Project: Research project

Project Details


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.
Effective start/end date4/1/933/31/96


  • National Institutes of Health
  • National Institutes of Health


  • Medicine(all)


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