title: Knockdown of tropomyosin-related kinase B receptor expression in the nucleus accumbens shell prevents intermittent social defeat stress-induced cross-sensitization to amphetamine in rats.
abstract: The nucleus accumbens (NAc) is a critical brain region for the rewarding effects of drugs of abuse. Brain-derived neurotrophic factor (BDNF) can facilitate stress- and drug-induced neuroadaptation in the mesocorticolimbic system. BDNF-containing projections to the NAc originate from the ventral tegmental area (VTA) and the prefrontal cortex, and BDNF release activates tropomyosin-related kinase B (TrkB). In this study, we examined the necessity for BDNF-TrkB signaling in the NAc shell during social defeat stress-induced cross-sensitization to amphetamine. Adeno-associated virus expressing short hairpin RNA directed against TrkB (AAV-shTrkB) was infused bilaterally into the NAc shell to knock down TrkB, whereas AAV-GFP (green fluorescent protein) was used as the control virus. Rats were exposed to intermittent social defeat stress or handling procedures; amphetamine challenge was given at 10 days after the last defeat and locomotor activity was measured. Stressed rats that received the control virus showed cross-sensitization to amphetamine compared with the handled rats. In contrast, NAc TrkB knockdown prevented social defeat stress-induced cross-sensitization. TrkB knockdown in the NAc was found to reduce the level of phospho-extracellular signal-regulated kinase 1 in this region. NAc TrkB knockdown also prevented stress-induced elevation of BDNF and the glutamate receptor type 1 (GluA1) subunit of AMPA receptor in the VTA, as well as ΔFosB expression in the NAc. These findings indicated that BDNF-TrkB signaling in the NAc shell was required for social defeat stress-induced cross-sensitization. NAc TrkB-BDNF signaling also appeared to be involved in the regulation of GluA1 in the VTA, as well as in the NAc ΔFosB accumulation that could trigger cross-sensitization after social defeat stress.
authors.affiliation: Neuroscience Program, Arizona State University, Tempe, AZ, USA.
authors.forename: Junshi
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Basic Medical Sciences, University of Arizona, College of Medicine, 425 N 5th Street, Phoenix, AZ, 85004, USA.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Bina
authors.affiliation: Beth Israel Deaconess Medical Center, Boston, MA, USA.
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Wingard
authors.affiliation: Beth Israel Deaconess Medical Center, Boston, MA, USA.
authors.forename: Ernest F
authors.initials: EF
authors.lastname: Terwilliger
authors.affiliation: Neuroscience Program, Arizona State University, Tempe, AZ, USA.|Department of Basic Medical Sciences, University of Arizona, College of Medicine, 425 N 5th Street, Phoenix, AZ, 85004, USA.|Departments of Pharmacology and Psychiatry, University of Arizona, College of Medicine, Phoenix, AZ, USA.
authors.forename: Ronald P
authors.initials: RP
authors.lastname: Hammer
authors.affiliation: Department of Basic Medical Sciences, University of Arizona, College of Medicine, 425 N 5th Street, Phoenix, AZ, 85004, USA.
authors.forename: Ella M
authors.initials: EM
authors.lastname: Nikulina
mesh_terms: D000661:Amphetamine / Q000494:pharmacology*; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D059333:Central Nervous System Sensitization; D008124:Locomotion; D008297:Male; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020813:Receptor, trkB / Q000235:genetics / Q000378:metabolism*; D018091:Receptors, AMPA / Q000235:genetics / Q000378:metabolism; D012919:Social Behavior; D013315:Stress, Psychological / Q000378:metabolism* / Q000503:physiopathology
chemical_list: D000661:Amphetamine; D019208:Brain-Derived Neurotrophic Factor; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D020813:Receptor, trkB; D018091:Receptors, AMPA; C483820:Fosb protein, rat
keywords: brain-derived neurotrophic factor; cross-sensitization; nucleus accumbens; social stress; tropomyosin-related kinase B; ventral tegmental area