Stress and Glucocorticoids Impair Memory Retrieval via β2-Adrenergic, Gi/o-Coupled Suppression of cAMP Signaling

Acute stress impairs the retrieval of hippocampus-dependent memory, and this effect is mimicked by exogenous administration of stress-responsive glucocorticoid hormones. It has been proposed that glucocorticoids affect memory by promoting the release and/or blocking the reuptake of norepinephrine (NE), a stress-responsive neurotransmitter. It has also been proposed that this enhanced NE signaling impairs memory retrieval by stimulating β 1 -adrenergic receptors and elevating levels of cAMP. In contrast, other evidence indicates that NE, β 1 , and cAMP signaling is transiently required for the retrieval of hippocampus-dependent memory. To resolve this discrepancy, wild-type rats and mice with and without gene-targeted mutations were stressed or treated with glucocorticoids and/or adrenergic receptor drugs before testing memory for inhibitory avoidance or fear conditioning. Here we report that glucocorticoids do not require NE to impair retrieval. However, stress- and glucocorticoid-induced impairments of retrieval depend on the activation of β 2 (but not β 1 )-adrenergic receptors. Offering an explanation for the opposing functions of these two receptors, the impairing effects of stress, glucocorticoids and β 2 agonists on retrieval are blocked by pertussis toxin, which inactivates signaling by G i/o -coupled receptors. In hippocampal slices, β 2 signaling decreases cAMP levels and greatly reduces the increase in cAMP mediated by β 1 signaling. Finally, augmenting cAMP signaling in the hippocampus prevents the impairment of retrieval by systemic β 2 agonists or glucocorticoids. These results demonstrate that the β 2 receptor can be a critical effector of acute stress, and that β 1 and β 2 receptors can have quite distinct roles in CNS signaling and cognition.