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 densi ty of binding sites for the K-ATP channel antagonists, the sulphonylur eas, and for sigma-ligands in the substantia nigra (SN), In view of th e high density of the two binding sites in the SN the possibility has been investigated that the K-ATP channel and the a-binding site are fu nctionally linked, The K-ATP channel-mediated membrane hyperpolarisati on and decrease in input resistance produced by hypoxia and by the met abolic inhibitor, cyanide, in rostral substantia nigra pars compacta n eurons are antagonised by the sigma-ligand EMS 181100, In addition, EM S 181100 antagonises activation of the K-ATP channel by diazoxide; cro makalim is found to be without effect in these neurons. Antagonism of the cyanide-induced hyperpolarisation is dose dependent and is observe d at concentrations of the drug which have no observable effect on the resting membrane properties of the neurons, By contrast, the nonselec tive sigma ligands 1,3-di-O-tolylguanidine (10 mu M) and (+)-3-(3-hydr oxyphenyl)-N-(1-propyl)piperidine (100 mu M), and the selective sigma( 1)-ligand (+)-pentazocine (5-10 mu M) have no effect on the cyanide-in duced hyperpolarisation. 5-HT (50-100 mu M) and the selective 5-HT1A r eceptor agonist 8-OH-DPAT (50 mu M) also fail to antagonise the cyanid e-induced hyperpolarisation, The antagonism of the cyanide-induced hyp erpolarisation by EMS 181100 persists in the presence of tetrodotoxin (1 mu M) and in the presence of high concentrations of (+)-3-(3-hydrox yphenyl)-N-(1-propyl)piperidine, but not under conditions of reduced c alcium (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, EMS 181100 antagonises K-ATP chann el activation in these neurons independently of sigma-binding sites an d 5-HT receptors, This action of EMS 181100 is TTX insensitive and Ca2 + dependent. (C) 1995 Wiley-Liss, Inc.