cl-316243 and zinterol

Normally noradrenaline release ~30 min after training in the day-old chick is essential for memory consolidation by simultaneously increasing both glycogenolysis, by its stimulation of β2-adrenergic (AR) receptors, and glycogen synthesis, by its stimulation of α2-AR receptors in astrocytes. At the same time noradrenaline stimulation of β3-AR receptors increases glucose uptake solely in astrocytes. Intracerebral injection of small oligomeric β-amyloid protein (Aβ1-42) (Aβ) 45 min before one-trial bead discrimination learning in day-old chicks abolishes consolidation of memory 30 min post-learning. The ensuing memory loss can be rescued by injection of selective β3- and β(2-AR agonists (CL316243 and zinterol), which also have the ability to consolidate weakly-reinforced learning into long-term memory. However, although CL316243 rescues Aβ-induced memory loss over a similar time period to when it consolidates weak learning (up to 25 min post training), zinterol is effective over a more limited time period and unexpectedly it does not rescue at the time it promotes glycogenolysis. Injection of Aβ into the hippocampus and the locus coeruleus (LoC) also produces similar memory deficits and injection of both AR agonists into a cortical area can rescue memory from LoC Aβ. We have previously shown that β3-AR stimulation increases astrocytic glucose uptake and have suggested there may be sensitization or upregulation of the receptor. Since β2-AR stimulation does not rescue memory at the time it promotes glycogenolysis, but the receptor does not appear to be impaired, it is suggested that Aβ may be causing an impairment in the synthesis of readily available glycogen.

Topics: Adrenergic beta-2 Receptor Agonists; Adrenergic beta-3 Receptor Agonists; Alzheimer Disease; Amyloid beta-Peptides; Animals; Astrocytes; Chickens; Dioxoles; Ethanolamines; Glucose; Glycogen; Glycogen Synthase Kinase 3; Glycogenolysis; Hippocampus; Locus Coeruleus; Memory Disorders; Memory, Long-Term; Models, Neurological; Peptide Fragments; Receptors, Adrenergic, beta-2; Time Factors

Isoprenaline, acting at beta-adrenoceptors (ARs), enhances memory formation in single trial discriminated avoidance learning in day-old chicks by mechanisms involving alterations in glucose and glycogen metabolism. Earlier studies of memory consolidation in chicks indicated that beta3-ARs enhanced memory by increasing glucose uptake, whereas beta2-ARs enhance memory by increasing glycogenolysis. This study examines the ability of beta-ARs to increase glucose uptake in chick forebrain astrocytes. The beta-AR agonist isoprenaline increased glucose uptake in a concentration-dependent manner, as did insulin. Glucose uptake was increased by the beta2-AR agonist zinterol and the beta3-AR agonist CL316243, but not by the beta1-AR agonist RO363. In chick astrocytes, reverse transcription-polymerase chain reaction studies showed that beta1-, beta2-, and beta3-AR mRNA were present, whereas radioligand-binding studies showed the presence of only beta2- and beta3-ARs. beta-AR or insulin-mediated glucose uptake was inhibited by phosphatidylinositol-3 kinase and protein kinase C inhibitors, suggesting a possible interaction between the beta-AR and insulin pathways. However beta2- and beta3-ARs increase glucose uptake by two different mechanisms: beta2-ARs via a Gs-cAMP-protein kinase A-dependent pathway, while beta3-ARs via interactions with Gi. These results indicate that activation of beta2- and beta3-ARs causes glucose uptake in chick astrocytes by distinct mechanisms, which may be relevant for memory enhancement.

Topics: Adrenergic beta-2 Receptor Agonists; Adrenergic beta-3 Receptor Agonists; Adrenergic beta-Agonists; Animals; Astrocytes; Brain; Cells, Cultured; Chick Embryo; Dioxoles; Dose-Response Relationship, Drug; Enzyme Inhibitors; Ethanolamines; Glucose; GTP-Binding Protein alpha Subunits, Gi-Go; GTP-Binding Protein alpha Subunits, Gs; Insulin; Isoproterenol; Memory; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Protein Kinase C; Receptors, Adrenergic, beta-2; Receptors, Adrenergic, beta-3; RNA, Messenger; Signal Transduction

Consolidation of a labile memory which would not normally be stored can be achieved by intracerebral administration of noradrenaline. In a series of experiments using discriminated, one trial passive avoidance learning with the day-old chick, the effect of noradrenaline has been shown to be due to actions at different subtypes of adrenoceptors. The effect of noradrenaline is dose-dependent, with a moderate dose producing memory consolidation. However, higher doses of noradrenaline (0.3-10 nmol/hemisphere) prevent consolidation, an effect not seen with isoprenaline suggesting that these doses stimulate alpha-adrenoceptors. The promotion of memory consolidation by noradrenaline or isoprenaline at low doses was attributable to beta3-adrenoceptors and at medium doses to beta2-adrenoceptors. At higher doses of noradrenaline, there was alpha1-adrenoceptor-mediated inhibition of memory consolidation. Consolidation can also be achieved by administration of either beta2- or beta3-adrenoceptor agonists at specific times after training. Although these two adrenoceptors both promoted memory consolidation, there was a differential action on the stages of memory formation. The dose-response curve to the beta3- and the beta2-agonists was shifted by the appropriate antagonist but not by the antagonist at the other beta-adrenoceptor. Although beta1-adrenoceptors are present in chick brain, they do not seem to have a role in memory formation. These results explain why noradrenaline, acting at different adrenoceptors, can have different effects on memory formation with memory being either consolidated or inhibited depending on the dose. The findings also demonstrate a role in memory formation for beta3-adrenoceptors found in the brain. Agonists acting specifically at beta2- or beta3-adrenoceptors may be of value in diseases involving cognitive impairment.

Topics: Adrenergic beta-Agonists; Animals; Animals, Newborn; Avoidance Learning; Brain; Catecholamines; Chickens; Dioxoles; Ethanolamines; Injections; Isoproterenol; Male; Memory; Protein Isoforms; Receptors, Adrenergic, beta