Xamoterol impairs hippocampus-dependent emotional memory retrieval via G_i/o-coupled β₂-adrenergic signaling

Abstract

Xamoterol, a partial β₁-adrenergic receptor agonist, has been reported to impair the retrieval of hippocampus-dependent spatial reference memory in rats. In contrast, xamoterol restores memory retrieval in gene-targeted mice lacking norepinephrine (NE) and in a transgenic mouse model of Down syndrome in which NE levels are reduced. Restoration of retrieval by xamoterol in these two models complements the observation that NE and β₁ signaling are required for hippocampus-dependent retrieval of contextual and spatial reference memory in wild-type mice and rats. Additional evidence indicates that cAMP-mediated PKA and Epac signaling are required for the retrieval of hippocampus-dependent memory. As a result, we hypothesized that xamoterol has effects in addition to the stimulation of β₁ receptors that, at higher doses, act to counter the effects of β₁ signaling. Here we report that xamoterol-induced disruption of memory retrieval depends on β₂-adrenergic receptor signaling. Interestingly, the impairment of memory retrieval by xamoterol is blocked by pretreatment with pertussis toxin, an uncoupling agent for G_i/o signaling, suggesting that β₂ signaling opposes β₁ signaling during memory retrieval at the level of G protein and cAMP signaling. Finally, similar to the time-dependent roles for NE, β₁, and cAMP signaling in hippocampus-dependent memory retrieval, xamoterol only impairs retrieval for several days after training, indicating that its effects are also limited by the age of the memory. We conclude that the disruption of memory retrieval by xamoterol is mediated by G_i/o-coupled β₂ signaling, which opposes the G_s-coupled β₁ signaling that is transiently required for hippocampus-dependent emotional memory retrieval.