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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: 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.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 induces deficits in the cognitive and the affective domain. (A) SDPS animals were exposed to 5 daily defeat sessions, immediately followed by social isolation (single-housing). Eight weeks following the last defeat episode, Social Approach Avoidance (SAA), and Object Place Recognition tests were employed to assess the effects of SDSP on the affective and cognitive domain. Animals were then subjected to a 7-weeks long operant sucrose self-administration paradigm. (B) Whereas both control and SDPS rats spent the majority of time interacting with the unfamiliar social target at the SAA test, SDPS triggered avoidance behavior, indicated by the significantly reduced interaction index as compared to controls. (C) SPDS rats failed to retain the position of the displaced object in the short-term spatial memory OPR test, in contrast to controls, which spent the majority of time exploring the object in its new location. *P < 0.050 for Student's t-test (gray); dotted gray line indicates the 50% preference index.
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Figure 1: SDPS induces deficits in the cognitive and the affective domain. (A) SDPS animals were exposed to 5 daily defeat sessions, immediately followed by social isolation (single-housing). Eight weeks following the last defeat episode, Social Approach Avoidance (SAA), and Object Place Recognition tests were employed to assess the effects of SDSP on the affective and cognitive domain. Animals were then subjected to a 7-weeks long operant sucrose self-administration paradigm. (B) Whereas both control and SDPS rats spent the majority of time interacting with the unfamiliar social target at the SAA test, SDPS triggered avoidance behavior, indicated by the significantly reduced interaction index as compared to controls. (C) SPDS rats failed to retain the position of the displaced object in the short-term spatial memory OPR test, in contrast to controls, which spent the majority of time exploring the object in its new location. *P < 0.050 for Student's t-test (gray); dotted gray line indicates the 50% preference index.

Mentions: Paired-housed male Wistar rats (Harlan CPB, Horst, Netherlands) 6–7 weeks old, weighing < 200 g upon arrival were habituated to the facility (2 weeks), and then were exposed to SDPS (Riga et al., 2014) followed by operant sucrose self-administration (SA) (Figure 1A). During the SDPS paradigm, residents (male Long-Evans, Charles River, UK) were paired-housed with age-matched tube-ligated females (Wistar, Harlan) in order to promote territorial behavior and aggression. The female Wistar and all cage enrichment were removed from the residents' cage before defeat commenced. During the SDPS paradigm, Wistar rats (n = 8) were exposed to five daily defeat sessions with the resident, according to the resident-intruder protocol. During the pre- and post-phases of each defeat session (5 min each), the Wistar rat was positioned in the Long Evans home-cage, however, the resident had no access to the intruder due to placement of a transparent, perforated plastic partition-wall. The fight-phase (5 min) was initiated and terminated by respectively, removing or replacing the partition wall. For each defeat session, intruders were matched to a different resident. At defeat days, control animals (n = 7) were transferred to the residents' holding room and allowed to explore an empty defeat cage for 15 min. From the first defeat session/cage exposure onwards, all animals were single-housed and remained in social isolation for the rest of the experimental conditions, in absence of further sensory interaction with the stressor (residents). All animals were housed in humidity/temperature-controlled rooms (50%/21 ± 1°C). Food and water were available ad libitum for the whole experimental period. All experimental manipulations were conducted during the dark phase of a reversed 12-h light-dark cycle (lights on at 19.00 h). All experiments were approved by the VU University Amsterdam Animal Users Care Committee.


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 induces deficits in the cognitive and the affective domain. (A) SDPS animals were exposed to 5 daily defeat sessions, immediately followed by social isolation (single-housing). Eight weeks following the last defeat episode, Social Approach Avoidance (SAA), and Object Place Recognition tests were employed to assess the effects of SDSP on the affective and cognitive domain. Animals were then subjected to a 7-weeks long operant sucrose self-administration paradigm. (B) Whereas both control and SDPS rats spent the majority of time interacting with the unfamiliar social target at the SAA test, SDPS triggered avoidance behavior, indicated by the significantly reduced interaction index as compared to controls. (C) SPDS rats failed to retain the position of the displaced object in the short-term spatial memory OPR test, in contrast to controls, which spent the majority of time exploring the object in its new location. *P < 0.050 for Student's t-test (gray); dotted gray line indicates the 50% preference index.
© Copyright Policy
Related In: Results  -  Collection

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

Figure 1: SDPS induces deficits in the cognitive and the affective domain. (A) SDPS animals were exposed to 5 daily defeat sessions, immediately followed by social isolation (single-housing). Eight weeks following the last defeat episode, Social Approach Avoidance (SAA), and Object Place Recognition tests were employed to assess the effects of SDSP on the affective and cognitive domain. Animals were then subjected to a 7-weeks long operant sucrose self-administration paradigm. (B) Whereas both control and SDPS rats spent the majority of time interacting with the unfamiliar social target at the SAA test, SDPS triggered avoidance behavior, indicated by the significantly reduced interaction index as compared to controls. (C) SPDS rats failed to retain the position of the displaced object in the short-term spatial memory OPR test, in contrast to controls, which spent the majority of time exploring the object in its new location. *P < 0.050 for Student's t-test (gray); dotted gray line indicates the 50% preference index.
Mentions: Paired-housed male Wistar rats (Harlan CPB, Horst, Netherlands) 6–7 weeks old, weighing < 200 g upon arrival were habituated to the facility (2 weeks), and then were exposed to SDPS (Riga et al., 2014) followed by operant sucrose self-administration (SA) (Figure 1A). During the SDPS paradigm, residents (male Long-Evans, Charles River, UK) were paired-housed with age-matched tube-ligated females (Wistar, Harlan) in order to promote territorial behavior and aggression. The female Wistar and all cage enrichment were removed from the residents' cage before defeat commenced. During the SDPS paradigm, Wistar rats (n = 8) were exposed to five daily defeat sessions with the resident, according to the resident-intruder protocol. During the pre- and post-phases of each defeat session (5 min each), the Wistar rat was positioned in the Long Evans home-cage, however, the resident had no access to the intruder due to placement of a transparent, perforated plastic partition-wall. The fight-phase (5 min) was initiated and terminated by respectively, removing or replacing the partition wall. For each defeat session, intruders were matched to a different resident. At defeat days, control animals (n = 7) were transferred to the residents' holding room and allowed to explore an empty defeat cage for 15 min. From the first defeat session/cage exposure onwards, all animals were single-housed and remained in social isolation for the rest of the experimental conditions, in absence of further sensory interaction with the stressor (residents). All animals were housed in humidity/temperature-controlled rooms (50%/21 ± 1°C). Food and water were available ad libitum for the whole experimental period. All experimental manipulations were conducted during the dark phase of a reversed 12-h light-dark cycle (lights on at 19.00 h). All experiments were approved by the VU University Amsterdam Animal Users Care Committee.

Bottom Line: 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.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