David Feifel
University Of California San Diego
Project start date: 2009-03-20
Project end date: 2014-01-31
Sponsored Links Excellgen http://Excellgen.com
NEUROTENSIN-1 RECEPTOR AS A THERAPEUTIC TARGET FOR SCHIZOPHRENIA
David Feifel, Associate Professor
University Of California San Diego, 9500 Gilman Dr, Dept 0934, La Jolla, Ca 92093-0934
Grant 5R01MH080910-02 from National Institute Of Mental Health
Abstract: Neurotensin (NT) is brain peptide that regulates brain pathways involved in psychosis and in the therapeutic effects of antipsychotic drugs. Converging evidence suggests that the therapeutic effects of current antipsychotic drugs are mediated by stimulation of endogenous NT. Based upon this evidence, it has been proposed that targeting the NT system may be a productive strategy for developing novel antipsychotic drugs. The NT1 receptor has been implicated in NT´s antipsychotic effects. Recently developed NT mimetics that enter the brain after peripheral administration and selectively target NT1 receptors have provided excellent tools to investigate this possibility. Preliminary findings from the Principal Investigator´s laboratory indicate that these NT1 agonists produce highly robust antipsychotic- like effects in animal models. In some cases the effects of the NT1 agonists are more robust than the effects exhibited by existing antipsychotic drugs. The mechanism underlying these highly robust effects is not known. The research proposed has two broad goals. First to expand on the promising evidence that that NT1 agonists have potential as novel antipsychotic drugs, focusing in particular on exciting preliminary findings that they may have efficacy on cognitive deficits associated with schizophrenia, an area strongly in need of better treatments. This goal will be accomplished by testing the effects of NT1 agonists in a battery of animal models of cognitive deficits that have relevance to schizophrenia. A second goal is to elucidate the brain circuitry underlying the APD-like effects of endogenous NT and exogenous NT1 agonists. Specifically, experiments will test the hypothesis that both exogenously administered NT1 agonists and endogenous NT released in response to existing antipsychotic drugs produce antipsychotic-like effects by activating NT1 receptors located downstream to the site of action of existing antipsychotic drugs in the antipsychosis pathway. This goal will be accomplished via a number of experimental techniques including administering selective NT1 antagonists into candidate brain sites in order to block the effects of an NT1 agonist and of existing antipsychotics in established animal models that are predictive of antipsychotic activity. If confirmed, this would strongly support the rationale for development of NT1 agonists as potential "breakthrough" antipsychotic drugs that could have advantages relative to existing antipsychotics because they bypass initial elements of the antipsychosis pathway activated by existing antipsychotic drugs. It would also significantly add to our current understanding of the mechanism by which existing antipsychotic drugs work. Schizophrenia is a debilitating disorder for which current treatments are unsatisfactory. We propose studies aimed at investigating the possibility of developing novel treatments that target neurotensin, a natural chemical in the brain. The proposed experiments may help lead to completely novel and superior treatments for schizophrenia
Keywords: 1-Buta, 4-(4-(4-chlorophenyl)-4-hydroxy-1-piperidinyl)-1-(4-fluorophenyl)-; 3, 4-Dihydroxyphenethylamine; 3-(2-Aminoethyl)-1H-indol-5-ol; 4-(2-Aminoethyl)-1, 2-benzenediol; 4-Aminobutanoic Acid; 4-Aminobutyric Acid; 5-HT; 5-Hydroxytryptamine; 5H-Dibenzo(b, e)(1, 4)diazepine, 8-chloro-11-(4-methyl-1-piperazinyl)-; 5HT; Abbreviations; Accounting; Affinity; Agonist; Aminalon; Aminalone; Amphetamines; Animal Model; Animal Models and Related Studies; Antipsychotic Agents; Antipsychotic Drugs; Antipsychotics; Area; Attenuated; Blood - brain barrier anatomy; Blood-Brain Barrier; Body of uterus; Brain; Butanoic acid, 4-amino-; Bypass; Cells; Central Nervous System; Chemicals; Clinical; Clozapine; Cognitive deficits; Common Rat Strains; Complement; Complement Proteins; Corpus; Corpus Uteri; Development; Discrimination, Social; Disease; Disorder; Dopamine; Down-Regulation; Down-Regulation (Physiology); Downregulation; Drug Delivery; Drug Delivery Systems; Drug Targeting; Drug Targetings; Elements; Encephalon; Encephalons; Enteramine; Exhibits; Future; GABA; Globus Pallidus; Goals; Haldol; Haloperidol; Hemato-Encephalic Barrier; Hippophaine; Hydroxytyramine; Knockout Mice; Knowledge; Laboratories; Lead; Major Tranquilizers; Mammals, Mice; Mammals, Rats; Medial; Mediating; Memory, Immediate; Memory, Short-Term; Memory, Shortterm; Methods and Techniques; Methods, Other; Mice; Mice, Knock-out; Mice, Knockout; Microdialysis; Murine; Mus; NIH; NT1-R protein; NTR-1 protein; National Institutes of Health; National Institutes of Health (U.S.); Nerve Transmitter Substances; Nervous System, Brain; Nervous System, CNS; Neuraxis; Neurochemistry; Neuroleptic Agents; Neuroleptic Drugs; Neuroleptics; Neuropeptides; Neurotensin; Neurotensin Receptors; Neurotransmitters; Norway; Nucleus Accumbens; Null Mouse; Pathway interactions; Pb element; Peptides; Peripheral; Pharmaceutical Resources; Population; Prefrontal Cortex; Principal Investigator; Process; Psychoses; Psychotic Disorders; Rat; Rats, Norway; Rattus; Rattus norvegicus; Receptor Protein; Receptors, Neurotensin; Relative; Relative (related person); Research; Role; Saline; Saline Solution; Schizophrenia; Schizophrenic Disorders; Science of neurochemistry; Serotonin; Short-Term Memory; Site; Social Discrimination; System; System, LOINC Axis 4; Techniques; Testing; Therapeutic; Therapeutic Effect; Tranquilizing Agents, Major; Transmission; United States National Institutes of Health; Uterine Body; Visual attention; Work; base; brain pathway; computer based prediction; dementia praecox; design; designing; disease/disorder; drug development; drug efficacy; experiment; experimental research; experimental study; gamma-Aminobutyric Acid; genetic manipulation; heavy metal Pb; heavy metal lead; improved; interest; intraperitoneal; mimetics; model organism; neurochemistry; neurotensin type 1 receptor; novel; overexpression; pallidum; pathway; postsynaptic; pre-clinical; preclinical; predictive modeling; prepulse inhibition; processing speed; public health relevance; receptor; research study; response; schizophrenic; social; social role; subcutaneous; theories; therapeutic target; tool; transmission process; working memory
Relevance: NARRATIVE Schizophrenia is a debilitating disorder for which current treatments are unsatisfactory. We propose studies aimed at investigating the possibility of developing novel treatments that target neurotensin, a natural chemical in the brain. The proposed experiments may help lead to completely novel and superior treatments for schizophrenia
Project start date: 2009-03-20
Project end date: 2014-01-31
Budget start date: 1-FEB-2010
Budget end date: 31-JAN-2011
PFA/PA: PA-07-070
5R01MH080910-02 (2010): $386250
Grants awarded to David Feifel
Antipsychotic-Like Drug Effects Of Neurotensin
David Feifel
Psychiatryuniversity Of California San Diego
9500 Gilman Dr, Dept 0934
la Jolla, Ca 920930934
Grant 1R01MH062451-01A2 from National Institute Of Mental Health IRG: IFCN
Abstract: Neurotensin (NT), a neuropeptide that does not have affinity for dopamine or serotonin receptors, has been shown to produce antipsychotic drug (APD)-like preclinical effects when administered directly into the brain. These findings have raised the possibility that NT agonists may be developed as novel APDs. Recently, NT agonists that access the brain after systemic administration have become available and they are excellent tools to study the APD potential of NT. Preliminary studies conducted in the PI´s laboratory testing these NT agonists in animal models of deficient prepulse inhibition (PPI) of the startle response, support the contention that they have APD-like potential. One aim of this application is to investigate the APD profile of NT agonists. Using prototypical APDs of the typical and atypical families as comparators, the proposed studies will test the NT agonist PD149163 in complementary behavioral and molecular animal models that are highly predictive of the clinical efficacy of APDs. These studies will specifically investigate whether systemically administered PD149163 is likely to have a therapeutic effect on positive psychotic symptoms and negative symptoms, and whether it is likely to induce extrapyramidal side effects. Whether PD149163´s APD-like effects are mediated by NT receptors will also be investigated by using selective NT antagonists. Established APDs stimulate synthesis and release of endogenous NT in the brain, and preliminary studies suggest that endogenous NT may mediate the effects of APDs. Therefore, a second aim of this proposal is to test the contention that endogenous NT contributes to the therapeutic effects of established APDs. Experiments will investigate the ability of NT antagonists to inhibit the effects of typical and atypical APDs in two nonpharmacological animal models of PPI that are predictive of clinical APD efficacy. Results of the proposed studies are predicted to support the contention that endogenous NT mediates the effects of APDs by activating NTR1 receptors and that exogenous NT agonists, like PD149163, produce atypical APD-like effects by activating the same receptors. These findings would support the development of NT-based, novel APDs and also drive future studies aimed at elucidating the circuitry for NT-mediated APD effects as a means of understanding the mechanisms underlying the therapeutic effects of APDs that occur beyond the well-established receptor actions they produce
Keywords: antipsychotic agent, drug design /synthesis /production, neuropeptide receptor, neurotensin, pharmacokinetics disease /disorder model, inhibitor /antagonist, schizophrenia, stimulant /agonist laboratory rat
Project start date: 2002-06-01
Project end date: 2005-05-31
1R01MH062451-01A2 (2002): $266000
5R01MH062451-03 (2004): $266000
5R01MH062451-02 (2003): $266000
Neurotensin-1 Receptor As A Therapeutic Target For Schizophrenia
David Feifel
Psychiatryuniversity Of California San Diego
Grant 1R01MH080910-01A2 from National Institute Of Mental Health IRG: BRLE
Abstract: Neurotensin (NT) is brain peptide that regulates brain pathways involved in psychosis and in the therapeutic effects of antipsychotic drugs. Converging evidence suggests that the therapeutic effects of current antipsychotic drugs are mediated by stimulation of endogenous NT. Based upon this evidence, it has been proposed that targeting the NT system may be a productive strategy for developing novel antipsychotic drugs. The NT1 receptor has been implicated in NT´s antipsychotic effects. Recently developed NT mimetics that enter the brain after peripheral administration and selectively target NT1 receptors have provided excellent tools to investigate this possibility. Preliminary findings from the Principal Investigator´s laboratory indicate that these NT1 agonists produce highly robust antipsychotic- like effects in animal models. In some cases the effects of the NT1 agonists are more robust than the effects exhibited by existing antipsychotic drugs. The mechanism underlying these highly robust effects is not known. The research proposed has two broad goals. First to expand on the promising evidence that that NT1 agonists have potential as novel antipsychotic drugs, focusing in particular on exciting preliminary findings that they may have efficacy on cognitive deficits associated with schizophrenia, an area strongly in need of better treatments. This goal will be accomplished by testing the effects of NT1 agonists in a battery of animal models of cognitive deficits that have relevance to schizophrenia. A second goal is to elucidate the brain circuitry underlying the APD-like effects of endogenous NT and exogenous NT1 agonists. Specifically, experiments will test the hypothesis that both exogenously administered NT1 agonists and endogenous NT released in response to existing antipsychotic drugs produce antipsychotic-like effects by activating NT1 receptors located downstream to the site of action of existing antipsychotic drugs in the antipsychosis pathway. This goal will be accomplished via a number of experimental techniques including administering selective NT1 antagonists into candidate brain sites in order to block the effects of an NT1 agonist and of existing antipsychotics in established animal models that are predictive of antipsychotic activity. If confirmed, this would strongly support the rationale for development of NT1 agonists as potential "breakthrough" antipsychotic drugs that could have advantages relative to existing antipsychotics because they bypass initial elements of the antipsychosis pathway activated by existing antipsychotic drugs. It would also significantly add to our current understanding of the mechanism by which existing antipsychotic drugs work. Schizophrenia is a debilitating disorder for which current treatments are unsatisfactory. We propose studies aimed at investigating the possibility of developing novel treatments that target neurotensin, a natural chemical in the brain. The proposed experiments may help lead to completely novel and superior treatments for schizophrenia
Project start date: 2009-03-20
Project end date: 2014-01-31
OLANZAPINE + DEVALPROEX VS PLACEBO + DEVALPROEX
David Feifel
University Of California San Diego 9500 Gilman Dr, Dept 0934 La Jolla, Ca 920930934
Grant 2M01RR000827-260988 from National Center For Research Resources IRG: RIRG
Abstract: Determine whether a pharmacokinetic or pharmacodynamic drug interaction occurs during the co-administration of divalproex sodium and olanzapine, determine the safety of the co-administered drugs, determine the physiologic disposition of olanazpine in combination with divalproex sodium, assess the effects of single dose and multiple doses of olanzapine on steady-state valproic acid concentrations, and evaluate the neuroendocrine effects of the combined drugs.
Keywords: antipsychotic agent, combination chemotherapy, human therapy evaluation, mental disorder chemotherapy, serotonin inhibitor, valproate, clinical trial phase II /III /IV, psychopharmacology, clinical research, human subject
Project start date: 1974-03-01
Project end date: 2004-11-30
A Novel Animal Model Of Relevance To Schizophrenia
David Feifel
University Of California San Diego 9500 Gilman Dr, Dept 0934 La Jolla, Ca 920930934
Grant 5R01MH070700-03 from National Institute Of Mental Health IRG: BRLE
Abstract: Brattleboro (BB) rats have a single gene mutation causing abnormal vasopressin production. Preliminary findings from the PI s laboratory indicate that the BB rat may be developed as an animal model of schizophrenia-relevant information processing abnormalities that has unique strong features and practical advantages compared to existing animal models including 1) genetically based (i.e., non-induced), stable deficits in prepulse inhibition (PPI), startle habituation, and cognitive function that are analogous to schizophrenia, 2) reversal by drugs with antipsychotic efficacy, 3) the ability to distinguish established antipsychotic drugs with distinct clinical profiles (e.g., "typical" versus "atypical"), 4) sensitivity to drugs that produce antipsychotic-like effects via non-traditional mechanisms (e.g., neuropeptides), 5) the ability to model the chronic time course associated with optimal therapeutic effects of antipsychotic drugs, 6) pathophysiology features that are analogous to schizophrenia (e.g., D2 receptor elevation), and 7) an apparent etiology (vasopressin deficiency) for these deficits that has not been well studied, and may therefore provide new insights into mechanisms contributing to schizophrenia. In a series of proposed experiments (Specific Aim 1) the sensitivity and specificity of the reversal of BB PPI deficits for drugs with antipsychotic efficacy will be further assessed. This will be done by testing several established typical and atypical antipsychotics, non-antipsychotic psychotropic drugs, as well as novel antipsychotics with non-conventional mechanisms (i.e., aripiprazole, amisulpride). A separate set of experiments (Specific Aim 2) will be aimed at characterizing the extent of the homology between BB rats and schizophrenia patients by assessing if the BB rat also exhibits antipsychotic-sensitive deficits in latent inhibition and social memory, whether their schizophrenia-like deficits are due to genetic versus parenting factors (via cross-fostering), and if they exhibit a schizophrenia-like ontological emergence. A third set of studies (Specific Aim 3) will investigate the mechanisms underlying BB PPI deficits by 1) examining the effects of selective dopamine and serotonin antagonists, 2) measuring brain levels of dopamine and serotonin receptors, and 3) examining whether central vasopressin replacement restores PPI. The successful development of this animal model could significantly enhance the understanding of the underlying causes of schizophrenia-associated abnormalities and improve drug discovery.
Keywords: arginine vasopressin, behavioral genetics, disease /disorder etiology, disease /disorder model, dopamine receptor, laboratory rat, model design /development, psychopathology, schizophrenia, antipsychotic agent, behavioral habituation /sensitization, dopamine antagonist, drug screening /evaluation, gene mutation, memory disorder, mental disorder chemotherapy, neurogenetics, nonhuman therapy evaluation, psychopharmacology, sedative /hypnotic, sensory feedback, serotonin receptor, behavior test, behavioral /social science research tag, transfection /expression vector
Project start date: 2005-08-05
Project end date: 2010-07-31
5R01MH070700-03 (2007): $219741
5R01MH070700-02 (2006): $226304
1R01MH070700-01A2 (2005): $225526
5R01MH070700-04 (2008): $219741
OLANZAPINE + DEVALPROEX VS PLACEBO + DEVALPROEX
David Feifel
University Of California San Diego 9500 Gilman Dr, Dept 0934 La Jolla, Ca 920930934
Grant 5M01RR000827-290988 from National Center For Research Resources IRG: RIRG
Sponsored Links Excellgen http://Excellgen.com