It has long been suspected that heavy smoking by people with schizophrenia, while as harmful to overall health as for anyone who smokes, is an attempt at self-medication. Nicotine in cigarette smoke rapidly finds its way to a class of keyhole-like molecules in brain cells called nicotinic receptors. Under normal conditions, one of the body’s naturally occurring neurotransmitters, acetylcholine, specifically fits into that keyhole when, for example, a person is recalling short-term memory or performing other cognitive tasks.

But this form of memory, also called working memory, is gravely impaired in the brain of the schizophrenia patient (in addition to other higher cognitive functions). A new study by 2012 NARSAD Young Investigator Grantee Dr. Yang Yang of Yale University Medical School, along with two former NARSAD Independent Investigator Grantees, Dr. Marina Picciotto and Dr. Amy Arnsten, explains for the first time at the level of individual brain cells how and where this self-medicating effect occurs. Equally important, the study, appearing online in Proceedings of the National Academy of Sciences on July 1st, provides strong support for the theory upon which a new class of medications is now being developed. These medications have potential applications for schizophrenia, attention-deficit hyperactivity disorder (ADHD), post-traumatic stress disorder (PTSD) and depression.

Dr. Yang and colleagues studied the brains of primates to locate and specify the functional role of acetylcholine nicotinic receptors in the brain. Also called nicotinic α7 receptors, these molecular keyholes were found in a brain area called the dorsolateral prefrontal cortex (dlPFC). Stimulation of the nicotinic α7 receptor was found to be essential for proper excitation of working-memory circuits in the cortex. When acetylcholine levels are abnormally low, working memory is severely impaired; inhalation of nicotine is an attempt to stimulate the nicotinic α7 receptors. But smoking is not therapy. Carefully designed, non-addictive drugs to stimulate the same receptor, now under development, are shown conceptually in Dr. Yang’s research to have great promise in improving cognitive function in schizophrenia and in addressing deficits in the prefrontal cortex in other brain and behavior disorders in which reductions in cortical activity cause or contribute to pathology.