Alpha2‐Adrenoceptor Blockade Accelerates the Neurogenic, Neurotrophic, and Behavioral Effects of Chronic Antidepressant Treatment

Abstract

Enhanced adult hippocampal neurogenesis and increased trophic factor expression mediate the behavioral effects of antidepressants. We investigated the influence of alpha2‐adrenoceptors on adult hippocampal neurogenesis. We found that alpha2 agonists selectively decrease adult hippocampal progenitor proliferation. These effects persist in Dbh−/− mice lacking norepinephrine, suggesting an action through alpha2‐heteroceptors. Adult hippocampal progenitors express all the alpha2‐adrenoceptor subtypes, and decreased neurosphere frequency and BrdU incorporation indicate direct effects of Alpha2‐adrenoceptor stimulation on progenitors. Furthermore, coadministration of the alpha2 antagonist yohimbine with the antidepressant imipramine accelerates effects on hippocampal progenitor proliferation, the maturation of newborn neurons, and the increase in expression of BDNF and VEGF implicated in the neurogenic and behavioral effects of antidepressants. Finally, short‐duration (7 d) yohimbine and imipramine treatment results in robust behavioral responses in the novelty suppressed feeding test, which normally requires 3 weeks of treatment with classical antidepressants. Our results highlight importance of alpha2‐adrenoceptors as targets for faster acting antidepressants.