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.
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