Corticotropin-releasing Factor in the Rat Dorsal Raphe Nucleus Promotes Different Forms of Behavioral Flexibility Depending on Social Stress History

Snyder, Kevin M.; Hill-Smith, Tiffany E.; Lucki, Irwin; Valentino, Rita J.

doi:10.1038/npp.2015.98

Cited by 17 publications

(9 citation statements)

References 51 publications

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“…CRF has been previously reported to exert different, and sometimes opposite effects on both physiological and behavioral endpoints at high and low concentrations within the VTA (Williams et al 2014), as well as the dorsal raphe (Price et al 1998, Kirby et al 2000; Snyder et al 2015) and locus coeruleus (Snyder et al 2012). These biphasic effects are likely determined by preferential binding at CRF-R1 at low concentrations, where higher CRF concentrations appear necessary to engage CRF-R2.…”

Section: Discussionmentioning

confidence: 99%

Escalated cocaine “binges” in rats: enduring effects of social defeat stress or intra-VTA CRF

2017

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Rationale Exposure to intermittent social defeat stress elicits CRF release into the VTA, and induces long-term modulation of mesocorticolimbic dopamine activity in rats. These adaptations are associated with an intense cocaine-taking phenotype, which is prevented by CRF receptor antagonists. Objective The present studies examine whether infusion of CRF into the VTA is sufficient to escalate cocaine-taking behavior, in the absence of social defeat experience. Additionally, we aimed to characterize changes in cocaine valuation that may promote binge-like cocaine intake. Methods Male Long-Evans rats were microinjected into the VTA with CRF (50 or 500 ng/side), vehicle, or subjected to social defeat stress, intermittently over 10 days. Animals were then trained to self-administer IV cocaine (FR5). Economic demand for cocaine was evaluated using a within-session behavioral-economics threshold procedure, which was followed by a 24-hour extended-access “binge”. Results Rats that experienced social defeat or received intra-VTA CRF microinfusions (50ng) both took significantly more cocaine than controls over the 24-hour “binge”, but showed distinct patterns of intake. Behavioral economic analysis revealed that individual demand for cocaine strongly predicts binge-like consumption, and demand elasticity (i.e. α) is augmented by intra-VTA CRF, but not by social defeat. The effects of CRF on cocaine-taking were also prevented by intra-VTA pretreatment with CP376395, but not Astressin-2B. Conclusions Repeated infusion of CRF into the VTA persistently alters cocaine valuation, and intensifies binge-like drug intake in a CRF-R1-dependent manner. Conversely, the persistent pattern of cocaine bingeing induced by social defeat stress may suggest impaired inhibitory control, independent of reward valuation.

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Section: Discussionmentioning

confidence: 99%

Escalated cocaine “binges” in rats: enduring effects of social defeat stress or intra-VTA CRF

2017

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“…When the role of CRF in the DR was probed by microinjecting a CRF antagonist, the effects of long‐term social isolation were reducible and isolated males spent more time in the open arms (females were not tested in this study). One possibility that has been raised is that social stress exposure (e.g., the resident intruder paradigm), shifts behavioral responses for reversal learning from a CRF 1 ‐mediated response to a more CRF 2 ‐mediated response (Snyder et al, ). Given that our females show significantly higher CRF 2 expression in the DRVL, we speculate that this may underlie sex differences in responsivity to stress‐related situations beginning in adolescence.…”

Section: Discussionmentioning

confidence: 99%

Sex differences in the ontogeny of CRF receptors during adolescent development in the dorsal raphe nucleus and ventral tegmental area

Lukkes

Norman

Meda

et al. 2016

Synapse

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Interactions between corticotropin-releasing factor (CRF) and monoaminergic systems originating from the dorsal raphe nucleus (DR) and ventral tegmental area (VTA) have been implicated in the etiology and pathophysiology of several stress-related neuropsychiatric disorders such as depression and substance abuse. Sub-regions within the DR and VTA give rise to specific projections that have unique roles in limbic- and reward-related behaviors. Given that these disorders typically emerge during adolescence, it is surprising that few studies have examined the age-, sex-, and region-dependent expression of CRF receptors throughout multiple stages of adolescence in these stress-relevant circuits. To determine the ontogeny of CRF receptors during adolescent development, three regions of the DR (dorsal, caudal, and ventrolateral parts) and the posterior VTA were microdissected from Sprague-Dawley male and female rats on postnatal day (P) 25, P35, P42, P56, and P90. Tissue was processed and analyzed with qRT-PCR to measure CRF1 and CRF2 receptors. The serotonin and catecholamine enzymes in the DR and VTA, tryptophan hydroxylase 2 (TPH2) and tyrosine hydroxylase, respectively, were also analyzed for maturational differences. This study identified that CRF1 receptors are lower in males than females within the dorsal, ventrolateral region of the DR (DRVL), which is involved in anxiety-, stress-, and panic-related responses. Females had higher CRF2 receptors compared to males in the DRVL only. Levels of TPH2 mRNA in the DRVL were overproduced transiently in females before declining into adulthood. These fundamental studies suggest that sex differences in CRF receptors should be considered when examining stress-related neuropsychiatric disorders and their treatment.

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“…Primary among these is the group setting approach in which all monkeys are given the same task, at the same time. Although this is a very efficient procedure for evaluating a large number of monkeys, each individual’s performance on cognitive tasks in a group environment might be differentially affected by social factors or distraction by the behavior of group-mates (Snyder K. et al, 2015 ; Snyder K. P. et al, 2015 ). Although this may be an advantage for evaluating attentional deficits in social settings, it confounds interpretation of what factors are influencing learning.…”

Section: Discussionmentioning

confidence: 99%

Ranking Cognitive Flexibility in a Group Setting of Rhesus Monkeys with a Set-Shifting Procedure

Shnitko

Allen

Gonzales

et al. 2017

Front. Behav. Neurosci.

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Attentional set-shifting ability is an executive function underling cognitive flexibility in humans and animals. In humans, this function is typically observed during a single experimental session where dimensions of playing cards are used to measure flexibility in the face of changing rules for reinforcement (i.e., the Wisconsin Card Sorting Test (WCST)). In laboratory animals, particularly non-human primates, variants of the WCST involve extensive training and testing on a series of dimensional discriminations, usually in social isolation. In the present study, a novel experimental approach was used to assess attentional set-shifting simultaneously in 12 rhesus monkeys. Specifically, monkeys living in individual cages but in the same room were trained at the same time each day in a set-shifting task in the same housing environment. As opposed to the previous studies, each daily session began with a simple single-dimension discrimination regardless of the animal’s performance on the previous session. A total of eight increasingly difficult, discriminations (sets) were possible in each daily 45 min session. Correct responses were reinforced under a second-order schedule of flavored food pellet delivery, and criteria for completing a set was 12 correct trials out of a running total of 15 trials. Monkeys progressed through the sets at their own pace and abilities. The results demonstrate that all 12 monkeys acquired the simple discrimination (the first set), but individual differences in the ability to progress through all eight sets were apparent. A performance index (PI) that encompassed progression through the sets, errors and session duration was calculated and used to rank each monkey’s performance in relation to each other. Overall, this version of a set-shifting task results in an efficient assessment of reliable differences in cognitive flexibility in a group of monkeys.

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Corticotropin-releasing Factor in the Rat Dorsal Raphe Nucleus Promotes Different Forms of Behavioral Flexibility Depending on Social Stress History

Cited by 17 publications

References 51 publications

Escalated cocaine “binges” in rats: enduring effects of social defeat stress or intra-VTA CRF

Escalated cocaine “binges” in rats: enduring effects of social defeat stress or intra-VTA CRF

Sex differences in the ontogeny of CRF receptors during adolescent development in the dorsal raphe nucleus and ventral tegmental area

Ranking Cognitive Flexibility in a Group Setting of Rhesus Monkeys with a Set-Shifting Procedure

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