The present proposal will extend our previous studies of the neuroanatomic basis of action of anti-depressant (AD) drugs in order to resolve some outstanding issues concerning the pharmacology of AD drug action. Based on data suggesting that not all AD drugs have common sties of action, one outstanding issue concerns where in brain drugs act. This issue will be pursued using autoradiographic localization of AD binding sires, autoradiography of sites where adaptive changes in receptor binding occur following chronic AD administration, and delineation of sites where microinjections of AD drugs produce behavioral responses in the forced swim test. These three approaches will permit us to test the hypothesis that AD drugs with different pharmacological profiles act at distinct sites in brain. The results from work testing these hypotheses will permit us to formulate a theoretical anatomical network through which we can describe how AD drugs with differing neural mechanisms can induce common behavioral and adaptive receptor changes. Another outstanding issue is the lack of congruence between biochemical measures of monoamine receptor adaptation and measures of electrophysiological responses to monoamines receptors adaptation treatment. Two hypotheses will be tested to resolve this issue. First, studies will examine the hypotheses that anatomical specificity of receptor adaptation is responsible for the lack of congruence. It is anticipated that consistent changes in electrophysiological responses to monoamines will be observed only at cellular sites where receptor adaptation occurs. The second hypothesis, that receptor-receptor interactions are responsible for the lack of congruence between measures of receptor adaptation and electrophysiological responses, will involve electrophysiological examination of neurotransmitter interactions observed in biochemical studies. This work is expected to resolve the question of why down-regulation of a receptor subtype for a neurotransmitter by AD drugs can lead to an enhancement of the effect of a neurotransmitter on neural activity. This multidisciplinary grant provides new strategies to explore the pharmacological effects of AD drugs which will advance our knowledge of AD drugs action and lead to the development of new hypotheses to guide future research.
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