BLOCKADE BY SIGMA-SITE LIGANDS OF HIGH VOLTAGE-ACTIVATED CA2+ CHANNELS IN RAT AND MOUSE CULTURED HIPPOCAMPAL PYRAMIDAL NEURONS

1 The effects of a series of structurally-dissimilar sigma site ligand s were examined on high voltage-activated Ca2+ channel activity in two preparations of cultured hippocampal pyramidal neurones. 2 In mouse h ippocampal neurones under whole-cell voltage-clamp, voltage-activated Ca2+ channel currents carried by barium ions (I-Ba) were reduced with the rank order (IC50 values in mu M): -)-cis-N-methyl-N-[2-(3,4-dichlo rophenyl)ethyl]-2- (1-pyrrolidinyl)cyclohexylamine (7.8)>rimcazole (13 )> haloperidol (16)>ifenprodil (18)>opipramol (32)>carbetapentane piro [1,2,3,4-tetrahydronaphthalene-1,4-piperidine] (42)>caramiphen (47)>de xtromethorphan (73). At the highest concentrations tested, the compoun ds almost abolished I-Ba in the absence of any other pharmacological a gent. 3 The current-voltage characteristics of the whole-cell I-Ba wer e unaffected by the test compounds. The drug-induced block was rapid i n onset and offset, with the exceptions of carbetapentane and caramiph en where full block was achieved only after two to three voltage-activ ated currents and was associated with an apparent increase in the rate of inactivation of I-Ba. 4 In rat hippocampal neurones loaded with th e Ca2+-sensitive dye Fura-2, rises in intracellular free Ca2+ concentr ation evoked by transient exposure to 50 mM K+-containing medium, eith er in the absence or in the presence of 10 mu M nifedipine (to block L -type high voltage-activated Ca2+ channels), were also reversibly atte nuated by the sigma ligands. The rank order potencies for the compound s in these experimental paradigms were similar to that observed for bl ockade of I-Ba in the electrophysiological studies. 5 These results in dicate that, at micromolar concentrations, the compounds tested block multiple subtypes of high voltage-activated Ca2+ channels. These actio ns, which do not appear to be mediated by high-affinity sigma binding sites, may play a role in some of the functional effects previously de scribed for the compounds.