Regulation of cyclic AMP formation in brain tissue by alpha-adrenergic receptors: requisite intermediacy of prostaglandins of the E series.

Abstract

The accumulations of cyclic AMP elicited by norepinephrine in slices of rat cerebral cortex or hypothalamus were markedly reduced after incubations with prostaglandin synthetase (8,11,14-eicosatrienoate, hydrogen-donor The molecular mechanisms through which prostaglandins exert their effects in the brain remain uncertain. Prostaglandins do appear to be involved with regulation of the adenylate cyclase [ATP pyrophosphate-lyase (cyclizing), EC 4.6.1.1] system, either directly, through prostaglandin receptor-mediated activation of adenylate cyclase (1), or indirectly, through prostaglandin-mediated effects on norepinephrine uptake and release (2). Prostaglandin El (PGEI) has been reported to antagonize 3-adrenergic receptor-mediated inhibition of spontaneous activity of central neurons and it was suggested that this was related to inhibition of adenylate cyclase (3). In homogenates of brain tissue, the activation of adenylate cyclase by prostaglandins has been inconsistent (1) In the central nervous system, prostaglandins are not stored and released as are putative neurotransmitters, but are synthesized from arachidonic acid by the prostaglandin synthetase (8,11,14-eicosatrienoate, hydrogen donor:oxygen oxidoreductase, EC 1.14.99.1) system and continually released into the interstitial space (5). The released prostaglandins are metabolized only slowly in brain, diffusion into the circulation or cerebral spinal fluid being the primary means of elimination (6). Thus, the primary factors governing the levels of prostaglandins in the brain are those which control the activity of prostaglandin synthetase. Substances such as bacterial pyrogens and painproducing substances appear to activate prostaglandin synthetase and increase brain prostaglandin levels (7), whereas analgesic antipyretics, such as aspirin and indomethacin, inhibit prostaglandin synthetase (8, 9) and decrease brain prostaglandin levels (10)(11)(12). Correlations between the analgesic and antipyretic potency of indomethacin, aspirin, and other nonsteroid anti-inflammatory drugs and their ability to inhibit prostaglandin synthetase from brain in vitro (10, 11) and to depress brain prostaglandin levels in vivo (12) have implicated the inhibition of prostaglandin synthesis as a central mode of action for these drugs.Indomethacin, aspirin, and other related compounds inhibit prostaglandin synthetase in rat brain slices, leading to reductions in endogenous levels of prostaglandin (6) 3024The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U. S. C. §1734 solely to indicate this fact.

Release of Prostaglandin E₂ from the Hypothalamus Depends on Extracellular Ca²⁺ Availability: Relation to LHRH Release

“…NE interacts with a-adrenergic receptors to stimulate the release of PGE2, which in turn induces LHRH release [28]. This obli gatory intermediacy of PGE2 in a-receptor-mediated NE effects appears to be a more general phenomenon within the central nervous system, as it has been shown to operate in both cerebral cortex and hypothalamus [31] in relation to the NE-induced accumulation of cyclic AMP. The a-adren ergic mediated effect of NE on cyclic AMP has been shown to be completely dependent on extracellular Ca2+ [35] and on PGE synthesis [31].…”

“…This obli gatory intermediacy of PGE2 in a-receptor-mediated NE effects appears to be a more general phenomenon within the central nervous system, as it has been shown to operate in both cerebral cortex and hypothalamus [31] in relation to the NE-induced accumulation of cyclic AMP. The a-adren ergic mediated effect of NE on cyclic AMP has been shown to be completely dependent on extracellular Ca2+ [35] and on PGE synthesis [31]. More remarkable, evidence exists that a-adrenergic antagonists may operate as calcium chan nel inhibitors [1], thereby further suggesting that activation of membrane Ca2+ gates is intimately involved in the mechanism of NE-induced PGE2 release.…”

The Role of Prostaglandins in Neuroendocrine Junctions:Studies in the Pineal Gland and the Hypothalamus

“…PG synthesis inhibitors greatly reduce the cAMP accu mulation elicited by NE in incubated rat cerebral cortical and hypothalamic slices [54]. The addition of very low con centrations of PGE2 counteracted the effect of cyclooxygen ase inhibitors.…”

Post-Training Cyclooxygenase-2 (COX-2) Inhibition Impairs Memory Consolidation

“…Newly formed prostanoids exit the cell via prostaglandin transporters and activate specific G protein-coupled receptors present on the plasma membrane (for review, see Coleman et al 1994). Prostaglandins are important modulators of adrenergic, noradrenergic (Partington et al 1980), and glutamatergic (Kimura et al 1985) neurotransmission.…”