title: Antidepressant effects on serotonin 1A/1B receptors in the rat brain using a gene x environment model.
abstract: A gene-environment (GxE) interaction is implicated in both the pathophysiology and treatment of major depressive disorder (MDD). This study modeled the effects of genetic vulnerability by using the Flinders sensitive line (FSL), a rat model of depression and its control counterpart-the Flinders resistant line (FRL). The effects of environmental vulnerability (e.g., early-life stress) were modeled by using maternal separation. Rats (n=105) were drawn from four groups reflecting experimental crossing of strain (FSL vs. FRL) and early-life stress (high vs. low) to assess the effects of two antidepressants (escitalopram or nortriptyline) compared to vehicle. Quantitative in vitro autoradiography was performed using [(125)I]MPPI (5-HT1A) and [(125)I]CYP (5-HT1B) in prefrontal cortex (PFC) and hippocampus. Stringent, Bonferroni-corrected statistical analyses showed significant strain-by-rearing-by-treatment (three-way) interactions in PFC 5-HT1A and hippocampal 5-HT1B receptors. Either vulnerability reduced serotonergic binding; no additive effects were associated with the two vulnerabilities. Both antidepressants increased hippocampal 5-HT1B receptor binding; however, only nortriptyline selectively increased PFC 5-HT1A receptor binding. Taken together, our findings demonstrate that antidepressant effects on the serotonergic system are shaped by a GxE interaction that depends on antidepressant class and brain region.
authors.affiliation: Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Molecular Imaging Branch, National Institute of Mental Health, Bethesda, MD, USA. Electronic address: shresthas@mail.nih.gov.
authors.forename: Stal Saurav
authors.initials: SS
authors.lastname: Shrestha
authors.affiliation: Molecular Imaging Branch, National Institute of Mental Health, Bethesda, MD, USA.
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Pine
authors.affiliation: Molecular Imaging Branch, National Institute of Mental Health, Bethesda, MD, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Luckenbaugh
authors.affiliation: Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Katarina
authors.initials: K
authors.lastname: Varnäs
authors.affiliation: Molecular Imaging Branch, National Institute of Mental Health, Bethesda, MD, USA.
authors.forename: Ioline D
authors.initials: ID
authors.lastname: Henter
authors.affiliation: Molecular Imaging Branch, National Institute of Mental Health, Bethesda, MD, USA.
authors.forename: Robert B
authors.initials: RB
authors.lastname: Innis
authors.affiliation: Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Aleksander A
authors.initials: AA
authors.lastname: Mathé
authors.affiliation: Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Per
authors.initials: P
authors.lastname: Svenningsson
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001923:Brain Chemistry / Q000235:genetics*; D003863:Depression / Q000188:drug therapy / Q000235:genetics*; D004195:Disease Models, Animal; D005260:Female; D059647:Gene-Environment Interaction; D050172:Genes, X-Linked / Q000502:physiology; D008297:Male; D008426:Maternal Deprivation; D011485:Protein Binding / Q000235:genetics; D051381:Rats; D055647:Rats, Transgenic; D044282:Receptor, Serotonin, 5-HT1A / Q000235:genetics* / Q000378:metabolism; D044302:Receptor, Serotonin, 5-HT1B / Q000235:genetics* / Q000378:metabolism; D012931:Social Environment; D013045:Species Specificity
chemical_list: D000928:Antidepressive Agents; D044302:Receptor, Serotonin, 5-HT1B; D044282:Receptor, Serotonin, 5-HT1A
keywords: Escitalopram; FSL/FRL (Flinders sensitive/resistant line); Gene-environment (GxE); Hippocampus; Nortriptyline; PFC (prefrontal cortex); Serotonin 1A/1B (5-HT(1A/1B)) receptors