Synergistic Interactions Between α 1 ‐ and α 2 ‐Adrenergic Receptors in Activating 3 H‐Inositol Phosphate Formation in Primary Glial Cell Cultures

Norepinephrine (NE)‐stimulated 3 H‐inositol phosphate ( 3 H‐InsP) formation in primary glial cell cultures is thought to be due to α 1 ‐adrenergic receptor activation. Surprisingly, the α 1 ‐selective agonists phenylephrine and methoxamine showed only 12–21% of the intrinsic activity of NE in activating this response. Although the α 2 ‐selective agonist UK 14,304 was itself inactive, inclusion of UK 14,304 increased the response to the α 1 ‐selective agonists by about threefold. This increase was concentration‐dependent and occurred at all time points examined. 6‐Fluoro‐NE and α‐methyl‐NE mimicked the effect of NE in glial cultures, although with lower potencies. However, several partial agonists were ineffective in activating this response, in both the presence and absence of UK 14,304. Synergistic interactions were not observed for α 1 ‐mediated responses in slices of rat cerebral cortex, either for formation of 3 H‐InsPs or potentiation of isoproterenol‐ or adenosine‐stimulated cyclic AMP accumulation. Both UK 14,304 and phenylephrine inhibited NE‐stimulated 3 H‐InsP formation in concentrations similar to those necessary to activate this response directly. These results suggest that NE activates 3 H‐InsP formation in primary glial cultures by synergistic actions on both α 1 ‐ and α 2 ‐adrenergic receptors. The agonists UK 14,304 and phenylephrine also can act to inhibit the response to NE competitively.