The major objective of this grant is to examine the hypothesis that antidepressants act at selected brain site(s) to produce their action in a standard screening procedure for antidepressant drugs and that rapid induction of adaptive mechanisms is essential for drug effect. Experiments to test these views will require integration of behavioral, neuroanatomical and neurochemical approaches. The test procedure is the forced swim test - a paradigm requiring the administration of at least two doses of the antidepressant drug on consecutive days for a positive result. Since preliminary data indicate that the amygdala is a site of action for imipramine to reduce immobility in the forced swim test, initial work will determine if this site alone is responsible for this effect or whether other brain sites contribute. Experiments are also planned to determine if other classes of therapeutic agents will be effective at this site as well as whether other chemical classes of antidepressant drugs will be active when administered into the amygdala or other sites found to be associated with imipramine's effect in this test. Subsequent work will focus on understanding the neurochemical basis of action of antidepressant drugs in the forced swim procedure. Attention will be given the preliminary finding that imipramine plus the test procedure "down-regulates" Beta - receptors providing support for the hypothesis that stress plus antidepressant treatment causes rapid adaptation of these receptors, similar to that produced by chronic antidepressant treatment. A variety of antidepressant agents as well as psychotropic drugs from other therapeutic classes will be combined with stress to explore whether change in Beta-adrenergic receptor binding seen with imipramine relates to the antidepressant drugs in general. Examination of the site specificity of antidepressants and their effects on Beta-adrenergic receptors have suggested that these procedures may provide additional means to assess with greater certainty whether a compound has potential as a therapeutic agent (i.e., eliminate "false positive" drugs). Finally, experiments will be undertaken to define the role of monoamine mechanisms in adaptive processes induced by antidepressants in the swim test. Our goal will be to integrate results of neurochemical studies with neuroanatomical data. These series of investigations should provide new insights into the neuroanatomical and neurochemical basis of the action of antidepressant agents and permit a critical assessment of monoamine involvement in the pharmacological effects of these drugs and the adaptive processes they produce.
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NIH ExPorter