Recent studies have implicated neurotensin and gamma-endorphin fragments of beta endorphin as potential """"""""endogenous neuroleptics"""""""". Our hypothesis is directed at determining if neuroleptic drugs such as haloperidol and chlorpromazine versus centrally acting non-neuroleptics such as apomorphine or promethazine alter the synaptosomal levels or metabolism of neurotensin and/or beta-endorphin in specific brain regions associated with known anatomical projections of these peptidergic systems under consideration. To accomplish our goals, we will use in vivo perfusions of drugs coupled to in vitro incubations for specific tissue organelles with neurotensin and beta-endorphin to determine if the proteolytic metabolism of these peptides is altered. HPLC separations of peptides formed will be coupled to RIA for synaptosomal content of peptides and fragments. A disruption in the synaptosomal levels and/or metabolism of beta- endorphin or neurotensin could lead to an imbalance in homeostatic levels of these peptides. This disruption may be associated with neuroleptic drug treatment causing some of the side effects noted by patients taking these drugs. Therefore, the long-term objective of this proposal is to provide a better understanding of the mode of action of haloperidol and chlorpromazine through peptidergic mechanisms. Since these two drugs are commonly proscribed neuroleptics, it is very important that we clearly understand their effect on beta-endorphin and neurotensin.

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Waters, S M; Rounseville, M P; Davis, T P (1997) Effect of dopaminergic drugs on processing and degradative neuropeptidase mRNA in rat frontal cortex and caudate-putamen. Brain Res 754:28-34
Waters, S M; Davis, T P (1997) Alterations of peptide metabolism and neuropeptidase activity in senile dementia of the Alzheimer's type. Ann N Y Acad Sci 814:30-9
Mania-Farnell, B L; Botros, I; Day, R et al. (1996) Differential modulation of prohormone convertase mRNA by second messenger activators in two cholecystokinin-producing cell lines. Peptides 17:47-54
Waters, S M; Konkoy, C S; Davis, T P (1996) Haloperidol and apomorphine differentially affect neuropeptidase activity. J Pharmacol Exp Ther 277:113-20
Konkoy, C S; Waters, S M; Davis, T P (1996) Subchronic haloperidol administration decreases aminopeptidase N activity and [Met5]enkephalin metabolism in rat striatum and cortex. Eur J Pharmacol 297:47-51
Waters, S M; Konkoy, C S; Davis, T P (1995) Neuropeptide metabolism on intact, regional brain slices: effect of dopaminergic agents on substance P, cholecystokinin and Met-enkephalin degradation. J Pharmacol Exp Ther 274:783-9
Mania-Farnell, B L; Botros, I W; Davis, T P (1995) Modulation of CCK mRNA in cell lines in response to isoproterenol and retinoic acid. Neuropeptides 29:221-7
Waters, S M; David, T P (1995) Alterations of substance P metabolism and neuropeptidases in Alzheimer's disease. J Gerontol A Biol Sci Med Sci 50:B315-9
Mania-Farnell, B L; Merrill, B J; Yamamura, H I et al. (1994) Second messenger activators regulate CCK mRNA in the human neuroepithelioma cell line SK-N-MCIXC. Ann N Y Acad Sci 713:446-8
Brownson, E A; Abbruscato, T J; Gillespie, T J et al. (1994) Effect of peptidases at the blood brain barrier on the permeability of enkephalin. J Pharmacol Exp Ther 270:675-80

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