Removal of the main olfactory bulbs in rats has been shown to alter neuronal function in brain areas involved in emotional regulation and homeostasis. These neuronal alterations result in maladaptive behavioral patterns and elevated plasma corticosterone that are suggestive of the symptom profile of patients with primary unipolar depression. Moreover, the endocrine and behavioral deficits of bulbectomized rats are reversed by the chronic administration of drugs that reverse the symptoms of depression in people when given chronically. However, the therapeutic improvements seen in patients with depression are not directly due to molecules of the antidepressant drug but rather to some relatively long-lasting compensatory change induced in the neuronal substrate by the drug. The present research demonstrates that the reversal of the olfactory bulb lesion deficits following chronic antidepressant drug administration in rats is not due to molecules of the drug per se but rather to some drug-induced change in the neuronal substrate that continues for at least 5 days after the last dose of drug. These endocrine, behavioral, and pharmacological similarities suggest that the study of rats with olfactory bulb ablation may make significant contributions to the understanding of the neuroscience of primary unipolar depression in humans.