The firing of hippocampal cells was studied in rats treated with desipramine 10 mg/kg per day i.p. for various periods of time. These cells were neurophysiologically identified to be noradrenergic postsynaptic by their decreased firing during stimulation of the locus coeruleus (LC). While desipramine given for 1 day produced no change, the drug given for 7, 14, and 21 days produced a 20%, 38% and 89% increase, respectively; only the last increase reached a statistical significance. This time course closely resembles that of the therapeutic action of the drug in depressed patients. Desipramine also altered the firing of norepinephrine-containing cells in the LC. While desipramine given for 1 day produced no change, the drug given for 7, 14 and 21 days produced a 12%, 29% and 34% decrease, respectively; only the last two decrements reached a statistical significance. This time course resembles that of the change in firing of hippocampal cells. Based on this and other data it is suggested that the decrease in the firing of LC cells plays a major role in the increased firing of hippocampal cells obtained after desipramine treatment.