The project will continue evaluations of DA-agonist binding sites and receptor functions in mammalian forebrain (striatal and limbic tissues). DA-agonist analog ligands are prepared for use in binding studies to help define the chemical/stereochemical nature of DA-agonist receptor surfaces. The binding will be combined with specific lesions to remove pre- vs. postsynaptic sites to define locations of binding sites, emphasizing explorations aimed at demonstrating presynaptic or autoreceptors. Binding assays are combined with HPLC and radioenzymatic assay methods to measure aporphine levels in tissue as a function of development, aging, drug-interactions--all in correlation with actions on behavior (stimulation of activity via postsynaptic sites vs. inhibition via autoreceptors). Effects of chronic pretreatments with neuroleptics, reserpine, methyltryosine; amphetamine; alone or with LiCl will be evaluated re. receptor binding and function in control of DA turnover and behavioral actions of DA-agonists, as well as binding kinetics in vitro. Similar methods will be applied to study of development, emphasizing characterization of DA-autoreceptor development in young rats. Aporphines with selective activity at DA-autoreceptors will be sought, starting with leads given by at least three candidate novel aporphines now available. Possibly irreversible interactions of alkylating analogs of apomorphine at DA-receptors will continue to be explored, based on our pioneering studies of phenoxybenzamine and chloroethylapomorphine. We will complete promising pilot studies of DA-agonist receptor sites and actions in BALB/c vs. C57BL mouse strains to assess feasibility of genetic studies. We will continue to try to improve methods used in this field, including ligand assays, electronically-assisted behavioral techniques to assess activity patterns and jaw movements induced by high vs. low doses of DA-agonist aporphines, aporphine assays (radioreceptor and HPLC methods), and application of microcomputer technology to all of the above. These studies ar pertinent to neural mechanisms that may underlie the actions of antipsychotic agents, if not the pathophysiology of psychoses and other neuropsychiatric disorders, and which may lead to novel routes of developing antipsychotic and antidyskinetic agents.
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