Cues Associated with Social Defeat Stress Recruit CRF in the Nucleus Accumbens and Invigorate Drug‐Seeking following Abstinence from Cocaine
Authors: Leonard Michael Z. , Miczek Klaus A. 
Published: May 2022

Cocaine‐dependent individuals experience intense drug cravings in anticipation of imminent drug availability. Notably, acute stressors can further exacerbate the heightened state of arousal produced by drug‐related stimuli and increase propensity to seek and consume drug – rendering individuals highly susceptible to relapse. The present studies extend ongoing work examining the stress peptide corticotropin releasing factor (CRF) as a candidate mechanism for maladaptive arousal evoked by drug‐predictive stimuli. In rats, CRF enhances instrumental behavior directed towards gaining access to cocaine, in part through local control of DA transmission in the nucleus accumbens (NAc). Because CRF modulates motivational states in both appetitive and aversive contexts, we explored the extent to which an ecologically relevant stressor (ie social defeat) augments cocaine self‐administration under a chained operant response sequence (ie seeking‐taking), and whether NAc‐CRF is recruited. On alternating days, male Long‐Evans rats were exposed to acute social defeat in the presence of a compound stimulus (CS+: peppermint odor + 3kHz tone) or placed in an empty cage (CS‐: almond odor + 25kHz tone) for 4 sessions each. Microdialysis conducted in the presence of the conditioned cues revealed that the stress‐CS+ produced a rapid increase in both CRF and DA in the NAc, which was temporally distinct from a delayed rise in corticosterone. Separate rats were trained to self‐administer cocaine under a chained schedule of reinforcement (FI‐FR) in order to dissociate anticipatory (‘drug‐seeking’) from consummatory (‘drug‐taking’) behavior. Completion of a fixed‐interval (5m) produced access to continuous cocaine reinforcement (FR1) on a separate lever (5m). Here, accelerating responding across the FI captures an index of arousal in anticipation of impending drug‐availability – ostensibly, when craving is heightened. After a 7d drug‐free (ABST) period, rats were reintroduced to the drug context to self‐administer cocaine in the presence of either the stress‐paired stimuli (CS+) or neutral cues (CS‐) in a counterbalanced manner. Compared to pre‐ABST baseline, responding during the FI was elevated under both stimulus conditions, presumably reflecting an “incubation”‐like enhancement of behavior. Critically, CS+ exposure produced significantly higher anticipatory responding for cocaine than the neutral condition (CS+> CS‐ > Baseline), suggesting that stress stimuli augmented the effects of ABST. Cocaine intake was unaffected by either condition. These data support the concept that environmental stressors can amplify the impact of being re‐exposed to a drug‐context after a period of abstinence, such to invigorate putative “drug‐seeking” behavior. Anticipation of threat may engage common motivational salience circuits that generate arousal during cocaine expectation, whereas the unconditioned aspects of drug‐reward are differentially controlled. Ongoing studies seek to further clarify the functional role of stress‐evoked NAc‐CRF in cocaine‐related behavior.