title: Enduring deficits in brain reward function after chronic social defeat in rats: susceptibility, resilience, and antidepressant response.
abstract: BACKGROUND
  Anhedonia, or diminished interest or pleasure in rewarding activities, characterizes depression and reflects deficits in brain reward circuitries. Social stress induces anhedonia and increases risk of depression, although the effect of social stress on brain reward function is incompletely understood.
  
  
  METHODS
  This study assessed the following: 1) brain reward function in rats (using the intracranial self-stimulation procedure) and protein levels of brain-derived neurotrophic factor and related signaling molecules in response to chronic social defeat, 2) brain reward function during social defeat and long-term treatment with the antidepressants fluoxetine (5 mg/kg/day) and desipramine (10 mg/kg/day), and 3) forced swim test behavior after social defeat and fluoxetine treatment.
  
  
  RESULTS
  Social defeat profoundly and persistently decreased brain reward function, reflecting an enduring anhedonic response, in susceptible rats, whereas resilient rats showed no long-term brain reward deficits. In the ventral tegmental area, social defeat, regardless of susceptibility or resilience, decreased brain-derived neurotrophic factor and increased phosphorylated AKT, whereas only susceptibility was associated with increased phosphorylated mammalian target of rapamycin. Fluoxetine and desipramine reversed lower, but not higher, stress-induced brain reward deficits in susceptible rats. Fluoxetine decreased immobility in the forced swim test, as did social defeat.
  
  
  CONCLUSIONS
  These results suggest that the differential persistent anhedonic response to psychosocial stress may be mediated by ventral tegmental area signaling molecules independent of brain-derived neurotrophic factor and indicate that greater stress-induced anhedonia is associated with resistance to antidepressant treatment. Consideration of these behavioral and neurobiological factors associated with resistance to stress and antidepressant action may promote the discovery of novel targets to treat stress-related mood disorders.
authors.affiliation: Department of Psychiatry, University of California San Diego, La Jolla, California.
authors.forename: Andre
authors.initials: A
authors.lastname: Der-Avakian
authors.affiliation: Department of Physiology, Michigan State University, East Lansing, Michigan.
authors.forename: Michelle S
authors.initials: MS
authors.lastname: Mazei-Robison
authors.affiliation: Department of Psychiatry, University of California San Diego, La Jolla, California.
authors.forename: James P
authors.initials: JP
authors.lastname: Kesby
authors.affiliation: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Nestler
authors.affiliation: Department of Psychiatry, University of California San Diego, La Jolla, California. Electronic address: amarkou@ucsd.edu.
authors.forename: Athina
authors.initials: A
authors.lastname: Markou
mesh_terms: D059445:Anhedonia / Q000187:drug effects / Q000502:physiology*; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D003891:Desipramine / Q000494:pharmacology; D004558:Electric Stimulation; D005473:Fluoxetine / Q000494:pharmacology; D007031:Hypothalamus / Q000503:physiopathology*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D012201:Reward; D012653:Self Stimulation; D015398:Signal Transduction; D012919:Social Behavior; D013315:Stress, Psychological / Q000378:metabolism / Q000503:physiopathology*; D013550:Swimming; D017557:Ventral Tegmental Area / Q000378:metabolism / Q000503:physiopathology*
chemical_list: D000928:Antidepressive Agents; D019208:Brain-Derived Neurotrophic Factor; D005473:Fluoxetine; D003891:Desipramine
keywords: Anhedonia; BDNF; ICSS; depression; mTOR; stress