NORADRENALINE-INDUCED INOSITOL PHOSPHATE FORMATION IN RAT STRIATUM ISMEDIATED BY ALPHA-1A-ADRENOCEPTORS

The aim of this study was to assess the contribution of alpha(1)-adren oceptor subtypes to noradrenaline (NA)-induced inositol phosphate form ation in rat striatum. In cross-chopped slices and in the presence of 10 mM LiCl, NA stimulated the accumulation of [H-3]inositol phosphates . After 60-min incubation with 100 mu M NA, [H-3]IP1 was the major pro duct detected (82 +/- 3% of total [H-3]inositol phosphates). Best-fit values for the concentration-response curve for NA-induced [H-3]IP1 ac cumulation yielded an EC(50) of 9.4 +/- 1.1 mu M, maximum effect of 21 0 +/- 3% of basal, and Hill coefficient (n(H)) of 1.1 +/- 0.1. Pre-tre atment of the slices for 30 min with the alkylating agent chloroethylc lonidine (100 mu M) failed to decrease significantly the response to 1 00 mu M NA. Inhibition curves for four alpha(1)-antagonists, (+)-nigul dipine, prazosin, WB-4101 and 5-methylurapidil (5-MU), best-fit to a s ingle-site model with pK(i) values of 9.4 ((+)-niguldipine), 9.2 (praz osin and WB-4101) and 8.8 (5-MU). The putative alpha(1D)-selective ant agonist BMY 7378 reduced the response to NA only partially (30 +/- 3% inhibition at 1 mu M; pK(i) 7.24). NA-induced [H-3]IP1 accumulation wa s significantly reduced (to 20 +/- 9% of controls) by Ca2+ removal and increased as the extracellular Ca2+ concentration was raised from nom inally zero (no added Ca2+) to 1 mM Ca2+. NA-induced [3H]IP1 accumulat ion was reduced by both the non-selective Ca2+ channel blocker Ni2+ (5 8 +/- 3% inhibition at 2 mM) and nimodipine, an antagonist of L-type v oltage-operated Ca2+ channels (77 +/- 4% inhibition at 3 mu M). Taken together these results indicate that NA-induced inositol phosphate for mation in striatal slices is mediated by activation of alpha(1A)-adren oceptors coupled to Ca2+ entry and Ca2+ activation of phospholipase C. Copyright (C) 1996 Elsevier Science Ltd.