An Examination of the Involvement of Phospholipases A 2 and C in the α‐Adrenergic and γ‐Aminobutyric Acid Receptor Modulation of Cyclic AMP Accumulation in Rat Brain Slices

Experiments were undertaken to define the role of two calcium‐associated enzyme systems in modulating transmitter‐stimulated production of cylic nucleotides in rat brain. Cyclic AMP (cAMP) accumulation was examined in cerebral cortical slices using a prelabeling technique. The enhancement of isoproterenol‐stimulated cAMP production by α‐adrenergic and γ‐aminobutyric acid‐B (GABA B ) agonists was reduced by exposing the tissue to EGTA, a chelator of divalent cations, or quinacrine, a nonselective inhibitor of phospholipase A 2 . Likewise, chronic (2 weeks) administration of corticosterone decreased the α‐adrenergic and GABA B receptor modulation of second messenger production. Neither cyclooxygenase nor iipoxygenase inhibitors selectively influenced the facilitating response of α‐adrenergic and GABA B agonists. Other experiments revealed that although norepinephrine and 6‐fluoronorepinephrine stimulated inositol phosphate (IP) production in cerebral cortical slices with potencies equal to those displayed in the cyclic nucleotide assay, selective α 1 ,‐adrenergic agonists were less efficacious on IP formation and were without effect in the cAMP assay. Conversely, a selective α 2 ‐adrenergic receptor agonist facilitated the cAMP response to a β‐adrenergic agonist without affecting IP formation. The rank orders of potency of a series of α‐adrenergic antagonists suggest that IP accumulation is mediated solely by α 1 ‐adrenergic receptors, whereas the augmentation of cAMP accumulation is regulated by a mixed population of α‐adrenergic sites. The results suggest that the α‐adrenergic and GABA B receptor‐mediated enhancement of isoproterenol‐stimulated cAMP formation appears to be more closely associated with phospholipase A 2 than phospholipase C and may be mediated by arachidonate or some other fatty acid.