Studies are proposed on a novel peptide anaolog of neurotensin (NT), called NT69L, which may be representative of a new class of drugs for treatment of schizophrenia. This compound is presently in preclinical toxicology testing for an Investigational New Drug application to the U.S. Food and Drug Administration so that we can do a pilot study in schizophrenic patients. Experiments to date on NT69L in rodents animals, including prepulse inhibition studies, strongly suggest that it will have antischizophrenic effects. In addition, preliminary in vivo microdialysis studies, suggest that it will also have cognitive- enhancing effects. We are hypothesizing that NT69L is similar in its behavioral and in its biochemical effects to clozapine, the classical, atypical antipsychotic drug. Additionally, we are hypothesizing that some of the behavioral effects of clozapine are mediated through neurotensin receptors (subtype 1).
The Specific Aims of the proposed research are: 1) Determine the time course for the onset and offset of the reversal by NT69L of drug-induced disruption of prepulse inhibition and the dose-response for its effects, after a single injection and after 21 daily injections (subchronic treatment) of NT69L;2) Compare the effects of the typical antipsychotic drug haloperidol and the atypical antipsychotic drug clozapine with those of NT69L on the reversal of drug-induced disruption of prepulse inhibition, after a single injection and after 21 daily injections of these antipsychotic drugs;3) Determine the ability of NT69L to regulate protein expression with acute treatment and subchronic treatment and compare these effects on protein expression with those of clozapine and those of haloperidol, given once and after 21 daily injections;4) Determine the neurotensin receptor subtype specificity of NT69L for several of its behavioral effects;6) Determine whether some of clozapine's behavioral effects require NT receptors, subtype 1. To do these studies we will make use of animal behavioral tests predictive of antipsychotic efficacy (e.g., drug-induced disruption of prepulse inhibition);advanced methods of proteomics research;antisense peptide nucleic acids targeting neurotensin receptors, subtype 1 and 2;and knockout mice lacking neurotensin receptors (either subtype 1 or subtype 2).
