The behavioral effects of antidepressant drugs in experimental animals are poorly understood, at least in part because these effects have been studied very infrequently under treatment conditions similar to those used clinically (i.e., given once or more daily for at least a several week period). Although the neurochemical mechanism of action of these drugs has been elusive, recent evidence suggests that there are adaptive changes in CNS adrenoreceptor function during the course of chronic treatment with antidepressant drugs, and that these are temporally parallel to the development of therapeutic effects. This correlation between neurochemical change and therapeutic effect offers promise for understanding both the basis of depression and its treatment. In contrast to what is known about neurochemical changes during antidepressant treatment, little is known about behavioral changes during treatment or about the extent to which changes in behavior may be correlated with changes in receptor regulation. Accordingly, this project has two general aims. The first is to systematically study the behavioral effects of chronic treatment with antidepressant drugs of various classes (tricyclics, """"""""atypical"""""""" antidepressants, monoamine oxidase inhibitors). Spontaneous locomotion, operant behavior maintained by various reinforcing events, and behavior suppressed by aversive events will be studied in rats and squirrel monkeys. The second general aim is to explore the behavioral correlates of altered receptor function that occur during chronic antidepressant treatment. Changes in receptor function will be assessed through studies of the behavioral effects of neurotransmitter agonists and antagonists, and through studies of specific binding of radiolabeled agonists and antagonists in brain tissue. Changes in Alpha2- and Beta-adrenoreceptor function will receive primary attention, but possible changes in other neurotransmitter systems will be examined as well. We will also explore the possibility that certain environmental conditions (e.g., scheduled exposure to noxious stimuli) might lead to changes in neurotransmitter function that are opposite to those produced by antidepressants (i.e., changes that might characterize depression). Through systematic work of this nature we hope to better understand the behavioral and neurochemical mechanisms of action of antidepressant drugs.
