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 depression risk, although the effect of social stress on brain reward function remains incompletely understood. Methods We assessed: 1) brain reward function in rats (using the intracranial self-stimulation procedure) and protein levels of brain-derived neurotrophic factor (BDNF) and related signaling molecules in response to chronic social defeat; 2) brain reward function during social defeat and chronic treatment with the antidepressants fluoxetine (5 mg/kg/day) or 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, while resilient rats showed no long-term brain reward deficits. In the ventral tegmental area (VTA), social defeat, regardless of susceptibility or resilience, decreased and increased BDNF and phosphorylated AKT, respectively, whereas only susceptibility was associated with increased phosphorylated mammalian target of rapamycin (mTOR). 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 VTA signaling molecules independent of BDNF, and indicate that greater stress-induced anhedonia is associated with antidepressant treatment resistance. 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.

Social defeat disrupts reward learning and potentiates striatal nociceptin/orphanin FQ mRNA in rats

“…Consistent with our results, stress has been shown to increase brain PAC1 expression in rats (Lezak et al 2014), and treatment with a PAC1 antagonist during stress exposure prevents several of the behavioral consequences of stress (Roman et al 2014). Additionally, increased CREB expression in the NAc shell has been shown to increase brain stimulation reward thresholds in the intracranial self-stimulation procedure in rats (Muschamp et al 2011), similar to the effects of social defeat (Der-Avakian et al 2014; Donahue et al 2014). Conversely, environmental enrichment, which is associated with a reduction in depression-like behaviors, decreases CREB activity in the NAc (Green et al 2010), which produces antidepressant and antistress-like effects (Carlezon and Krystal 2016; Pliakas et al 2001).…”

“…Stress can precipitate mood disorders, or the expression of related symptoms, such as anhedonia, in healthy individuals (Berenbaum and Connelly 1993; Charney and Manji 2004; Kendler et al 1999), as well as deficits in brain reward system function in laboratory animals (Der-Avakian et al 2014; Donahue et al 2014). Critically, stress has also been shown to disrupt reward learning in humans as assessed with the PRT, as reflected by reductions in the development of response biases directed toward the rich stimulus (Bogdan et al 2010; Bogdan and Pizzagalli 2006; Bogdan et al 2011; Pizzagalli et al 2007).…”

“…Given these parallels, we predicted that stress exposure in rats would blunt response biases in the PRT, exactly as in humans (Bogdan et al 2010; Bogdan and Pizzagalli 2006; Bogdan et al 2011; Pizzagalli et al 2007). To test this hypothesis, we exposed rats to social defeat, a rodent model of psychosocial stress that has been shown to disrupt brain reward system function in rats and mice (Der-Avakian et al 2014; Donahue et al 2014), and assessed reward learning in our preclinical analog of the PRT.…”

Treatment-resistant depression: are animal models of depression fit for purpose?

“…When using chronic social defeat to differentiate stress-susceptible and stress-resistant rats, a greater anhedonic response (stress-induced reward threshold elevation) is associated with poor antidepressant-like effects of fluoxetine or desipramine (Der-Avakian et al 2014), which suggests that the susceptible population can be considered as a model in which increased stress sensitivity is associated with antidepressant resistance. But applying the same strategy to mice, those selected for higher social avoidance after chronic social defeat showed good behavioural and neurochemical responses to chronic fluoxetine (Cao et al 2010): so this strategy cannot be used to model antidepressant resistance in mice.…”

Forebrain glucocorticoid receptor gene deletion attenuates behavioral changes and antidepressant responsiveness during chronic stress

“…Although there is no ready explanation for the contradictory direction of these stress-induced changes, there is precedent in the literature for the paradoxical behavioral changes observed in the current experiments. Chronic stress, including repeated social defeat, has been found by other investigators to decrease forced swim immobility or increase sucrose preference (6, 14, 15, 41, 45, 52, 58, 62). These atypical behavioral responses to stress, although less common, have been proposed to be part of a continuum of behavioral repertoires that is represented to varying degrees in all study populations and may account for inconsistent results in any given behavioral assay (62).…”