Project: Research project

Project Details


Considerable information now exists on the distribution of neurotensin
(NT), an endogenous tridecapeptide in the mammalian central nervous system
(CNS). The presence of high affinity binding sites for the peptide in the
CNS, its depolarization-induced release and the alteration in neuronal
firing rates after central application of the peptide all provide evidence
of its role as a neurotransmitter or neuromodulator in the CNS. Much work
conducted by our group, as well as by others, has demonstrated interactions
of NT with CNS dopamine (DA) neurons. Neuroanatomical studies in which NT
or NT binding sites have been localized have shown the presence of both the
peptide and its receptors in proximity to or on DA neurons. In previous
studies, we have demonstrated that centrally administered NT induces
effects reminiscent of antipsychotic drugs. Thus, injection of NT into the
nucleus accumbens, a major terminal site of the mesolimbic DA system, like
antipsychotic drugs, blocks the effects of DA. Chronic antipsychotic drug
treatment produces selective alterations in NT concentration in certain
brain areas such as the neostriatum and nucleus accumbens. Previous
studies have also shown reduced concentrations of NT in cerebrospinal fluid
(CSF) of schizophrenic patients. In the present proposal we shall study in
more detail the neurobiology of NT with particular emphasis on NT-DA
interactions. The goals in our preclinical studies include: (1) elucidate
NT-containing neural pathways in the rat brain, (2) determine whether high
affinity NT binding sites are altered after destruction of NT pathways, (3)
determine the effect of NT on DA-dependent and DA-independent
phosphorylation in the rat CNS, (4) characterize in greater detail the
effects of chronic antipsychotic drug treatment on NT-containing neurons in
the CNS, (5) determine the effect of NT on DA autoreceptors, (6) determine
the effect of NT on the supersensitivity induced by destruction of DA
neurons, and (7) evaluate the effects of chronic NT administration on CNS
DA systems. In our clinical studies we shall continue to assess the
activity of NT-containing neurons by measurement of NT in CSF and
post-mortem brain tissue of schizophrenic patients and measurement of high
affinity NT receptors in post-mortem brain tissue. These studies of NT-DA
interactions should provide novel findings relevant to the neurobiology of
schizophrenia, as well as to the mechanism of action of antipsychotic drugs.
Effective start/end date2/1/9012/31/95


  • National Institute of Mental Health
  • National Institute of Mental Health
  • National Institute of Mental Health


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