The
nitric oxide (NO)/
soluble guanylyl cyclase (sGC)/
protein kinase G (PKG) pathway is important for memory processing, but the identity of its downstream effectors as well as its actual participation in the consolidation of nonaversive declarative long-term memory (LTM) remain unknown. Here, we show that training rats in an object recognition (OR) learning task rapidly increased
nitrites/
nitrates (NOx) content in the CA1 region of the dorsal hippocampus while posttraining intra-CA1 microinfusion of the neuronal
NO synthase (nNOS) inhibitor L-NN hindered OR LTM retention without affecting memory retrieval or other behavioral variables. The amnesic effect of L-NN was not state dependent, was mimicked by the sGC inhibitor
LY83583 and the PKG inhibitor
KT-5823, and reversed by coinfusion of the NO donor
S-nitroso-N-acetylpenicillamine (SNAP) and the PKG activator
8-bromoguanosine 3',5'-cyclic monophosphate (8Br-cGMP). SNAP did not affect the amnesic effect of
LY83583 and
KT-5823. Conversely, 8Br-cGMP overturned the
amnesia induced by
LY83583 but not that caused by
KT-5823. Intra-CA1 infusion of the
beta-adrenergic receptor blocker
timolol right after training hindered OR LTM and, although coadministration of
noradrenaline reversed the
amnesia caused by L-NN,
LY83583, and
KT5823, the amnesic effect of
timolol was unaffected by coinfusion of 8Br-cGMP or SNAP, indicating that hippocampal
beta-adrenergic receptors act downstream NO/sGC/PKG signaling. We also found that posttraining intra-CA1 infusion of function-blocking anti-
brain-derived neurotrophic factor (
BDNF)
antibodies hampered OR LTM retention, whereas OR training increased CA1
BDNF levels in a nNOS- and
beta-adrenergic receptor-dependent manner. Taken together, our results demonstrate that NO/sGC/PKG signaling in the hippocampus is essential for OR memory consolidation and suggest that
beta-adrenergic receptors link the activation of this pathway to
BDNF expression during the consolidation of declarative memories.