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

Abstract

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.

phMRI, neurochemical and behavioral responses to psychostimulants distinguishing genetically selected alcohol‐preferring from genetically heterogenous rats

“…; Hansson et al . ; Han, DeBold, & Miczek ; Leonard, DeBold, & Miczek ). A remaining open question is whether msP and Wistar rats differ also in their propensity to relapse in response to environmental cues.…”

Non-pharmacological factors that determine drug use and addiction

“…higher rates during 24-h unlimited access (Fig. 6;Boyson et al 2014;Holly et al 2012;Leonard et al 2017;Miczek and Mutschler 1996;Shimamoto et al 2015;Tidey and Miczek 1997). Ongoing studies in mice provide further evidence of escalated cocaine self-administration several weeks after experiencing ten intermittent episodes of social defeat stress (Yap et al 2015;Arena et al in progress).…”

“…Intra-VTA antagonism of CRFR1 in the posterior VTA and CRFR2 in the anterior VTA during each of four intermittent social defeat episodes prevented subsequent escalated cocaine self-administration in a 24-h binge and later, after forced abstinence, cocaine seeking in a reinstatement test (Fig. 10;Holly et al 2016;Leonard et al 2017). These findings point to CRF in the VTA as a critical signal during the social stress episode that engenders not only a phasic response, but also induces a persistent elevation in CRF tone (Holly et al 2016).…”

“…Both mice and rats with a history of intermittent episodes of social defeat stress self-administered cocaine at higher rates. Specifically, mice and rats acquired cocaine self-administration at higher rates (Leonard et al 2017;Tidey and Miczek 1996;Arena et al unpublished…”

Social defeat stress and escalation of cocaine and alcohol consumption: Focus on CRF

“…During these binges, both male and female rats with a history of episodic social defeat stress often accumulate twice as much cocaine as non-stressed controls ( Fig. 2 F; Boyson et al, 2011 ; Boyson et al, 2014 ; Burke et al, 2016 ; Burke and Miczek, 2015 ; Covington et al, 2005 ; Covington et al, 2008 ; Covington and Miczek, 2001 ; Covington and Miczek, 2005 ; Cruz et al, 2011 ; Holly et al, 2012 ; Leonard et al, 2017 ; Quadros and Miczek, 2009 ; Yap et al, 2015 ).…”