Nicotinic agonist therapy for schizophrenia arose from the Center's discovery of the role of the alpha 7 nicotinic acetylcholine receptor and its gene CHRNA7 in the pathophysiology and genetic transmission of risk for schizophrenia. Although nicotine itself has many undesirable properties, its effects on neurocognition and sensory gating in schizophrenia prompted the search for a safer, more effective agonist. 3-2,4 dimethoxybenzylidene anabaseine (DMXB-A), first synthesized by William Kem in Core C, can be administered orally and produces less tachyphylaxis than nicotine. It also has a more favorable safety profile. Phase 1 and Phase 2 trials conducted by the Center showed promising effects on neurocognition in patients with schizophrenia. Nevertheless, the full possibilites of this target have not yet been determined. DMXB-A's relatively short half life may limit its ability to achieve maximal effects on neurocognition and clinical symptoms. Therefore, we will test a sustained release preparation to assess if more robust effects can be obtained. Imaging of the neurobiological effects using fMRI shows that DMXB-A diminishes hyperactivation of the hippocampus, a trait associated with schizophenia, and increases activity in the medial septal nucleus, the source of cholinergic innervation to the hippocampus, including the alpha 7 nicotinic receptors on inhibitiory interneurons. This imaging strategy will be used to determine if longer acting DMXB-A has increased neurobiological effects or whether its effects are limited by tachyphylaxis. Our studies have been performed in non-smokers to avoid interference from the possible desensitizing effects of nicotine from schizophrenics'heavy chronic nicotine abuse. With the new sustained release preparation, we can test whether DMXB-A will substitute for nicotine in the contextof a smoking cessation treatment program. We will use fMRI to help assess the degree to which nicotine interferes with DMXB-A's effects as persons with schizophrenia who are trying to stop smoking are treated with DMXB-A. Project 1 receives basic research support from Projects 3, 4, 5, and 6. Core C provides DMXB-A.

Public Health Relevance

New therapeutic strategies for schizophrenia are needed to improve cognitive dysfunction and negative symptoms and to prevent the development of psychosis. The Center investigates a nicotinic acetylcholine receptor as a new therapeutic target. Investigational results are used to design a new drug treatment for schizophrenia and a preventative nutrient intervention during infant development, both of which activate this r(arp>ntnr

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Specialized Center (P50)
Project #
3P50MH086383-04S1
Application #
8515782
Study Section
Special Emphasis Panel (ZMH1-ERB-F)
Project Start
2009-08-01
Project End
2014-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
4
Fiscal Year
2012
Total Cost
$17,116
Indirect Cost
$6,005
Name
University of Colorado Denver
Department
Type
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
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