the SNr (2), leading to a decrease in GABAergic nigrothalamic activity (3), an increase in corticostriatal GLU release (4), and a consequent long-term depletion of striatal DA content (5).
Mark
Karla A
KA
Laboratory of Neurochemistry, Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, Massachusetts 02118, USA.
Soghomonian
Jean-Jacques
JJ
Yamamoto
Bryan K
BK
D000818:Animals; D001552:Benzazepines / Q000494:pharmacology; D001640:Bicuculline / Q000494:pharmacology; D000697:Central Nervous System Stimulants / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D058787:GABA-A Receptor Antagonists; D005968:Glutamate Decarboxylase / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism*; D007527:Isoenzymes / Q000378:metabolism; D008297:Male; D008694:Methamphetamine / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D017072:Neostriatum / Q000187:drug effects* / Q000378:metabolism; D009434:Neural Pathways / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D017447:Receptors, Dopamine D1 / Q000037:antagonists & inhibitors; D013378:Substantia Nigra / Q000187:drug effects*; D013788:Thalamus / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D001552:Benzazepines; D000697:Central Nervous System Stimulants; D058787:GABA-A Receptor Antagonists; D007527:Isoenzymes; D017447:Receptors, Dopamine D1; D018698:Glutamic Acid; D008694:Methamphetamine; D005680:gamma-Aminobutyric Acid; D005968:Glutamate Decarboxylase; C401141:glutamate decarboxylase 2; D004298:Dopamine; D001640:Bicuculline