Neurotensin (NT), an endogenous tridecapeptide, is closely associated with CNS dopamine (DA) systems within the mammalian central nervous system (CNS). When administered directly into the CNS of laboratory animals, NT produces pharmacological, neurochemical and behavioral effects similar to those of antipsychotic drugs, particularly those classified as atypical. Typical antipsychotic drugs such as haloperidol increase NT concentrations and proNT mRNA expression in both the nucleus accumbens (a terminal area of the mesolimbic DA system) and the caudate nucleus (a terminal area of the nigroneostriatal DA system). Atypical antipsychotic drugs such as clozapine increase NT concentration and proNT mRNA expression only in the nucleus accumbens. These and other data suggest that the increase in these measures of NT biosynthesis in the nucleus accumbens are predictive of antipsychotic efficacy, whereas the increase in the caudate nucleus are predictive of extrapyramidal side effect (EPS) liability. There is also evidence that NT neuronal function is altered in schizophrenia. The present competitive renewal application seeks to focus on effects of typical and atypical antipsychotic drugs on the synaptic availability of NT in the nucleus accumbens and caudate nucleus, as well as on NT receptor kinetics and NT receptor mRNA expression. The intracellular signalling pathways mediating antipsychotic drug effects on c-fos and NT gene expression will be explored in primary neuronal cultures. Ontogeny and gender effects of antipsychotic drugs on NT neurons and on the CNS effects of NT will be scrutinized, a study of particular interest, in view of increasing evidence that schizophrenia is a neurodevelopmental disorder, and that there are gender differences in this disorder. We will study whether the behavioral effects of typical and atypical antipsychotics are mediated through NT receptor mechanisms. The brain sites of action of intracerebroventricularly administered NT will be mapped by fos immunohistochemistry. The electrophysiological effects of NT itself, and its actions on DA in the major subdivisions of the nucleus accumbens will be characterized. Signal transduction mechanisms mediating the effects of NT receptor activation will be explored in primary neuronal cultures. Finally, a major focus of the present proposal is assessing the role of NT neuronal system alterations in the pathophysiology of schizophrenia by measurement of various indices of NT neuronal function (NT, NT mRNA expression, NT receptor binding and NT receptor mRNA expression) in post- mortem brain tissue of patients who in life were diagnosed as schizophrenic, age- and sex-matched controls and a unique control group (patients with bipolar disorder treated with antipsychotic drugs). These studies will provide novel information concerning the role of NT systems in the mechanism of action of antipsychotic drugs, and in the pathophysiology of schizophrenia.
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