Much evidence has gathered that nitric oxide (NO) signaling, via cGMP-dependent mechanisms, may activate pro-survival pathways in hippocampal neurons and inhibit apoptosis. Past research has revealed that the enhancement of monoaminergic neurotransmission via exercise or treatment with antidepressant medications leads to an enhanced expression of brain-derived neurotrophic factor (BDNF). In isolated hippocampal neurons, norepinephrine (NE) application also increases the immunoreactivity of BDNF and several pro-survival signaling molecules. The data herein support the possibility that NO signaling plays an important role in enhancing neurotrophin expression and activation of the pro-survival phosphatidylinositol 3' kinase (PI-3K) pathway stimulated by NE. In isolated hippocampal neurons, the NO donor, sodium nitroprusside, increases BDNF, PI-3K, and phospho-ERK1 immunoreactivity. Specific inhibitors of the NO system suggest that NE-induced increases in hippocampal BDNF and the PI-3K pathway, but not stimulation of the MAPK pathway, depend upon NO signaling. In addition, inhibiting cGMP suggest that the effects of NE on BDNF immunoreactivity and Akt phosphorylation are also cGMP-dependent. Finally, the application of l-NAME to hippocampal neurons increases cell death. This is the first study of its kind demonstrating the involvement of NE-induced pro-survival signaling in three distinct signaling pathways: PI-3K, MAPK, and NO/cGMP. Possible mechanisms are discussed in light of the results.