ABSTRACT
This paper describes research that seeks to increase our understanding of physiological processes responsible for depression. The research uses an animal model in which rats are exposed to strong uncontrollable shocks after which they show depressed behavior. Evidence is presented that such stress-induced depression in rats represents a good model of clinical depression in humans. Over the last decade, this model has been used extensively to study neurochemical changes underlying depression. The earliest hypothesis offered to explain stress-induced depression (the “motor activation deficit” hypothesis) stated that such depression is caused by disturbance of norepinephrine (NE) in the brain, and the research that gave rise to this concept is summarized. Recent work is then described which indicates that stress-induced depression is caused by substantial depletion of NE specifically in the locus coeruleus (LC) region of the brain stem resulting in a functional blockade of α2 receptors in this brain region. These recent studies show that (a) NE depletion in the LC is correlated with stress-induced depression, (b) similar behavioral depression can be produced by pharmacologically blocking α2 receptors in the LC, and (c) stress-induced depression can be overcome either by eliminating NE depletion in the LC or by microinfusion into the LC of drugs that stimulate α2 receptors. In addition, functional blockade of α2 receptors in the LC will increase NE release in the distal areas to which LC axons project, and it was found that mimicking the consequences of this by infusing α1 and β adrenergic receptor agonists outside the LC will also produce behavioral depression. The findings may well represent a breakthrough in determining the mechanism by which highly stressful conditions lead to behavioral depression, pointing to changes within a particular brain region (the locus coeruleus) as being especially important. Of course, as a result of changes in the LC region, transmitters in other brain regions will be affected, and recent advances made in other laboratories, though achieved by using somewhat different animal models, indicate that serotonin (5-HT) and perhaps acetylcholine (ACh) are also involved in the process by which uncontrollable shock leads to behavioral depression. These results are compatible with clinical findings that point to disturbance of NE and 5-HT and possibly ACh in human depression. The neurochemical changes underlying stress-induced depression in the particular animal model described in this paper are also consistent with known actions of antidepressant treatments. In concluding, the suggestion is make that the animal model described in this paper may best reproduce human depressive conditions in which anxiety is an associated feature. Based on these beginnings, animal models in which behavioral depression is produced by stressful conditions may well represent one of the principal tools that can be employed for discovering neurochemical disturbances that occur in human depression.
