In transfected cells and non-neuronal tissues many G-protein-coupled receptors activate p44/42 MAP kinase (ERK), a kinase involved in both hippocampal synaptic plasticity and learning and memory. However, it is not clear to what degree these receptors couple to ERK in brain. G(s)-coupled beta-adrenergic receptor activation of ERK in neurons is critical in the regulation of synaptic plasticity in area CA1 of the hippocampus. In addition, alpha(1)- and alpha(2)-adrenergic receptors, present in CA1, could potentially activate ERK. We find that, like the beta-adrenergic receptor, the G(q)-coupled alpha(1)AR activates ERK in adult mouse CA1. However, activation of the G(i/o)-coupled alpha(2)AR does not activate ERK, nor does activation of a homologous G(i/o)-coupled receptor enriched in adult mouse CA1, the 5HT(1A) receptor. In contrast, the nonhomologous G(i/o)-coupled gamma-aminobutyric acid type B receptor does activate ERK in adult mouse CA1. Surprisingly, activation of alpha(2)ARs in CA1 from immature animals where basal phospho-ERK is low induces ERK phosphorylation. These data suggest that although most G-protein-coupled receptor subtypes activate ERK in non-neuronal cells, the coupling of G(i/o) to ERK is tightly regulated in brain.