Figure 7.

β₂ signaling opposes β₁ signaling in retrieval and in cAMP production via G_i/o. A, The impairment of contextual fear retrieval by betaxolol (Bet, 1 mg/kg, 30 min before testing 1 d after training) is prevented by concurrent administration of ICI (1 mg/kg). The deficits in contextual fear retrieval exhibited by Dbh^−/− and β₁ KO mice 1 d after training are reversed by treatment with ICI 30 min before testing. Finally, β₁/β₂ double KO (DKO) mice do not exhibit a deficit in contextual fear. F_(7,68) = 7.1 and p < 0.0001 for the main effect of group (5–16 per group). B, Infusion of PTx (10 ng) into the DH 1 d before training prevents the impairment of contextual fear retrieval by cort (50 ng), zinterol (100 ng), or restraint (2 min). Restraint was administered 30 min and cort and zinterol were infused 15 min before testing, which was 2 d after training. F_(1,48) = 35 and p < 0.0001 for the main effect of pretreatment; F_(4,45) = 5.6 and p = 0.001 for the main effect of treatment; and F_(4,45) = 5.6 and p = 0.001 for the interaction of pretreatment and treatment (5 per group). C–F, Hippocampal slices were incubated in aCSF with various concentrations of the nonselective β receptor agonist Iso. C, Iso was without effect on cAMP in slices from β₁/β₂/β₃ triple KO (TKO) mice. F_(3,21) = 0.01 and p = 1.0 for the main effect of concentration (5–10 per group). D, Selective stimulation of β₁ receptors by Iso at 0.3 and 1 μm increased cAMP in slices from β₃ KO mice treated with the β₂ antagonist ICI. F_(3,34) = 7.2 and p = 0.0008 for the main effect of concentration (7–15 per group). E, Selective stimulation of β₂ receptors by Iso decreased cAMP in slices from β₁/β₃ DKO mice. F_(3,48) = 5.2 and p = 0.001 for the main effect of concentration (8–35 per group). F, Combined stimulation of β₁ and β₂ receptors by Iso at 1 μm modestly elevated cAMP levels in slices from β₃ KO mice. F_(3,38) = 4.1 and p = 0.013 for the main effect of concentration (8–17 per group). G, DH infusion of the cAMP agonist Sp-8-Br-cAMPS (2 μg) prevents retrieval impairment induced by systemic cort (1 mg/kg) or procaterol (10 μg/kg). Veh is systemic injection of vehicle 30 min before testing mice trained with normal shock intensity (1 mA), while Veh-LS is systemic injection of vehicle 30 min before testing mice trained with low shock intensity (0.3 mA). F_(3,52) = 26 and p < 0.0001 for the main effect of systemic treatment; F_(1,54) = 21 and p < 0.0001 for the main effect of DH treatment; and F_(3,52) = 2.9 and p = 0.043 for the interaction of systemic and DH treatment (5–10 per group).