The spontaneous activity of the norepinephrine-containing cells of the locus coeruleus was recorded in chloral hydrate-anesthetized rats. The effect of seven tricyclic antidepressants on the firing rate of single cells in the locus coeruleus was studied. All the drugs tested, except iprindole markedly decreased the rate of firing of the noradrenergic cells. Antidepressants having a secondary amine in the side chain, desipramine, nortriptyline and chlordesipramine, were more potent than their respective tertiary amine analogues, imipramine, amitriptyline and chlorimipramine. Alteration of the rate of drug metabolism by pretreatment with SKF-525A or phenobarbital did not change the doses of tertiary antidepressnats required to decrease norepinephrine cell firing. Depletion of the norepinephrine stores by pretreatment with alpha-methyl-p-tyrosine and reserpine markedly increased the dose of desipramine required to depress the norepinephrine cells. The results are in good agreement with previous studies showing that secondary amine antidepressants are more potent than their tertiary amine homologues in blocking the uptake of norepinephrine into brain and peripheral tissues. Despite their lower potency it is concluded that tertiary antidepressants act on noradrenergic neurons in their unchanged form and not via secondary amine metabolites formed during the recording experiments since alterations in liver metabolism did not influence the response. The findings are consistent with the suggestion made from studies on transmitter turnover that antidepressants by inhibiting reuptake of norepinephrine cause a stimulation of postsynaptic receptors which decreases the activity of the presynaptic neurons by a feed-back mechanism. This view is further supported by the finding of an inverse relation between the norepinephrine content of the brain and the dose of desipramine required to decrease the firing rate of the noradrenergic neurons.