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). ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH071241-02
Application #
7228467
Study Section
Neural Basis of Psychopathology, Addictions and Sleep Disorders Study Section (NPAS)
Program Officer
Winsky, Lois M
Project Start
2006-05-15
Project End
2010-03-31
Budget Start
2007-04-01
Budget End
2008-03-31
Support Year
2
Fiscal Year
2007
Total Cost
$282,270
Indirect Cost
Name
Mayo Clinic Jacksonville
Department
Type
DUNS #
153223151
City
Jacksonville
State
FL
Country
United States
Zip Code
32224
Smith, Kristin E; Boules, Mona; Williams, Katrina et al. (2011) The role of NTS2 in the development of tolerance to NT69L in mouse models for hypothermia and thermal analgesia. Behav Brain Res 224:344-9
Oliveros, Alfredo; Heckman, Michael G; Del Pilar Corena-McLeod, Maria et al. (2010) Sensorimotor gating in NTS1 and NTS2 null mice: effects of d-amphetamine, dizocilpine, clozapine and NT69L. J Exp Biol 213:4232-9
Li, Zhimin; Boules, Mona; Williams, Katrina et al. (2010) The novel neurotensin analog NT69L blocks phencyclidine (PCP)-induced increases in locomotor activity and PCP-induced increases in monoamine and amino acids levels in the medial prefrontal cortex. Brain Res 1311:28-36
Boules, Mona; Liang, Yanqi; Briody, Siobhan et al. (2010) NT79: A novel neurotensin analog with selective behavioral effects. Brain Res 1308:35-46
Li, Zhimin; Boules, Mona; Williams, Katrina et al. (2010) Similarities in the behavior and molecular deficits in the frontal cortex between the neurotensin receptor subtype 1 knockout mice and chronic phencyclidine-treated mice: relevance to schizophrenia. Neurobiol Dis 40:467-77
Liang, Yanqi; Boules, Mona; Li, Zhimin et al. (2010) Hyperactivity of the dopaminergic system in NTS1 and NTS2 null mice. Neuropharmacology 58:1199-205
Li, Zhimin; Liang, Yanqi; Boules, Mona et al. (2010) Effect of amphetamine on extracellular concentrations of amino acids in striatum in neurotensin subtype 1 and 2 receptor null mice: a possible interaction between neurotensin receptors and amino acid systems for study of schizophrenia. Neuropharmacology 58:1174-8
Briody, Siobhan; Boules, Mona; Oliveros, Alfredo et al. (2010) Chronic NT69L potently prevents drug-induced disruption of prepulse inhibition without causing tolerance. Behav Brain Res 207:118-24