Inhibition of the ATP-sensitive potassium channel in the guinea pig substantia nigra by BMS 181100 is not mediated by a sigma-binding site.
Quantitative autoradiography of brain tissue has revealed a high density of binding sites for the K-ATP channel antagonists, the sulphonylureas, and for sigma-ligands in the substantia nigra (SN). In view of the high density of the two binding sites in the SN the possibility has been investigated that the K-ATP channel and the sigma-binding site are functionally linked. The K-ATP channel-mediated membrane hyperpolarisation and decrease in input resistance produced by hypoxia and by the metabolic inhibitor, cyanide, in rostral substantia nigra pars compacta neurons are antagonised by the sigma-ligand BMS 181100. In addition, BMS 181100 antagonises activation of the K-ATP channel by diazoxide; cromakalim is found to be without effect in these neurons. Antagonism of the cyanide-induced hyperpolarisation is dose dependent and is observed at concentrations of the drug which have no observable effect on the resting membrane properties of the neurons. By contrast, the nonselective sigma ligands 1,3-di-O-tolylguanidine (10 microM) and (+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine (100 microM), and the selective sigma 1-ligand (+)-pentazocine (5-10 microM) have no effect on the cyanide-induced hyperpolarisation. 5-HT (50-100 microM) and the selective 5-HT1A receptor agonist 8-OH-DPAT (50 microM) also fail to antagonise the cyanide-induced hyperpolarisation. The antagonism of the cyanide-induced hyperpolarisation by BMS 181100 persists in the presence of tetrodotoxin (1 microM) and in the presence of high concentrations of (+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine, but not under conditions of reduced calcium (0.1-0.2 mM) and raised magnesium (6 mM) concentrations, which block synaptic transmission. It is concluded that in substantia nigra phasic neurons the sigma-binding site does not regulate activation of the ATP-sensitive channel. However, BMS 181100 antagonises K-ATP channel activation in these neurons independently of sigma-binding sites and 5-HT receptors. This action of BMS 181100 is TTX insensitive and Ca2+ dependent.
University Department of Pharmacology, Oxford, UK.
J F
JF
O'Callaghan
S A
SA
Greenfield
D000255:Adenosine Triphosphate / Q000494:pharmacology*; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001665:Binding Sites / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D010423:Pentazocine / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects*; D011743:Pyrimidines / Q000494:pharmacology*; D012701:Serotonin / Q000494:pharmacology; D013378:Substantia Nigra / Q000187:drug effects*; D013779:Tetrodotoxin / Q000494:pharmacology
D014150:Antipsychotic Agents; D015221:Potassium Channels; D011743:Pyrimidines; C050408:alpha-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazine butanol; D012701:Serotonin; D013779:Tetrodotoxin; D000255:Adenosine Triphosphate; D010423:Pentazocine