β₂and α₂adrenergic receptors mediate the proneurogenic in vitro effects of norquetiapine

Positive modulation of adult hippocampal neurogenesis may contribute to the therapeutic effects of clinically relevant antidepressant drugs, including atypical antipsychotics. Quetiapine, an antipsychotic which represents a therapeutic option in patients who are resistant to classical antidepressants, promotes adult hippocampal neurogenesis in preclinical studies. Norquetiapine, the key active metabolite of quetiapine in humans, has a distinctive receptor profile than the parent compound. The drug is indeed a high affinity norepinephrine transporter inhibitor and such activity has been proposed to contribute to its antidepressant effect. At present, no information is available on the effects of norquetiapine on adult neurogenesis. We extensively investigated the activity of quetiapine and norquetiapine on adult murine neural stem/progenitor cells and their progeny. Additionally, selective antagonists for β₂/α₂adrenergic receptors allowed us to evaluate if these receptors could mediate quetiapine and norquetiapine effects. We demonstrated that both drugs elicit in vitro proneurogenic effects but also that norquetiapine had distinctive properties which may depend on its ability to inhibit norepinephrine transporter and involve β₂/α₂adrenergic receptors. Animal care and experimental procedures were approved by the Institutional Animal Care and Use Committees (IACUC) at University of Piemonte Orientale, Italy (approval No. 1033/2015PR) on September 29, 2015.