Enduring Deficits in Brain Reward Function after Chronic Social Defeat in Rats: Susceptibility, Resilience, and Antidepressant Response

doi:10.1016/j.biopsych.2014.01.013

Biological Psychiatry

Volume 76, Issue 7, 1 October 2014, Pages 542-549

https://doi.org/10.1016/j.biopsych.2014.01.013 Get rights and content

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.

Section snippets

Subjects

Adult male Wistar and adult male and female Long-Evans rats (Charles River Laboratories, Raleigh, North Carolina) were used as intruders and residents, respectively, for the social defeat procedure (see below and Supplemental Methods in Supplement 1 for details). All procedures were conducted in accordance with the guidelines from the National Institutes of Health and the Association for the Assessment and Accreditation of Laboratory Animal Care and were approved by the institutional animal

Experiment 1: Effects of Chronic Social Defeat on Brain Reward Function

Social defeat elevated reward thresholds compared with control animals [stress × day interaction: F_41,1025 = 4.98, p < .001]. Post hoc analyses revealed significant stress-induced threshold elevations that returned to baseline after termination of social defeat (Figure 1A). Cluster analysis of social defeat and control groups revealed the existence of two discrete clusters; all resilient rats based on criterion 1 (i.e., stress-induced threshold elevations within 2 SDs above baseline levels)

Discussion

Chronic exposure to social defeat immediately elevated ICSS reward thresholds in all rats, reflecting a stress-induced decrease in brain reward function. Thresholds remained elevated in a subset of susceptible rats, whereas thresholds in resilient rats were only acutely elevated during the initial 4 days of social defeat and were subsequently unaffected despite ongoing stress exposure. Although stress-induced thresholds remained elevated in all susceptible rats, larger threshold elevations were

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Archival ReportEnduring Deficits in Brain Reward Function after Chronic Social Defeat in Rats: Susceptibility, Resilience, and Antidepressant Response

Background

Methods

Results

Conclusions

Section snippets

Subjects

Experiment 1: Effects of Chronic Social Defeat on Brain Reward Function

Discussion

J Affect Disord

Compr Psychiatry

Behav Brain Res

Biol Psychiatry

J Affect Disord

Pharmacol Ther

Neurosci Lett

Cell

Behav Brain Res

Eur Neuropsychopharmacol

Horm Behav

Physiol Behav

Trends Neurosci

Biol Psychiatry

Neuroscience

Physiol Behav

Neuron

Neurosci Biobehav Rev

Eur Neuropsychopharmacol

J Am Acad Child Adolesc Psychiatry

Neuron

Biol Psychiatry

Life Sci

Psychoneuroendocrinology

Neuroscience

Brain Res

J Affect Disord

Archival Report
Enduring Deficits in Brain Reward Function after Chronic Social Defeat in Rats: Susceptibility, Resilience, and Antidepressant Response