title: Hippocampal transcriptional and neurogenic changes evoked by combination yohimbine and imipramine treatment.
abstract: Adjunct α2-adrenoceptor antagonism is a potential strategy to accelerate the behavioral effects of antidepressants. Co-administration of the α2-adrenoceptor antagonist yohimbine hastens the behavioral and neurogenic effects of the antidepressant imipramine. We examined the transcriptional targets of short duration (7days), combination treatment of yohimbine and imipramine (Y+I) within the adult rat hippocampus. Using microarray and qPCR analysis we observed functional enrichment of genes involved in intracellular signaling cascades, plasma membrane, cellular metal ion homeostasis, multicellular stress responses and neuropeptide signaling pathways in the Y+I transcriptome. We noted reduced expression of the α2A-adrenoceptor (Adra2a), serotonin 5HT2C receptor (Htr2c) and the somatostatin receptor 1 (Sstr1), which modulate antidepressant action. Further, we noted a regulation of signaling pathway genes like inositol monophosphatase 2 (Impa2), iodothyronine deiodinase 3 (Dio3), regulator of G-protein signaling 4 (Rgs4), alkaline ceramidase 2 (Acer2), doublecortin-like kinase 2 (Dclk2), nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha (Nfkbia) and serum/glucocorticoid-regulated kinase 1 (Sgk1), several of which are implicated in the pathophysiology of mood disorders. Comparative analysis revealed an overlap in the hippocampal regulation of Acer2, Nfkbia, Sgk1 and Impa2 between Y+I treatment, the fast-acting electroconvulsive seizure (ECS) paradigm, and the slow-onset chronic (21days) imipramine treatment. Further, Y+I treatment enhanced the quiescent neural progenitor pool in the hippocampal neurogenic niche similar to ECS, and distinct from chronic imipramine treatment. Taken together, our results provide insight into the molecular and cellular targets of short duration Y+I treatment, and identify potential leads for the development of rapid-action antidepressants.
authors.affiliation: Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai, Maharashtra, India.
authors.forename: Basma Fatima Anwar
authors.initials: BF
authors.lastname: Husain
authors.affiliation: Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai, Maharashtra, India.
authors.forename: Ishira N
authors.initials: IN
authors.lastname: Nanavaty
authors.affiliation: Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai, Maharashtra, India.
authors.forename: Swananda V
authors.initials: SV
authors.lastname: Marathe
authors.affiliation: Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai, Maharashtra, India.
authors.forename: Rajeev
authors.initials: R
authors.lastname: Rajendran
authors.affiliation: Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai, Maharashtra, India. Electronic address: vvaidya@tifr.res.in.
authors.forename: Vidita A
authors.initials: VA
authors.lastname: Vaidya
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D002452:Cell Count; D000089662:Doublecortin Protein; D004338:Drug Combinations; D004597:Electroshock / Q000379:methods; D005786:Gene Expression Regulation / Q000187:drug effects*; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D007099:Imipramine / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D064231:Nestin / Q000235:genetics / Q000378:metabolism; D055495:Neurogenesis / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D044405:Receptor, Serotonin, 5-HT2C / Q000235:genetics / Q000378:metabolism; D018341:Receptors, Adrenergic, alpha-2 / Q000235:genetics / Q000378:metabolism; D017481:Receptors, Somatostatin / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D015016:Yohimbine / Q000494:pharmacology*
chemical_list: C000599853:5-hydroxytryptamine2C receptor, mouse; C547769:Adra2a protein, mouse; D000927:Anticonvulsants; C000714848:Dcx protein, rat; D000089662:Doublecortin Protein; D004338:Drug Combinations; D005904:Glial Fibrillary Acidic Protein; D064231:Nestin; D044405:Receptor, Serotonin, 5-HT2C; D018341:Receptors, Adrenergic, alpha-2; D017481:Receptors, Somatostatin; C570770:somatostatin receptor 1, mouse; D015016:Yohimbine; D007099:Imipramine
keywords: Antidepressant; Electroconvulsive seizure; Hippocampal neurogenesis; Microarray; Neural stem cell; α(2) adrenoceptor