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

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 micrograms/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 cyclic AMP-generating systems between brain regions.(ABSTRACT TRUNCATED AT 250 WORDS)

Diurnal Differences and Adrenal Involvement in Calmodulin Stimulation of Hippocampal Adenylate Cyclase Activity

“…The results of the present study may be contrasted with those of chronic elevation of glucocorticoids, either by repeated stress Or by corticosterone injection, which attenuated calmodulinstimulated adenylate cyclase activity in cortical, but not hippocampal, membranes (14). However, the conditions of cc?rticosterone administration are important in that corticosterone achinistered in the drinking water failed to mimic the effects of stress or corticosterone injection on calmodulin-stimulated adenYldte cyclase activity (14).…”

“…The time of day may also influence the magnitude of chronic glucocorticoid effects on cortical cyclic AMP responses. Thus, the failure of chronic corticosterone ingestion to mimic the effects of stress or corticosterone injection on cyclic AMP generating systems in brain (14) may be due t o the fact that ingestion occurs primarily during the dark, whereas corticosterone injections and stress were given in the daytime. These diurnal differences in responsiveness to glucocorticoids require further investigation.…”

“…Thus, in the hippocampal, as well as cortical slice, there is some inhibitory influence of glucocortieoids on cyclic AMP generation. In fact, both chronic stress and glucocorticoid injection suppress the cyclic AMP response to noradrenaline in both hippocampal (14) and cortical slices (14)(15)(16)(17), although, as noted, calmodulin adenylate cyclase activity is only suppressed in cortical membranes (14). Moreover, while ADX increased the cyclic A M P response to noradrenaline in cortical brain slices (10, 11, 37), membrane adenylate cyclase activity was either little affected or even attenuated (this study).…”

“…In cortical slices, exogenously administered corticosterone prevented ADXinduced changes in the cyclic AMP response to noradrenaline (10,11). Stress and stress levels of corticosterone decreased the cyclic AMP response to noradrenaline in both cortical (14)(15)(16)(17) and hippocampal (14) slices, by mechanisms(s) which appear to involve alterations in calcium-dependent component(s) of this response (14,18). These regulatory effects on cyclic AMP formac m ,'l'spon&nce to: M. N. Gannon Calmodulin is a calcium-dependent regulator of adenylate cyclase, the enzyme responsible for generation of the intracellular second messenger, cyclic A M P (1 9,20).…”

Emerging Evidence for a Central Epinephrine-Innervated α1-Adrenergic System that Regulates Behavioral Activation and is Impaired in Depression

“…We originally found that repeated footshock, restraint stress, ACTH, or corticosterone administration to rats reduced the a 1 -receptor-stimulated potentiation of cAMP responses in slices of the rat cerebral cortex and hypothalamus (Stone, 1979). These findings were confirmed by three other groups (Duman et al, 1985;Gannon and McEwen, 1990;Izumi et al, 1996), one of which showed that cotreatment with the antidepressant citalopram (but not imipramine) reversed this desensitization and also reversed the reduced behavioral activity that accompanied it (Izumi et al, 1997a, b). However, repeated stress in rats was not found by a different group to reduce the a 1 -receptor-elicited phosphatidylinositol hydrolysis response to NE in slices of the cerebral cortex (Morinobu et al, 1992).…”