Oxygen free radicals, any chemical moiety containing an oxygen atom with an unpaired electron in the outer orbital shell, are generated during many normal biochemical reactions in living tissue. The unpaired electron makes these compounds highly reactive and they can initiate disruptive peroxidation reactions with various substrates important to the survival of cells such as proteins, lipids and nucleic acids. A fairly complex defense system has evolved to protect living tissue from free radicals and to minimize the damage they might cause. Neurons are especially vulnerable to free radical attack and impaired defenses or exposure to excess free radicals can lead to neuronal death. Free radicals contribute to neuronal loss in cerebral ischemia and hemorrhage and may be involved in the degeneration of neurons in epilepsy, schizophrenia, tardive dyskinesia, normal aging, Parkinson's Disease and Alzheimer's Disease. The development of drugs that limit or prevent the attack of free radicals on neurons would be an important advance in the treatment of these conditions.

Mounting evidence indicates that the emotional, cognitive, neurovegetative and behavioral symptoms of patients with major depressive disorder are due to abnormal neurochemical substrates in the brain. Although the specific neurochemical abnormalities responsible have not been identified, the presenting symptoms of major depression are consistent with a disruption of normal neural communications between the limbic system and hypothalamus. Following removal of the olfactory bulbs, rats display a syndrome of behavioral deficits that also reflect a disruption of the limbic-hypothalamic axis. Moreover, the bulbectomy induced deficits are selectively reduced by the chronic administration of the same drugs that alleviate the symptoms of depression when given chronically to the patients. In addition to this pharmacological similarity, there are also numerous behavioral parallels between bulbectomized rats and major depression patients. The bulbectomized rat provides a good model in which to study antidepressant drugs and also may provide neurochemical and neuroanatomical data that are relevant to understanding the biological substrates of emotion and the causes of depression in humans.

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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.

The role of aberrant neurochemical substrates in the etiology of depression and the neurochemical mechanisms of antidepressant therapies have been the subjects of many hypotheses in the last 30 years. Pharmacological studies of early antidepressant drugs indicated that brain monoamines were significantly affected by these drugs and these led to the formulation of the biogenic amine hypothesis of depression. Although this hypothesis has been of heuristic value in the study of drug mechanisms and has provided a basis for screening drugs for antidepressant potential, deficiencies in it have become apparent. Neuroanatomical and neurochemical considerations favour the view that brain noradrenaline and serotonin systems may serve as bias adjusting systems for each other and numerous other neural systems. As a consequence of such a relationship, a primary defect in some other neural system would appear amplified in measurements of serotonin or noradrenaline. A possible site for this primary defect may be in membrane composition and function. Recent studies have found that typical and other antidepressant therapies have a pronounced effect on membrane lipids. Thus, in view of the important functions of membrane lipids and the fact that they have been linked to the initiation and development of a number of other disease processes, it is now suggested that consideration be given to them as playing primary causal roles in the etiology of depression and as a site of action for antidepressant drugs.