Advertisement

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

Published:February 03, 2014DOI:https://doi.org/10.1016/j.biopsych.2014.01.013

      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.

      Key Words

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Biological Psychiatry
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • American Psychiatric Association
        Diagnostic and Statistical Manual of Mental Disorders.
        5th Ed. American Psychiatric Association, Arlington, VA2013
        • Loas G.
        Vulnerability to depression: A model centered on anhedonia.
        J Affect Disord. 1996; 41: 39-53
        • Schrader G.D.
        Does anhedonia correlate with depression severity in chronic depression?.
        Compr Psychiatry. 1997; 38: 260-263
        • Charney D.S.
        • Manji H.K.
        Life stress, genes, and depression: Multiple pathways lead to increased risk and new opportunities for intervention.
        Sci STKE. 2004; (2004:re5)
        • Kendler K.S.
        • Karkowski L.M.
        • Prescott C.A.
        Causal relationship between stressful life events and the onset of major depression.
        Am J Psychiatry. 1999; 156: 837-841
        • Zacharko R.M.
        • Bowers W.J.
        • Kokkinidis L.
        • Anisman H.
        Region-specific reductions of intracranial self-stimulation after uncontrollable stress: Possible effects on reward processes.
        Behav Brain Res. 1983; 9: 129-141
        • Bogdan R.
        • Pizzagalli D.A.
        Acute stress reduces reward responsiveness: Implications for depression.
        Biol Psychiatry. 2006; 60: 1147-1154
        • Brown G.W.
        • Harris T.O.
        • Hepworth C.
        Loss, humiliation and entrapment among women developing depression: A patient and non-patient comparison.
        Psychol Med. 1995; 25: 7-21
        • Gilbert P.
        • Allan S.
        • Brough S.
        • Melley S.
        • Miles J.N.
        Relationship of anhedonia and anxiety to social rank, defeat and entrapment.
        J Affect Disord. 2002; 71: 141-151
        • Allan S.
        • Gilbert P.
        Submissive behaviour and psychopathology.
        Br J Clin Psychol. 1997; 36: 467-488
        • Miczek K.A.
        • Yap J.J.
        • Covington 3rd, H.E.
        Social stress, therapeutics and drug abuse: Preclinical models of escalated and depressed intake.
        Pharmacol Ther. 2008; 120: 102-128
        • Rygula R.
        • Abumaria N.
        • Havemann-Reinecke U.
        • Ruther E.
        • Hiemke C.
        • Zernig G.
        • et al.
        Pharmacological validation of a chronic social stress model of depression in rats: Effects of reboxetine, haloperidol and diazepam.
        Behav Pharmacol. 2008; 19: 183-196
        • Covington 3rd, H.E.
        • Vialou V.F.
        • LaPlant Q.
        • Ohnishi Y.N.
        • Nestler E.J.
        Hippocampal-dependent antidepressant-like activity of histone deacetylase inhibition.
        Neurosci Lett. 2011; 493: 122-126
        • Miczek K.A.
        • Nikulina E.M.
        • Shimamoto A.
        • Covington 3rd, H.E.
        Escalated or suppressed cocaine reward, tegmental BDNF, and accumbal dopamine caused by episodic versus continuous social stress in rats.
        J Neurosci. 2011; 31: 9848-9857
        • Krishnan V.
        • Han M.H.
        • Graham D.L.
        • Berton O.
        • Renthal W.
        • Russo S.J.
        • et al.
        Molecular adaptations underlying susceptibility and resistance to social defeat in brain reward regions.
        Cell. 2007; 131: 391-404
        • Von Frijtag J.C.
        • Reijmers L.G.
        • Van der Harst J.E.
        • Leus I.E.
        • Van den Bos R.
        • Spruijt B.M.
        Defeat followed by individual housing results in long-term impaired reward- and cognition-related behaviours in rats.
        Behav Brain Res. 2000; 117: 137-146
        • Kanarik M.
        • Alttoa A.
        • Matrov D.
        • Koiv K.
        • Sharp T.
        • Panksepp J.
        • et al.
        Brain responses to chronic social defeat stress: Effects on regional oxidative metabolism as a function of a hedonic trait, and gene expression in susceptible and resilient rats.
        Eur Neuropsychopharmacol. 2011; 21: 92-107
        • Hollis F.
        • Wang H.
        • Dietz D.
        • Gunjan A.
        • Kabbaj M.
        The effects of repeated social defeat on long-term depressive-like behavior and short-term histone modifications in the hippocampus in male Sprague-Dawley rats.
        Psychopharmacology (Berl). 2010; 211: 69-77
        • Hollis F.
        • Duclot F.
        • Gunjan A.
        • Kabbaj M.
        Individual differences in the effect of social defeat on anhedonia and histone acetylation in the rat hippocampus.
        Horm Behav. 2011; 59: 331-337
        • Bowens N.
        • Heydendael W.
        • Bhatnagar S.
        • Jacobson L.
        Lack of elevations in glucocorticoids correlates with dysphoria-like behavior after repeated social defeat.
        Physiol Behav. 2012; 105: 958-965
        • Vialou V.
        • Robison A.J.
        • Laplant Q.C.
        • Covington 3rd, H.E.
        • Dietz D.M.
        • Ohnishi Y.N.
        • et al.
        DeltaFosB in brain reward circuits mediates resilience to stress and antidepressant responses.
        Nat Neurosci. 2010; 13: 745-752
        • Chaudhury D.
        • Walsh J.J.
        • Friedman A.K.
        • Juarez B.
        • Ku S.M.
        • Koo J.W.
        • et al.
        Rapid regulation of depression-related behaviours by control of midbrain dopamine neurons.
        Nature. 2013; 493: 532-536
        • Zisook S.
        • Paulus M.
        • Shuchter S.R.
        • Judd L.L.
        The many faces of depression following spousal bereavement.
        J Affect Disord. 1997; 45 (discussion 94–95): 85-94
        • Bonanno G.A.
        • Wortman C.B.
        • Lehman D.R.
        • Tweed R.G.
        • Haring M.
        • Sonnega J.
        • et al.
        Resilience to loss and chronic grief: A prospective study from preloss to 18-months postloss.
        J Pers Soc Psychol. 2002; 83: 1150-1164
        • Der-Avakian A.
        • Markou A.
        The neurobiology of anhedonia and other reward-related deficits.
        Trends Neurosci. 2012; 35: 68-77
        • Gorwood P.
        Neurobiological mechanisms of anhedonia.
        Dialogues Clin Neurosci. 2008; 10: 291-299
        • Keedwell P.A.
        • Andrew C.
        • Williams S.C.
        • Brammer M.J.
        • Phillips M.L.
        The neural correlates of anhedonia in major depressive disorder.
        Biol Psychiatry. 2005; 58: 843-853
        • Der-Avakian A.
        • Markou A.
        Neonatal maternal separation exacerbates the reward-enhancing effect of acute amphetamine administration and the anhedonic effect of repeated social defeat in adult rats.
        Neuroscience. 2010; 170: 1189-1198
        • Markou A.
        • Koob G.F.
        Construct validity of a self-stimulation threshold paradigm: effects of reward and performance manipulations.
        Physiol Behav. 1992; 51: 111-119
        • Kornetsky C.
        • Esposito R.U.
        • McLean S.
        • Jacobson J.O.
        Intracranial self-stimulation thresholds: A model for the hedonic effects of drugs of abuse.
        Arch Gen Psychiatry. 1979; 36: 289-292
        • Mazei-Robison M.S.
        • Koo J.W.
        • Friedman A.K.
        • Lansink C.S.
        • Robison A.J.
        • Vinish M.
        • et al.
        Role for mTOR signaling and neuronal activity in morphine-induced adaptations in ventral tegmental area dopamine neurons.
        Neuron. 2011; 72: 977-990
        • Harrison A.A.
        • Markou A.
        Serotonergic manipulations both potentiate and reduce brain stimulation reward in rats: Involvement of serotonin-1A receptors.
        J Pharmacol Exp Ther. 2001; 297: 316-325
        • Lin D.
        • Koob G.F.
        • Markou A.
        Differential effects of withdrawal from chronic amphetamine or fluoxetine administration on brain stimulation reward in the rat—interactions between the two drugs.
        Psychopharmacology (Berl). 1999; 145: 283-294
        • Markou A.
        • Hauger R.L.
        • Koob G.F.
        Desmethylimipramine attenuates cocaine withdrawal in rats.
        Psychopharmacology (Berl). 1992; 109: 305-314
        • Phillips A.G.
        • Blaha C.D.
        • Fibiger H.C.
        Neurochemical correlates of brain-stimulation reward measured by ex vivo and in vivo analyses.
        Neurosci Biobehav Rev. 1989; 13: 99-104
        • Friedman E.S.
        • Davis L.L.
        • Zisook S.
        • Wisniewski S.R.
        • Trivedi M.H.
        • Fava M.
        • et al.
        Baseline depression severity as a predictor of single and combination antidepressant treatment outcome: results from the CO-MED trial.
        Eur Neuropsychopharmacol. 2012; 22: 183-199
        • McMakin D.L.
        • Olino T.M.
        • Porta G.
        • Dietz L.J.
        • Emslie G.
        • Clarke G.
        • et al.
        Anhedonia predicts poorer recovery among youth with selective serotonin reuptake inhibitor treatment-resistant depression.
        J Am Acad Child Adolesc Psychiatry. 2012; 51: 404-411
        • Warden D.
        • Rush A.J.
        • Wisniewski S.R.
        • Lesser I.M.
        • Kornstein S.G.
        • Balasubramani G.K.
        • et al.
        What predicts attrition in second step medication treatments for depression? A STAR*D Report.
        Int J Neuropsychopharmacol. 2009; 12: 459-473
        • Wood S.K.
        • Walker H.E.
        • Valentino R.J.
        • Bhatnagar S.
        Individual differences in reactivity to social stress predict susceptibility and resilience to a depressive phenotype: Role of corticotropin-releasing factor.
        Endocrinology. 2010; 151: 1795-1805
        • Laplante M.
        • Sabatini D.M.
        mTOR signaling at a glance.
        J Cell Sci. 2009; 122: 3589-3594
        • Saal D.
        • Dong Y.
        • Bonci A.
        • Malenka R.C.
        Drugs of abuse and stress trigger a common synaptic adaptation in dopamine neurons.
        Neuron. 2003; 37: 577-582
        • Krishnan V.
        • Han M.H.
        • Mazei-Robison M.
        • Iniguez S.D.
        • Ables J.L.
        • Vialou V.
        • et al.
        AKT signaling within the ventral tegmental area regulates cellular and behavioral responses to stressful stimuli.
        Biol Psychiatry. 2008; 64: 691-700
        • Berton O.
        • McClung C.A.
        • Dileone R.J.
        • Krishnan V.
        • Renthal W.
        • Russo S.J.
        • et al.
        Essential role of BDNF in the mesolimbic dopamine pathway in social defeat stress.
        Science. 2006; 311: 864-868
        • Boyer P.
        • Tassin J.P.
        • Falissart B.
        • Troy S.
        Sequential improvement of anxiety, depression and anhedonia with sertraline treatment in patients with major depression.
        J Clin Pharm Ther. 2000; 25: 363-371
        • Trivedi M.H.
        • Rush A.J.
        • Wisniewski S.R.
        • Nierenberg A.A.
        • Warden D.
        • Ritz L.
        • et al.
        Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: Implications for clinical practice.
        Am J Psychiatry. 2006; 163: 28-40
        • Rush A.J.
        • Trivedi M.H.
        • Stewart J.W.
        • Nierenberg A.A.
        • Fava M.
        • Kurian B.T.
        • et al.
        Combining medications to enhance depression outcomes (CO-MED): Acute and long-term outcomes of a single-blind randomized study.
        Am J Psychiatry. 2011; 168: 689-701
        • Klein D.F.
        Endogenomorphic depression. A conceptual and terminological revision.
        Arch Gen Psychiatry. 1974; 31: 447-454
        • DiLeone R.J.
        • Georgescu D.
        • Nestler E.J.
        Lateral hypothalamic neuropeptides in reward and drug addiction.
        Life Sci. 2003; 73: 759-768
        • Berridge K.C.
        • Valenstein E.S.
        What psychological process mediates feeding evoked by electrical stimulation of the lateral hypothalamus?.
        Behav Neurosci. 1991; 105: 3-14
        • Slattery D.A.
        • Uschold N.
        • Magoni M.
        • Bar J.
        • Popoli M.
        • Neumann I.D.
        • et al.
        Behavioural consequences of two chronic psychosocial stress paradigms: Anxiety without depression.
        Psychoneuroendocrinology. 2012; 37: 702-714
        • Ver Hoeve E.S.
        • Kelly G.
        • Luz S.
        • Ghanshani S.
        • Bhatnagar S.
        Short-term and long-term effects of repeated social defeat during adolescence or adulthood in female rats.
        Neuroscience. 2013; 249: 63-73
        • Harro J.
        • Tonissaar M.
        • Eller M.
        • Kask A.
        • Oreland L.
        Chronic variable stress and partial 5-HT denervation by parachloroamphetamine treatment in the rat: Effects on behavior and monoamine neurochemistry.
        Brain Res. 2001; 899: 227-239
        • Harro J.
        Long-term partial 5-HT depletion: Interference of anxiety and impulsivity?.
        Psychopharmacology (Berl). 2002; 164: 433-434
        • Swann A.C.
        • Steinberg J.L.
        • Lijffijt M.
        • Moeller F.G.
        Impulsivity: Differential relationship to depression and mania in bipolar disorder.
        J Affect Disord. 2008; 106: 241-248
        • Strekalova T.
        • Couch Y.
        • Kholod N.
        • Boyks M.
        • Malin D.
        • Leprince P.
        • et al.
        Update in the methodology of the chronic stress paradigm: Internal control matters.
        Behav Brain Funct. 2011; 7: 9

      Linked Article

      • Chronic Social Defeat and Intracranial Self-Stimulation: Unmasking the Many Faces of Depression?
        Biological PsychiatryVol. 76Issue 7
        • Preview
          Depression is a highly complex psychiatric disorder owing in part to the great variability in patient symptoms; treatment response; and, presumably, underlying biological mechanisms (1). This complexity as well as the inherent difficulty in studying mental symptoms in rodents has made depression very difficult to model in the laboratory. Chronic social defeat stress (CSDS) offers construct, face, and predictive validity; it induces many of the core symptoms of depression that are measurable in rodents.
        • Full-Text
        • PDF