We have developed a system, the rat olfactory tubercle (a part of the limbic cortex located at the ventral forebrain) that is particularly useful for chemical and anatomical studies of dopaminergic and neuroleptic function. This region is rich in dopamine (DA) and DA receptors and its neuronal populations are organized in well separated laminae. We have identified two neuronal populations, the pyramidal and granule neurons of the olfactory tubercle, that are rich in DA receptors and seem likely targets for the actions of DA and neuroleptics. We have shown that intracranial injection of DA directly into the olfactory tubercle in vivo produces a substantial (3-5-fold) increase in cyclic AMP levels. We propose in vivo and in vitro studies of neuronal and receptor response to DA and to neuroleptics. We propose to inject dopaminergic agonists and neuroleptic drugs, separately and in combination, directly into the olfactory tubercle and quantitate the effects upon cyclic AMP levels. We will identify the neuronal populations in which the increases occur. We will compare the dose response curves obtained for rats acutely and chronically treated with neuroleptics and for animals that have been depleted of dopamine or steroids by denevation with 6 OH-DA or castration. In vitro studies of D1 and D2 receptors, glutamic acid decarboxylase, and aromatase, will be carried out as well. The proposed experiments will provide information about neuroleptic action at D1 and D2 receptors in vivo and enable us to compare the relative efficacies of a range of different neuroleptics. They bear directly upon the hypotheses that dopamine and neuroleptics act at both D1 and D2 receptors in vivo, that the action of DA at D2 receptors in vivo inhibits adenylate cyclase, and that antipsychotic drugs exert their therapeutic effects by their actions at DA receptors. The in vivo protocol we have developed provides neurochemical criteria (i.e. changes in cyclic AMP levels) that could help to predict antipsychotic potencies anc could provide the basis for a method of screening neuroleptic drugs. Our long term objectives are the development of more effective drugs for the treatment of psychosis and insight into its organic pathology.
