Nicotinic agonist improves cognitive performance

Anyone who has spent some time around individuals diagnosed with schizophrenia can tell you one thing: they smoke. Even now that smoking amongst the general population has fallen to around 25% (depending upon who is doing the measuring and who is being measured) prevalence of smoking behavior amongst patients with schizophrenia ranges from 60 to 90%. So, why is that?

Researchers have believed for some time that this is a form of self-medication, and there is evidence that smoking improves performance on cognitive tasks (for both patients and controls). It is believed that the acetylcholine agonist nicotine is responsible for this improvement, and it just so happens that a polymorphism of nicotinic receptors (of the alpha 7 type) is associated with schizophrenia. But it probably isn’t a good idea to prescribe smoking to patients. So what do you do? Develop an alpha 7 agonist of your own.

Castner, et. al (2010) administered ADZ0328 (developed by AstraZeneca) to rhesus macaques and measured performance on a delayed matching to sample task. One limitation of this study is the use of one cognitive task as a behavioral measure of improved cognition. Despite this, the nicotinic agonist improved performance in a dose dependent manner (with an inverted U curve). After determining the optimal dose, researchers showed that their drug improved performance on both long and short delays, was present in all subjects (not just a few outliers), and led to improved performance over an extended period of time (two months). This last piece of data was not particularly convincing to me as the effect was not strong, and I’m not certain that practice effects didn’t come in to play. Oh, and they did measure plasma levels of the drug to make sure it was in the monkey’s system. That’s always kind of important.

So what is the utility of this study? For years there were two somewhat competing theories of schizophrenia, the dopaminergic and glutamatergic hypotheses. In the past few decades work has been done to try reconciling these theories. For example, neuregulin (NRG1) alters LTP (a glutamate dependent activity) through through a dopamine dependent mechanism. Others have shown that kynurenic acid, an antagonist of the NMDA glutamate receptor, also blocks the alpha-7 nicotinic receptor … which is associated with dopaminergic neurons. This study may add some more meat to this putative connection and offer a treatment for improving some of the negative symptoms of schizophrenia.

Castner SA, Smagin GN, Piser TM, Wang Y, Smith JS, Christian EP, Mrzljak L, & Williams GV (2011). Immediate and sustained improvements in working memory after selective stimulation of α7 nicotinic acetylcholine receptors. Biological psychiatry, 69 (1), 12-8 PMID: 20965497