Beta2 and Alpha2 adrenergic receptors mediate the proneurogenic in vitro effects of norquetiapine

Positive modulation of adult hippocampal neurogenesis (ahNG) may contribute to the therapeutic effects of clinically relevant antidepressant drugs, including atypical antipsychotics. Quetiapine (QTP), an antipsychotic which represents a therapeutic option in patients who are resistant to classical antidepressants, promotes ahNG in preclinical studies. Norquetiapine (NORQ), 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 (NET) 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 QTP and NORQ on adult murine neural stem/progenitor cells and their progeny. Additionally, selective antagonists for beta2/alpha2 adrenergic receptors (AR) allowed us to evaluate if these receptors could mediate QTP and NORQ 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 NET and involve beta2/alpha2 AR. Animal care and experimental procedures were approved by the Institutional Animal Care and Use Committees (IACUC) at University of Piemonte Orientale, Novara, Italy (approval No. 1033/2015PR) on September 29, 2015.