Modeling hypohedonia following repeated social defeat: Individual vulnerability and dopaminergic involvement

Abstract

Social defeat in rodents putatively can model hypohedonia. The present studies examined models for assessing hypohedonia-like behavior and tested the hypotheses that 1) individual differences in baseline reward sensitivity predict vulnerability, and 2) defeat elicits changes in pharmacological measures of striatal dopaminergic function. Male Wistar rats (n=142) received repeated defeat (3 "triad" blocks of 3 defeats) or control handling. To determine whether defeat influenced consumption of SuperSac (glucose-saccharin) over an isocaloric, less preferred, glucose solution, a 2-choice paradigm was used. To determine repeated defeat effects on the reinforcing efficacy of SuperSac, a progressive-ratio schedule of reinforcement was used. Amphetamine-induced locomotor activity (0.08mg/kg, s.c.) was determined as a measure sensitive to striatal dopaminergic function. Defeat reduced SuperSac consumption during the first two triads-an effect seen in the third triad only in defeated rats with High vs. Low baseline SuperSac intake. The characteristic escalation in PR breakpoint for SuperSac normally seen in controls was absent in defeated rats, leading to a significant difference by the third triad. Defeat-induced blunting of the escalation in PR performance was greater in rats with High antecedent PR breakpoints and persisted 2.5weeks post-defeat. Repeated defeat also blunted amphetamine-induced locomotion 13days post-defeat. Thus, hypohedonic-like effects of social defeat were detected and accompanied by persistently attenuated striatal dopamine function. Early effects were seen for consumption of differentially-palatable solutions, and persistent effects were seen for the "breakpoint" motivational measure. The results implicate initial reward sensitivity as a risk factor for stress-induced hypohedonia.

Keywords: Amphetamine or dopamine reuptake inhibitor or dopaminergic; Anhedonia or anhedonic or hypohedonia or reward; Major depression or depressive or depressed; Motivation or volition or avolition; Repeated or chronic defeat or social stress; Sugar or glucose or saccharin or SuperSac.

Figure 1

A. Defeat significantly reduced SuperSac consumption as compared to non-defeated controls (Defeat main effect). By Bonferroni-corrected comparisons for each triad, defeated rats consumed significantly less SuperSac compared to both their own baseline consumption (indicated by dashed line) and non-defeated controls only during the first and second triads. B. Repeated defeat reduced SuperSac consumption of High compared to Low baseline rats during the third triad. C. In triad three, defeated rats showed decreased preference ratios for SuperSac (vs. isocaloric glucose) compared to control rats. D. By the third triad, intake of isocaloric glucose significantly increased, relative to baseline, in defeated rats but not non-defeated controls. * p< 0.05, ** p<0.01

Figure 2

A. Defeat significantly blunted the increase in PR breakpoints for SuperSac compared to non-defeated controls (Defeat main effect, Defeat X Triad linear contrast interaction). The blunting of PR breakpoints becomes more evident across triads as controls increase, showing mild blunting by triad 2, and significant blunting by triad 3. B. Defeat only blunted the PR breakpoint increase during triad three, relative to baseline, in High, but not Low, rats as compared to their respective controls C. After 2.5 weeks of SuperSac deprivation, upon renewed access to SuperSac, defeated rats that had an initially High baseline breakpoint persisted in showing blunted breakpoint increase as compared to their controls. * p< 0.05, ** p<0.01, *** p<0.001

Figure 3

A. Prior to drug or vehicle treatment, rats that had previously experienced repeated defeat show increased initial locomotion when placed in the locomotor activity chambers for the first time compared to controls. B. A significant Defeat X Amphetamine interaction reflected that defeated rats showed similar activity to non-defeated controls under saline conditions but consistently showed less locomotion than non-defeated controls following amphetamine injection. * p< 0.05, ***p<0.001