Vasopressin and oxytocin are neuropeptides which exert a variety of central nervous system effects in addition to their well-known peripheral hormonal actions. However, very little is known about how these peptides are metabolized in brain. Knowledge of the mechanism of inactivation of these putative neurotransmitters at peptidergic synapses is of key importance to the development of drugs which are designed to influence the central nervous system effects of vasopressin and oxytocin. The purpose of this porposal, therefore, is to identify membrane-bound peptidases in brain which can degrade the neurohypophyseal peptide hormones and to determine the physiological role of these peptidases in the central actions of vasopressin and oxytocin. The problem will be studied at various levels of complexity using both in vitro and in vivo techniques. Metabolism of vasopressin and oxytocin by rat brain slices and synaptosomal plasma membranes will be determined, and relevant enzymes will be purified and characterized. The physiological importance of these enzymes will be elucidated by determining whether specific peptidase inhibitors will prevent the degradation of the peptides in vivo. Furthermore, analogs of vasopressin and oxytocin, designed to be resistant to specific enzymatic clevages, will be tested for their ability to produce prolonged behavioral effects in mice and rats. Metabolism of the peptides in local brain areas rich in vasopressin and oxytocin synapses will be determined by push-pull perfusion of radiolabelled peptide into these areas. Finally, major metabolites identified from these various experimental approaches will be prepared and tested for central nervous system effects of their own.
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