title: Alpha2-adrenoceptor blockade accelerates the neurogenic, neurotrophic, and behavioral effects of chronic antidepressant treatment.
abstract: Slow-onset adaptive changes that arise from sustained antidepressant treatment, such as enhanced adult hippocampal neurogenesis and increased trophic factor expression, play a key role in the behavioral effects of antidepressants. alpha(2)-Adrenoceptors contribute to the modulation of mood and are potential targets for the development of faster acting antidepressants. We investigated the influence of alpha(2)-adrenoceptors on adult hippocampal neurogenesis. Our results indicate that alpha(2)-adrenoceptor agonists, clonidine and guanabenz, decrease adult hippocampal neurogenesis through a selective effect on the proliferation, but not the survival or differentiation, of progenitors. These effects persist in dopamine beta-hydroxylase knock-out (Dbh(-/-)) mice lacking norepinephrine, supporting a role for alpha(2)-heteroceptors on progenitor cells, rather than alpha(2)-autoreceptors on noradrenergic neurons that inhibit norepinephrine release. Adult hippocampal progenitors in vitro express all the alpha(2)-adrenoceptor subtypes, and decreased neurosphere frequency and BrdU incorporation indicate direct effects of alpha(2)-adrenoceptor stimulation on progenitors. Furthermore, coadministration of the alpha(2)-adrenoceptor antagonist yohimbine with the antidepressant imipramine significantly accelerates effects on hippocampal progenitor proliferation, the morphological maturation of newborn neurons, and the increase in expression of brain derived neurotrophic factor and vascular endothelial growth factor 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 demonstrate that alpha(2)-adrenoceptors, expressed by progenitor cells, decrease adult hippocampal neurogenesis, while their blockade speeds up antidepressant action, highlighting their importance as targets for faster acting antidepressants.
authors.affiliation: Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai 400005, India.
authors.forename: Sudhirkumar U
authors.initials: SU
authors.lastname: Yanpallewar
authors.forename: Kimberly
authors.initials: K
authors.lastname: Fernandes
authors.forename: Swananda V
authors.initials: SV
authors.lastname: Marathe
authors.forename: Krishna C
authors.initials: KC
authors.lastname: Vadodaria
authors.forename: Dhanisha
authors.initials: D
authors.lastname: Jhaveri
authors.forename: Karen
authors.initials: K
authors.lastname: Rommelfanger
authors.forename: Uma
authors.initials: U
authors.lastname: Ladiwala
authors.forename: Shanker
authors.initials: S
authors.lastname: Jha
authors.forename: Verena
authors.initials: V
authors.lastname: Muthig
authors.forename: Lutz
authors.initials: L
authors.lastname: Hein
authors.forename: Perry
authors.initials: P
authors.lastname: Bartlett
authors.forename: David
authors.initials: D
authors.lastname: Weinshenker
authors.forename: Vidita A
authors.initials: VA
authors.lastname: Vaidya
mesh_terms: D058669:Adrenergic alpha-2 Receptor Antagonists; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D000928:Antidepressive Agents / Q000494:pharmacology*; D000978:Antiparkinson Agents / Q000494:pharmacology; D001205:Ascorbic Acid / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects*; D019208:Brain-Derived Neurotrophic Factor; D001973:Bromodeoxyuridine / Q000378:metabolism; D002478:Cells, Cultured; D004299:Dopamine beta-Hydroxylase / Q000235:genetics; D000089622:Doublecortin Domain Proteins; D015103:Droxidopa / Q000494:pharmacology; D004334:Drug Administration Schedule; D004347:Drug Interactions; D004622:Embryo, Mammalian; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000235:genetics; D006624:Hippocampus / Q000187:drug effects*; D007099:Imipramine / Q000494:pharmacology*; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D055495:Neurogenesis / Q000187:drug effects*; D009479:Neuropeptides / Q000378:metabolism; D010656:Phenylephrine / Q000494:pharmacology; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000473:pathology; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011930:Reaction Time / Q000187:drug effects; D018341:Receptors, Adrenergic, alpha-2 / Q000502:physiology; D013234:Stem Cells / Q000187:drug effects; D015016:Yohimbine / Q000494:pharmacology
chemical_list: D058669:Adrenergic alpha-2 Receptor Antagonists; D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D000318:Adrenergic beta-Agonists; D000928:Antidepressive Agents; D000978:Antiparkinson Agents; D019208:Brain-Derived Neurotrophic Factor; D000089622:Doublecortin Domain Proteins; D008869:Microtubule-Associated Proteins; D009419:Nerve Tissue Proteins; D009479:Neuropeptides; D018809:Proliferating Cell Nuclear Antigen; D018341:Receptors, Adrenergic, alpha-2; D010656:Phenylephrine; D015016:Yohimbine; D004299:Dopamine beta-Hydroxylase; D001973:Bromodeoxyuridine; D015103:Droxidopa; D007545:Isoproterenol; D007099:Imipramine; D001205:Ascorbic Acid