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

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Specialized Center (P50)
Project #
Application #
Study Section
Special Emphasis Panel (ZMH1-ERB-F)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Colorado Denver
United States
Zip Code
Kem, William R; Olincy, Ann; Johnson, Lynn et al. (2018) Pharmacokinetic Limitations on Effects of an Alpha7-Nicotinic Receptor Agonist in Schizophrenia: Randomized Trial with an Extended-Release Formulation. Neuropsychopharmacology 43:583-589
Smucny, Jason; Tregellas, Jason R (2017) Targeting neuronal dysfunction in schizophrenia with nicotine: Evidence from neurophysiology to neuroimaging. J Psychopharmacol 31:801-811
Hutchison, Amanda K; Hunter, Sharon K; Wagner, Brandie D et al. (2017) Diminished Infant P50 Sensory Gating Predicts Increased 40-Month-Old Attention, Anxiety/Depression, and Externalizing Symptoms. J Atten Disord 21:209-218
Paterson, Clare; Wang, Yanhong; Hyde, Thomas M et al. (2017) Temporal, Diagnostic, and Tissue-Specific Regulation of NRG3 Isoform Expression in Human Brain Development and Affective Disorders. Am J Psychiatry 174:256-265
Wu, Wei-Li; Hsiao, Elaine Y; Yan, Zihao et al. (2017) The placental interleukin-6 signaling controls fetal brain development and behavior. Brain Behav Immun 62:11-23
Papaleo, Francesco; Yang, Feng; Paterson, Clare et al. (2016) Behavioral, Neurophysiological, and Synaptic Impairment in a Transgenic Neuregulin1 (NRG1-IV) Murine Schizophrenia Model. J Neurosci 36:4859-75
Chow, Ke-Huan; Yan, Zihao; Wu, Wei-Li (2016) Induction of Maternal Immune Activation in Mice at Mid-gestation Stage with Viral Mimic Poly(I:C). J Vis Exp :e53643
D'Anna-Hernandez, Kimberly L; Garcia, Esmeralda; Coussons-Read, Mary et al. (2016) Sleep Moderates and Mediates the Relationship Between Acculturation and Depressive Symptoms in Pregnant Mexican-American Women. Matern Child Health J 20:422-33
Reed, Alexandra C; Harris, Josette G; Olincy, Ann (2016) Schizophrenia, smoking status, and performance on the matrics Cognitive Consensus Battery. Psychiatry Res 246:1-8
Ross, Randal G; Hunter, Sharon K; Hoffman, M Camille et al. (2016) Perinatal Phosphatidylcholine Supplementation and Early Childhood Behavior Problems: Evidence for CHRNA7 Moderation. Am J Psychiatry 173:509-16

Showing the most recent 10 out of 65 publications