Blockade of dopamine storage, but not of dopamine synthesis, prevents activation of a tolbutamide-sensitive K+ channel in the guinea-pig substantia nigra.
The substantia nigra has one of the highest levels of ATP-sensitive K+ channel in the brain. Since this channel is controlled by cell metabolism, the aim of this study was to see how closely it is associated with nigral dopamine systems, which are decreased in Parkinson's disease. In a sub-population of neurons within the rostral substantia nigra pars compacta of the guinea-pig, a brief period of hypoxia resulted in a tolbutamide (100-500 microM) sensitive hyperpolarisation [input resistance (IR) decrease from 144.88 +/- 14.04 M omega pre-hypoxia to 105.91 +/- 13.25 M omega during hypoxia]. Maximal blockade of this decrease was seen in presence of 500 microns tolbutamide [IR decrease only from 161.35 +/- 32.82 M omega to 155.02 +/- 34.29 M omega]. Reserpine (which depletes dopamine stores) but not alpha-methyl-para-tyrosine (which decreases de novo synthesis of dopamine) caused a marked attenuation of this hyperpolarisation [IR decrease only from 163.32 +/- 44.42 M omega pre-hypoxia to 154.42 +/- 50.97 M omega during hypoxia]. This observation suggests that blockade of dopamine storage, but not of de novo synthesis, leads to a loss of responsiveness of certain mid-brain neurons to hypoxia, rendering them potentially more susceptible to subsequent degeneration. The possible link between nigral dopamine systems and ATP-sensitive K+ channels is discussed.
McGroarty
A
A
University Department of Pharmacology, Oxford, UK. alan.mcgroarty@pharmacology.ox.ac.uk
Greenfield
S A
SA
D000818:Animals; D004298:Dopamine / Q000096:biosynthesis / Q000378:metabolism*; D018492:Dopamine Antagonists / Q000494:pharmacology*; D006168:Guinea Pigs; D002534:Hypoxia, Brain / Q000378:metabolism*; D066298:In Vitro Techniques; D008297:Male; D008781:Methyltyrosines / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects*; D012110:Reserpine / Q000494:pharmacology; D013378:Substantia Nigra / Q000187:drug effects* / Q000378:metabolism; D014044:Tolbutamide / Q000037:antagonists & inhibitors*; D019805:alpha-Methyltyrosine
D018492:Dopamine Antagonists; D008781:Methyltyrosines; D015221:Potassium Channels; D019805:alpha-Methyltyrosine; D012110:Reserpine; D014044:Tolbutamide; D004298:Dopamine