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 #
5P50MH086383-05
Application #
8515788
Study Section
Special Emphasis Panel (ZMH1-ERB-F)
Project Start
Project End
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
5
Fiscal Year
2013
Total Cost
$263,123
Indirect Cost
$91,149
Name
University of Colorado Denver
Department
Type
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
Wilking, Jennifer A; Stitzel, Jerry A (2015) Natural genetic variability of the neuronal nicotinic acetylcholine receptor subunit genes in mice: Consequences and confounds. Neuropharmacology 96:205-12
Bates, R C; Stith, B J; Stevens, K E et al. (2014) Reduced CHRNA7 expression in C3H mice is associated with increases in hippocampal parvalbumin and glutamate decarboxylase-67 (GAD67) as well as altered levels of GABA(A) receptor subunits. Neuroscience 273:52-64
Stevens, Karen E; Choo, Kevin S; Stitzel, Jerry A et al. (2014) Long-term improvements in sensory inhibition with gestational choline supplementation linked to ?7 nicotinic receptors through studies in Chrna7 null mutation mice. Brain Res 1552:26-33
McClure-Begley, Tristan D; Grady, Sharon R; Marks, Michael J et al. (2014) Presynaptic GABAB autoreceptor regulation of nicotinic acetylcholine receptor mediated [(3)H]-GABA release from mouse synaptosomes. Biochem Pharmacol 91:87-96
Wildeboer-Andrud, Kristin M; Zheng, Lijun; Choo, Kevin S et al. (2014) Cotinine impacts sensory processing in DBA/2 mice through changes in the conditioning amplitude. Pharmacol Biochem Behav 117:144-50
Law, Amanda J (2014) Genetic mouse models of neuregulin 1: gene dosage effects, isoform-specific functions, and relevance to schizophrenia. Biol Psychiatry 76:89-90
Tregellas, Jason R (2014) Neuroimaging biomarkers for early drug development in schizophrenia. Biol Psychiatry 76:111-9
Tregellas, Jason R; Smucny, Jason; Harris, Josette G et al. (2014) Intrinsic hippocampal activity as a biomarker for cognition and symptoms in schizophrenia. Am J Psychiatry 171:549-56
Paterson, Clare; Wang, Yanhong; Kleinman, Joel E et al. (2014) Effects of schizophrenia risk variation in the NRG1 gene on NRG1-IV splicing during fetal and early postnatal human neocortical development. Am J Psychiatry 171:979-89
Smucny, Jason; Stevens, Karen E; Tregellas, Jason R (2014) Acute administration of ?? tetrahydrocannabinol does not prevent enhancement of sensory gating by clozapine in DBA/2 mice. Pharmacol Biochem Behav 118:22-9

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