John Streicher publishes in ‘Neuropsychopharmacology’

John Streicher, Ph.D., assistant professor in the Department of Biomedical Sciences, College of Osteopathic Medicine, and faculty for the Center for Excellence in the Neurosciences, co-authored an article titled “Clozapine acts as an agonist at serotonin 2A receptors to counter MK-801-induced behaviors through a βarrestin2-independent activation of Akt” that was accepted for publication in the journal Neuropsychopharmacology.

The article explores a unique property of the atypical anti-psychotic clozapine. Clozapine has a classical anti-psychotic effect by acting as an antagonist at the serotonin 2A receptor (5HT2AR). However, at the same time, clozapine acts as an agonist at the 5HT2AR to activate certain (but not all) downstream signaling pathways. This dual agonist/antagonist activity may be responsible for some of the unique effects seen with the atypical anti-psychotics.

In this study, Streicher and colleagues, including senior author Laura Bohn of The Scripps Research Institute in Florida, found that while both serotonin and clozapine activate the 5HT2AR, induce receptor internalization, and activate the downstream kinase Akt, this activity required the signaling regulator βarrestin2 for serotonin activity, but not for clozapine activity. In addition, they found that clozapine antagonism of MK-801 and PCP induced behaviors in mice did not require βarrestin2, but did require Akt.

The study, thus, demonstrated how clozapine uniquely activates a specific signaling pathway to induce its effects, which may explain in part the beneficial effects seen with the atypical anti-psychotics. In addition, this study demonstrated that clozapine is a functionally selective drug, with both agonist and antagonist properties.

The article will be available as an e-publication prior to full publication.

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