Targeting Nicotine Receptors to Treat Cognitive Impairments in Schizophrenia

Smoking is a common problem for patients with schizophrenia. The increased tendency of patients diagnosed with this disorder is to not only smoke, but to do so more heavily than the general public. This raises the possibility that nicotine may be acting as a treatment for some symptoms of schizophrenia.

Nicotine acts through two general classes of brain receptors, those with high and low affinity for nicotine. The low affinity class of nicotinic receptors contains the alpha-7 subunit, which is present in reduced numbers in people with schizophrenia.

Two papers published in the January 1st issue of Biological Psychiatry suggest that drugs that stimulate these alpha-7 subunit-containing nicotinic receptors might enhance cortical function and treat cognitive impairments associated with schizophrenia.

In their study of healthy monkeys, Graham Williams and colleagues at Yale University and AstraZeneca found that very low doses of AZD0328, a novel drug that acts as an alpha-7 agonist, produced both acute and persistent improvements in their performance on a spatial working memory task.

“Our work demonstrates that that the neuronal nicotinic alpha-7 receptor plays a critical role in the core cognitive function of working memory, which is a key indicator of outcome in patients with schizophrenia,” explained Dr. Williams. “The function of the alpha-7 receptor may account for the ability of a partial agonist to induce long-term beneficial changes for high-order cognition at such low doses.”

This influence on cortical function has been exemplified by the work of Jason Tregellas and colleagues. These researchers examined the effects of DMXB-A, a novel alpha-7 partial agonist, on the brain’s ‘default network’ in people with schizophrenia. Function of the default network, which is likely a major contributor to the intrinsic neuronal activity that accounts for 60-80% of the brain’s energy use, is different in people with schizophrenia.

Dr. Tregellas summarized their findings: “We found that DMXB-A altered default network activity in people with schizophrenia in a pattern consistent with improved function of the network. We also found that these neuronal differences were related to the genotype of the alpha-7 nicotinic receptor and to drug-related improvements in symptoms.”

Together, “these two studies provide additional support for a novel pharmacologic approach to treat cognitive impairments in schizophrenia”, observed Dr. John Krystal, Editor of Biological Psychiatry.


Notes to Editors
The first article mentioned is “Immediate and Sustained Improvements in Working Memory After Selective Stimulation of α7 Nicotinic Acetylcholine Receptors” by Stacy A. Castner, Gennady N. Smagin, Timothy M. Piser, Yi Wang, Jeffrey S. Smith, Edward P. Christian, Ladislav Mrzljak, and Graham V. Williams. Castner and Williams are affiliated with the Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut, and VA Connecticut Healthcare System, West Haven, Connecticut. Smagin, Piser, Wang, Smith, Christian, and Mrzljak are from AstraZeneca Pharmaceuticals, Wilmington, Delaware.

The second mentioned article is “Effects of an Alpha 7-Nicotinic Agonist on Default Network Activity in Schizophrenia” by Jason R. Tregellas, Jody Tanabe, Donald C. Rojas, Shireen Shatti, Ann Olincy, Lynn Johnson, Laura F. Martin, Ferenc Soti, William R. Kem, Sherry Leonard, and Robert Freedman. Tregellas, Tanabe, Rojas, Shatti, Olincy, Johnson, Martin, Leonard, and Freedman are affiliated with the Department of Psychiatry, Denver VA Medical Center, VISN19 MIRECC and University of Colorado—Denver, Aurora, Colorado. Tanabe is also from the Department of Radiology, University of Colorado—Denver, Aurora, Colorado. Soti and Kem are with the Department of Pharmacology and Therapeutics, University of Florida, Gainesville, Florida.

The articles appear in Biological Psychiatry, Volume 69, Number 1 (January 1, 2011), published by Elsevier.

The authors’ disclosures of financial and conflicts of interests are available in their respective articles.

John H. Krystal, M.D. is Chairman of the Department of Psychiatry at the Yale University School of Medicine and a research psychiatrist at the VA Connecticut Healthcare System. His disclosures of financial and conflicts of interests are available here.

The articles mentioned above are available upon request. Contact Chris J. Pfister at to obtain copies or to schedule an interview.

About Biological Psychiatry
This international rapid-publication journal is the official journal of the Society of Biological Psychiatry. It covers a broad range of topics in psychiatric neuroscience and therapeutics. Both basic and clinical contributions are encouraged from all disciplines and research areas relevant to the pathophysiology and treatment of major neuropsychiatric disorders. Full-length reports of novel results, commentaries, case studies of unusual significance, and correspondence judged to be of high impact to the field are published, particularly those addressing genetic and environmental risk factors, neural circuitry and neurochemistry, and important new therapeutic approaches. Concise reviews and editorials that focus on topics of current research and interest are also published rapidly.

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