Current neurobiological concepts attribute a central role of the hippocampal formation in cognitive and affective processes. Recent studies indicate that the hippocampus is affected in human depression, and antidepressant drugs induce hippocampal adaptive changes that are thought to be associated with their therapeutic action. In the present study, we investigated the action of various antidepressant drugs on the activity of the septo-hippocampal system, its oscillatory activity in particular. The acute effects of the norepinephrine (NE) reuptake inhibitors reboxetine and desipramine, and the selective serotonin reuptake inhibitor fluvoxamine were evaluated. Extracellular single-unit recordings were performed from the medial septum/diagonal band of Broca (MS/DBv), with simultaneous hippocampal EEG recordings of anesthetized rats. Systemic administration of reboxetine synchronized hippocampal EEG, resulting in a significant increase in power at theta frequency, and an increase in frequency and power of gamma-wave activity. Parallel to EEG synchrony, reboxetine induced or enhanced theta oscillation of MS/DBv neurons. Oscillatory frequencies of MS/DBv neurons were identical, and phase locked to the corresponding hippocamapal theta frequencies. Under the same experimental conditions, reboxetine induced a two-fold increase in extracellular NE (but not serotonin) levels in the hippocampus as revealed by microdialysis. Desipramine, but not the serotonin reuptake inhibitor fluvoxamine, evoked responses similar to those of reboxetine regarding septo-hippocampal theta activity. The present findings indicate that even though both NE and serotonin reuptake inhibitors are clinically effective antidepressant drugs, their action on the septo-hippocampal oscillatory behavior is different. It is presumed that selective NE reuptake inhibitors could modulate various cognitive processes associated with hippocampal oscillatory activity.