Disturbances of mood are among the most common and most debilitating of psychiatric disorders. A large proportion of patients with major depressive disorders suffer chronic or recurrent symptoms. The cost of depression is great, both in human and economic terms. While currently available antidepressant therapies are effective in many cases, they are limited by potentially serious side effects, poor patient compliance, and intentional overdose. Clinical depression most likely involves a disturbed and imbalanced functioning of CNS monoaminergic systems. A novel approach towards restoring imbalanced functioning in the CNS is the use of neural transplantation. When placed in appropriate regions, neural grafts can serve as a long-term and readily available source of neuroactive substances. A significant advantage of this approach for the chronically depressed patient would be the ability to provide a continually renewable source of monoamines on a long-term or permanent basis, reducing or eliminating the need for repeated antidepressant administration. The proposed study is an initial attempt to assess the potential for neural transplants to alleviate depression. To assess the potential for transplants of monoamine-producing cells to alleviate depression, two well established animals models will be used initially; the learned helplessness model and the behavioral despair model. The learned helplessness model is the best studied and is supported by a number of parallels between clinical depression and laboratory observations, including weight loss, lethargy, and reduced motivation, as well as similarities in biochemistry and treatment. The behavioral despair model is particularly sensitive as a screen for clinical antidepressants. Monoaminergic graft sources will include the pineal gland, which produces high levels of serotonin, and the adrenal medulla, which produces high levels of norepinephrine. Solid tissue, explants, and cell suspensions will be tested for ability to reduce behavioral deficits in the ra t depression models. Initially the transplants will be placed in the frontal neocortex, since this site has been implicated in human depression, as well as in animal depression models. The long term potential for neural transplants to reduce behavioral depression will be assessed over time, ranging from 1 week to 1 year. Specific antagonists will be used to assess the contribution of substances released from the grafts to the reduction of behavioral depression. The ability for the neural transplants to reduce deficits following neurotoxin administration will also be tested. Graft viability and function will be determined over time using biochemical assays and immunocytochemistry.
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| Dougherty, D D; Sortwell, C E; Sagen, J (1995) Pharmacologic specificity of antidepressive activity by monoaminergic neural transplants. Psychopharmacology (Berl) 118:10-8 |
| Sortwell, C E; Pappas, G D; Sagen, J (1995) Chromaffin cell xenografts in the rat neocortex can produce antidepressive activity in the forced swimming test. Exp Brain Res 103:59-69 |
| Sortwell, C E; Petty, F; Kramer, G et al. (1994) In vivo release of catecholamines from xenogeneic chromaffin cell grafts with antidepressive activity. Exp Neurol 130:1-8 |
