Neurotensin and cholecystokinin have both demonstrated """"""""neuroleptic- like"""""""" properties when tested in animal studies. Both of these peptides are contained in CNS projections to brain regions associated with behavior and alterations in CCK and NT levels have been reported in post-mortem brains from patients diagnosed with schizophrenia. These data together with the close morphological association of CCK and NT with dopamine leads us to speculate that there is a role for NT and CCK in schizophrenia. Antipsychotic drugs used to treat schizophrenia have also shown a well documented effect on CCK and NT brain levels and metabolic enzymes. Since the metabolic rates of peptide precursors are generally determined by the specific peptidases associated with peptide metabolism, insight into the mechanisms controlling CCK and NT metabolism in neuronal systems can further elucidate the role of CCK and NT in the brain with respect to mental disease. The hypothesis that we will test is that metabolic enzymes associated with CCK and NT-producing cells can be affected by antipsychotic drugs. Among the mechanisms proposed for modulation of peptidergic systems by antipsychotic drugs has been the regulation of the rate of peptide degradation at its site of action. In turn, enzymatic hydrolysis may also result in the formation of new and biologically active peptide fragments by the same enzymes. Therefore, proteolytic enzymes play a crucial role in peptidergic systems. Consequently, experiments in CCK-and NT areas of the brain in vivo in rats exposed to drug treatments are planned to evaluate the physiological significance using intact, discrete, regional brain slices. We are very confident that we will be successful in determining how CCK and NT are affected by antipsychotic drugs.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH042600-06
Application #
2245486
Study Section
Neurosciences Research Review Committee (BPN)
Project Start
1988-04-01
Project End
1996-08-31
Budget Start
1994-09-01
Budget End
1995-08-31
Support Year
6
Fiscal Year
1994
Total Cost
Indirect Cost
Name
University of Arizona
Department
Pharmacology
Type
Schools of Medicine
DUNS #
City
Tucson
State
AZ
Country
United States
Zip Code
85721
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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