Calmodulin Involvement in Stress‐ and Corticosterone‐Induced Down‐Regulation of Cyclic AMP‐Generating Systems in Brain

Publisher Website
Google Scholar
Abstract
Manipulation of the hypothalamic-pituitary-adrenal axis selectively alters .alpha.-adrenergic potentiation of the cyclic AMP response to .beta.-adrenergic receptor stimulation in rat cerebral cortex. Calcium has been implicated in this .alpha.-receptor-mediated response, which may involve activation of phospholipases A2 and C and/or calmodulin-dependent adenylate cyclase. We therefore investigated the effects of stress and corticosterone (CORT) on membrane calmodulin-dependent adenylate cyclase and noradrenaline-stimulated cyclic AMP accumulation in brain slices. Repeated stress for 21 days selectively attenuated the adenylate cyclase response to calcium/calmodulin in cerebral cortex membranes, without affecting basal or forskolin-stimulated enzyme activity. There was no such effect in hippocampal membranes. The same pattern of response was elicited by daily CORT injection (50 mg/kg s.c.) for 21 days, while vehicle injection had no effect. CORT in the drinking water (400 .mu.g/ml) elicited the same reduction of body weight as CORT injections, but had no effect on calmodulin adenylate cyclase. In parallel with calmodulin adenylate cyclase, cyclic AMP accumulation elicited by noradrenaline in slices of cerebral cortex was suppressed by both stress and daily CORT injections, with smaller effects observed with CORT in the drinking water. Unlike calmodulin adenylate cyclase, noradrenaline-stimulated cyclic AMP accumulation in hippocampus showed the same suppression as that in cerebral cortex. These results are discussed in relation to the differential mode of coupling of .alpha.-adrenergic receptors to the differential mode of coupling of .alpha.-adrenergic receptors to cyclic AMP-generating systems between brain regions. Glucocorticoid-mediated suppression of noradrenaline-stimulated cyclic AMP accumulation and calmodulin-dependent adenylate cyclase may represent parallel effects of the hormone, but their co-occurrence in cerebral cortex may also indicate some functional coupling and compartmentalization. The ability of daily CORT injections to mimic the effects of repeated stress, but inability of CORT ingestion at high doses in the drinking water to do so, suggests that the time course of CORT elevation and the coincidence of some type of stress may be important for the suppression of cyclic AMP-generating systems in brain.

This publication has 33 references indexed in Scilit: