title: Neuropeptidomics of mouse hypothalamus after imipramine treatment reveal somatostatin as a potential mediator of antidepressant effects.
abstract: Excessive activation of the hypothalamic-pituitary-adrenal (HPA) axis has been associated with numerous diseases, including depression, and the tricyclic antidepressant imipramine has been shown to suppress activity of the HPA axis. Central hypothalamic control of the HPA axis is complex and involves a number of neuropeptides released from multiple hypothalamic subnuclei. The present study was therefore designed to determine the effects of imipramine administration on the mouse hypothalamus using a peptidomics approach. Among the factors found to be downregulated after acute (one day) or chronic (21 days) imipramine administration were peptides derived from secretogranin 1 (chromogranin B) as well as peptides derived from cerebellin precursors. In contrast, peptides SRIF-14 and SRIF-28 (1-11) derived from somatostatin (SRIF, somatotropin release inhibiting factor) were significantly upregulated by imipramine in the hypothalamus. Because diminished SRIF levels have long been known to occur in depression, a second part of the study investigated the roles of individual SRIF receptors in mediating potential antidepressant effects. SRA880, an antagonist of the somatostatin-1 autoreceptor (sst1) which positively modulates release of endogenous SRIF, was found to synergize with imipramine in causing antidepressant-like effects in the tail suspension test. Furthermore, chronic co-administration of SRA880 and imipramine synergistically increased BDNF mRNA expression in the cerebral cortex. Application of SRIF or L054264, an sst2 receptor agonist, but not L803807, an sst4 receptor agonist, increased phosphorylation of CaMKII and GluR1 in cerebrocortical slices. Our present experiments thus provide evidence for antidepressant-induced upregulation of SRIF in the brain, and strengthen the notion that augmented SRIF expression and signaling may counter depressive-like symptoms. This article is part of a Special Issue entitled 'Anxiety and Depression'.
authors.affiliation: Department of Pharmaceutical Biosciences, Medical Mass Spectrometry, Uppsala University, BMC, P.O. Box 591, SE-751 24 Uppsala, Sweden.
authors.forename: Anna
authors.initials: A
authors.lastname: Nilsson
authors.forename: Nikolas
authors.initials: N
authors.lastname: Stroth
authors.forename: Xiaoqun
authors.initials: X
authors.lastname: Zhang
authors.forename: Hongshi
authors.initials: H
authors.lastname: Qi
authors.forename: Maria
authors.initials: M
authors.lastname: Fälth
authors.forename: Karl
authors.initials: K
authors.lastname: Sköld
authors.forename: Daniel
authors.initials: D
authors.lastname: Hoyer
authors.forename: Per E
authors.initials: PE
authors.lastname: Andrén
authors.forename: Per
authors.initials: P
authors.lastname: Svenningsson
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000929:Antidepressive Agents, Tricyclic / Q000494:pharmacology*; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D053378:Chromogranin B / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D019417:Hindlimb Suspension / Q000379:methods; D007031:Hypothalamus / Q000187:drug effects*; D007099:Imipramine / Q000494:pharmacology*; D008297:Male; D013058:Mass Spectrometry; D051379:Mice; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins; D009479:Neuropeptides / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology; D011498:Protein Precursors / Q000378:metabolism; D011804:Quinolines / Q000494:pharmacology; D013004:Somatostatin / Q000378:metabolism; D053561:Somatostatin-28 / Q000378:metabolism; D013997:Time Factors
chemical_list: C488795:1,2,3,4,4a,5,10,10a-octahydro-6-methoxy-1-methylbenz(g)quinoline-3-carboxylic acid 4-(4-nitrophenyl)piperazine amide; D000929:Antidepressive Agents, Tricyclic; C092370:Cbln1 protein, mouse; D053378:Chromogranin B; D009419:Nerve Tissue Proteins; D009479:Neuropeptides; D010879:Piperazines; D011498:Protein Precursors; D011804:Quinolines; D013004:Somatostatin; D053561:Somatostatin-28; D007099:Imipramine