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Social defeat-induced anhedonia: effects on operant sucrose-seeking behavior.

Riga D, Theijs JT, De Vries TJ, Smit AB, Spijker S - Front Behav Neurosci (2015)

Bottom Line: Moreover, SDPS induced initial resilience to extinction and rendered animals more sensitive to cue-induced reinstatement of sucrose-seeking.Guanfacine treatment attenuated SDPS-induced motivational overdrive and limited reinstatement of sucrose seeking, normalizing behavior to control levels.Together, our data indicate that long after the termination of stress exposure, SDPS induces guanfacine-reversible deficits in evaluation of a natural reward.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular and Cellular Neurobiology, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University Amsterdam, Netherlands.

ABSTRACT
Reduced capacity to experience pleasure, also known as anhedonia, is a key feature of the depressive state and is associated with poor disease prognosis and treatment outcome. Various behavioral readouts (e.g., reduced sucrose intake) have been employed in animal models of depression as a measure of anhedonia. However, several aspects of anhedonia are poorly represented within the repertoire of current preclinical assessments. We recently adopted the social defeat-induced persistent stress (SDPS) paradigm that models a maintained depressive-like state in the rat, including social withdrawal and deficits in short-term spatial memory. Here we investigated whether SDPS elicited persistent deficits in natural reward evaluation, as part of anhedonia. We examined cue-paired operant sucrose self-administration, enabling us to study acquisition, motivation, extinction, and relapse to sucrose seeking following SDPS. Furthermore, we addressed whether guanfacine, an α2-adrenergic agonist that reduces stress-triggered maladaptive behavioral responses to drugs of abuse, could relief from SDPS-induced anhedonia. SDPS, consisting of five social defeat episodes followed by prolonged (≥8 weeks) social isolation, did not affect sucrose consumption during acquisition of self-administration. However, it strongly enhanced the motivational drive to acquire a sucrose reward in progressive ratio training. Moreover, SDPS induced initial resilience to extinction and rendered animals more sensitive to cue-induced reinstatement of sucrose-seeking. Guanfacine treatment attenuated SDPS-induced motivational overdrive and limited reinstatement of sucrose seeking, normalizing behavior to control levels. Together, our data indicate that long after the termination of stress exposure, SDPS induces guanfacine-reversible deficits in evaluation of a natural reward. Importantly, the SDPS-triggered anhedonia reflects many aspects of the human phenotype, including impaired motivation and goal-directed conduct.

No MeSH data available.


Related in: MedlinePlus

SDPS triggers motivational overdrive toward a sucrose reward; guanfacine attenuates enhanced motivation. (A) The motivation to acquire a sucrose reward was examined in 6 treatment-free PR training sessions (highlighted; B,C). (B) SDPS increased responding during both the pre- (PR3–4) and post- (PR6–7) treatment sessions, and no carry-over effects of guanfacine treatment were detected (see E). (C) Break points, depicted as the maximum FR completed when averaging over the four treatment-free sessions, confirmed the SDPS-triggered exaggeration of motivational drive in defeated animals. (D) The effect of guanfacine on PR responding was assessed at PR sessions five and eight using a cross-over treatment administration design (highlighted, E). (E) Guanfacine administration reduced overall PR responding. Independently of treatment regime, the SDPS group showed significantly increased number of responses as compared with controls. *P < 0.050; **P < 0.010; (B): repeated ANOVA (group effect); (C): One-Way ANOVA (group effect); (E): repeated ANOVA (treatment effect).
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Figure 3: SDPS triggers motivational overdrive toward a sucrose reward; guanfacine attenuates enhanced motivation. (A) The motivation to acquire a sucrose reward was examined in 6 treatment-free PR training sessions (highlighted; B,C). (B) SDPS increased responding during both the pre- (PR3–4) and post- (PR6–7) treatment sessions, and no carry-over effects of guanfacine treatment were detected (see E). (C) Break points, depicted as the maximum FR completed when averaging over the four treatment-free sessions, confirmed the SDPS-triggered exaggeration of motivational drive in defeated animals. (D) The effect of guanfacine on PR responding was assessed at PR sessions five and eight using a cross-over treatment administration design (highlighted, E). (E) Guanfacine administration reduced overall PR responding. Independently of treatment regime, the SDPS group showed significantly increased number of responses as compared with controls. *P < 0.050; **P < 0.010; (B): repeated ANOVA (group effect); (C): One-Way ANOVA (group effect); (E): repeated ANOVA (treatment effect).

Mentions: The PR training schedule was introduced to examine SDPS-triggered differences in motivation towards sucrose acquisition (Figure 3A). Repeated measures ANOVA over the last 2 PR sessions before the first guanfacine challenge (PR3–4) showed no training effect [F(1, 13) = 0.05, P = 0.831], nor a training × group interaction [F(1, 13) = 0.65, P = 0.433], indicating stabilization of PR performance. Notably, a significant group effect was observed [F(1, 13) = 6.68, P = 0.023], as SDPS animals showed enhanced responding for sucrose when compared with controls (Figure 3B). Similar to active responses, break points, calculated based on the highest FR completed (average of treatment-free sessions PR3–4 and PR6–7), were significantly increased following SDPS [F(1, 14) = 6.15, P = 0.028] pointing toward heightened motivation to acquire sucrose (Figure 3C).


Social defeat-induced anhedonia: effects on operant sucrose-seeking behavior.

Riga D, Theijs JT, De Vries TJ, Smit AB, Spijker S - Front Behav Neurosci (2015)

SDPS triggers motivational overdrive toward a sucrose reward; guanfacine attenuates enhanced motivation. (A) The motivation to acquire a sucrose reward was examined in 6 treatment-free PR training sessions (highlighted; B,C). (B) SDPS increased responding during both the pre- (PR3–4) and post- (PR6–7) treatment sessions, and no carry-over effects of guanfacine treatment were detected (see E). (C) Break points, depicted as the maximum FR completed when averaging over the four treatment-free sessions, confirmed the SDPS-triggered exaggeration of motivational drive in defeated animals. (D) The effect of guanfacine on PR responding was assessed at PR sessions five and eight using a cross-over treatment administration design (highlighted, E). (E) Guanfacine administration reduced overall PR responding. Independently of treatment regime, the SDPS group showed significantly increased number of responses as compared with controls. *P < 0.050; **P < 0.010; (B): repeated ANOVA (group effect); (C): One-Way ANOVA (group effect); (E): repeated ANOVA (treatment effect).
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4528167&req=5

Figure 3: SDPS triggers motivational overdrive toward a sucrose reward; guanfacine attenuates enhanced motivation. (A) The motivation to acquire a sucrose reward was examined in 6 treatment-free PR training sessions (highlighted; B,C). (B) SDPS increased responding during both the pre- (PR3–4) and post- (PR6–7) treatment sessions, and no carry-over effects of guanfacine treatment were detected (see E). (C) Break points, depicted as the maximum FR completed when averaging over the four treatment-free sessions, confirmed the SDPS-triggered exaggeration of motivational drive in defeated animals. (D) The effect of guanfacine on PR responding was assessed at PR sessions five and eight using a cross-over treatment administration design (highlighted, E). (E) Guanfacine administration reduced overall PR responding. Independently of treatment regime, the SDPS group showed significantly increased number of responses as compared with controls. *P < 0.050; **P < 0.010; (B): repeated ANOVA (group effect); (C): One-Way ANOVA (group effect); (E): repeated ANOVA (treatment effect).
Mentions: The PR training schedule was introduced to examine SDPS-triggered differences in motivation towards sucrose acquisition (Figure 3A). Repeated measures ANOVA over the last 2 PR sessions before the first guanfacine challenge (PR3–4) showed no training effect [F(1, 13) = 0.05, P = 0.831], nor a training × group interaction [F(1, 13) = 0.65, P = 0.433], indicating stabilization of PR performance. Notably, a significant group effect was observed [F(1, 13) = 6.68, P = 0.023], as SDPS animals showed enhanced responding for sucrose when compared with controls (Figure 3B). Similar to active responses, break points, calculated based on the highest FR completed (average of treatment-free sessions PR3–4 and PR6–7), were significantly increased following SDPS [F(1, 14) = 6.15, P = 0.028] pointing toward heightened motivation to acquire sucrose (Figure 3C).

Bottom Line: Moreover, SDPS induced initial resilience to extinction and rendered animals more sensitive to cue-induced reinstatement of sucrose-seeking.Guanfacine treatment attenuated SDPS-induced motivational overdrive and limited reinstatement of sucrose seeking, normalizing behavior to control levels.Together, our data indicate that long after the termination of stress exposure, SDPS induces guanfacine-reversible deficits in evaluation of a natural reward.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular and Cellular Neurobiology, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University Amsterdam, Netherlands.

ABSTRACT
Reduced capacity to experience pleasure, also known as anhedonia, is a key feature of the depressive state and is associated with poor disease prognosis and treatment outcome. Various behavioral readouts (e.g., reduced sucrose intake) have been employed in animal models of depression as a measure of anhedonia. However, several aspects of anhedonia are poorly represented within the repertoire of current preclinical assessments. We recently adopted the social defeat-induced persistent stress (SDPS) paradigm that models a maintained depressive-like state in the rat, including social withdrawal and deficits in short-term spatial memory. Here we investigated whether SDPS elicited persistent deficits in natural reward evaluation, as part of anhedonia. We examined cue-paired operant sucrose self-administration, enabling us to study acquisition, motivation, extinction, and relapse to sucrose seeking following SDPS. Furthermore, we addressed whether guanfacine, an α2-adrenergic agonist that reduces stress-triggered maladaptive behavioral responses to drugs of abuse, could relief from SDPS-induced anhedonia. SDPS, consisting of five social defeat episodes followed by prolonged (≥8 weeks) social isolation, did not affect sucrose consumption during acquisition of self-administration. However, it strongly enhanced the motivational drive to acquire a sucrose reward in progressive ratio training. Moreover, SDPS induced initial resilience to extinction and rendered animals more sensitive to cue-induced reinstatement of sucrose-seeking. Guanfacine treatment attenuated SDPS-induced motivational overdrive and limited reinstatement of sucrose seeking, normalizing behavior to control levels. Together, our data indicate that long after the termination of stress exposure, SDPS induces guanfacine-reversible deficits in evaluation of a natural reward. Importantly, the SDPS-triggered anhedonia reflects many aspects of the human phenotype, including impaired motivation and goal-directed conduct.

No MeSH data available.


Related in: MedlinePlus