EFFECT OF NEUROLEPTICS ON NEUROTENSIN AND BETA-ENDORPHIN

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.