title: Na(+)/H(+) exchanger inhibition modifies dopamine neurotransmission during normal and metabolic stress conditions.
abstract: Na(+)/H(+) exchanger (NHE) proteins are involved in intracellular pH and volume regulation and may indirectly influence neurotransmission. The abundant NHE isoform 1 (NHE1) has also been linked to brain cell damage during metabolic stress. It is not known, however, whether NHE1 or other NHE isoforms play a role in striatal dopamine (DA) neurotransmission under normal or metabolic stress conditions. Our study tested the hypothesis that NHE inhibition with cariporide mesilate (HOE-642) modifies striatal DA overflow and DAergic terminal damage in mice caused by the mitochondrial inhibitor malonate. We also explored the expression of NHE1-5 in the striatum and substantia nigra. Reverse microdialysis of HOE-642 elicited a transient elevation followed by a reduction in DA overflow accompanied by a decline in striatal DA content. HOE-642 pre-treatment diminished the malonate-induced DA overflow without reducing the intensity of the metabolic stress or subsequent DAergic axonal damage. Although NHE isoforms 1-5 are expressed in the striatum and midbrain, NHE1 protein was not co-located on nigrostriatal DAergic neurons. The absence of NHE1 co-location on DAergic neurons suggests that the effects of HOE-642 on striatal DA overflow are either mediated via NHE1 located on other cell types or that HOE-642 is acting through multiple NHE isoforms.
authors: Department of Neurology, UMDNJ-Robert Wood Johnson Medical School, Piscataway, New Jersey 08854, USA.
authors: Marcelo A
authors: MA
authors: Rocha
authors: David P
authors: DP
authors: Crockett
authors: Lai-Yoong
authors: LY
authors: Wong
authors: Jason R
authors: JR
authors: Richardson
authors: Patricia K
authors: PK
authors: Sonsalla
mesh_terms: D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D001928:Brain Diseases, Metabolic / Q000378:metabolism* / Q000503:physiopathology; D027682:Cation Transport Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D004298:Dopamine / Q000378:metabolism*; D004734:Energy Metabolism / Q000187:drug effects / Q000502:physiology; D006146:Guanidines / Q000494:pharmacology; D008297:Male; D008314:Malonates / Q000494:pharmacology; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D028361:Mitochondrial Diseases / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology; D018384:Oxidative Stress / Q000502:physiology*; D017729:Presynaptic Terminals / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000378:metabolism; D000074082:Sodium-Hydrogen Exchanger 1; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism; D013450:Sulfones / Q000494:pharmacology; D009435:Synaptic Transmission / Q000187:drug effects* / Q000502:physiology; D014855:Wallerian Degeneration / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology
chemical_list: D000889:Anti-Arrhythmia Agents; D027682:Cation Transport Proteins; D006146:Guanidines; D008314:Malonates; D020033:Protein Isoforms; C490997:Slc9a1 protein, mouse; D000074082:Sodium-Hydrogen Exchanger 1; D017923:Sodium-Hydrogen Exchangers; D013450:Sulfones; C093373:cariporide; C030290:malonic acid; D004298:Dopamine