Separation and loss experiences frequently result in significant psychological and medical morbidity. These experiences are risk factors for development of major affective disorder, and medical disorders of several varieties. Treatment of individuals experiencing major losses with antidepressant medications has been recommended on clinical grounds, but no studies suggest which aspects of the loss response might be modified by such treatment. We propose to use an animal model system, specifically, a maternal separation paradigm in social group living non-human primates, to determine whether treatment with an antidepressant monoamine oxidase (MAO) inhibitor will prevent certain immunological and cardiovascular consequences of loss experiences. Using a double blind placebo controlled design, pigtail monkey infants (M.nemestrina) will be treated with placebo or the MAO-A inhibitor clorgyline at 2mg/kg delivered by osmotic minipump beginning shortly after separation from their mothers. Weekly blood samples will be obtained to for a variety of in vivo and in vitro immunological assessments of innate and acquired immunity. Weekly CSF samples obtained prior to and after separation will be analyzed for several catechol and indolamines and their metabolites, for determination of drug efficacy and estimation of whether certain CSF amine profiles suggest some animals may be at greater risk for adverse separation-induced effects. Continuous heart rate (HR) obtained by means of totally implantable biotelemetry will provide data for evaluation of autonomic homeostasis following separation, and specifically, possible prevention of parasympathetically mediated HR decreases, often found as a consequence of separation experiences. Salivary free-cortisol will be assessed as a measure of HPA activation. Behavioral observations will permit estimation of magnitude and type of the behavioral response to separation, and its correlation with treatment status, and physiological parameters. This research will determine whether clorgyline treatment at the time of a separation experience will prevent what we believe are adverse autonomic consequences (including cardiac and immunological changes) that might otherwise follow such an experience, and will pave the way for possible human treatment studies. It represents a major step in this research program, now in progress for nearly two decades, and which has been responsible in large part for the identification of the aberrant autonomic physiological response to loss.
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