CRF Release in the Nucleus Accumbens Promotes Arousal in Anticipation of Cocaine Availability: Implications for Stress‐Induced Drug‐Seeking

Abstract

Dopamine signaling within the nucleus accumbens core (NAcC) is critical to the generation of motivated behaviors in both appetitive and aversive contexts. Within the accumbens, various neuropeptides influence motivational states through the modulation of dopamine release dynamics. Here, microdialysis studies show that the stress peptide corticotropin releasing factor (CRF) is released in the NAcC when rats are exposed to environmental contexts that predict either an aversive outcome (i.e. social defeat) or drug‐reward opportunity (i.e. cocaine availability), and moreover, intra‐NAcC infusion of exogenous CRF elicits a robust increase in extracellular dopamine. The present studies further interrogate accumbens‐specific CRF actions as a candidate mechanism for maladaptive arousal evoked by drug‐predictive stimuli – a hallmark feature of cocaine dependence. In order to assess the role of NAcC‐CRF on instrumental responding directed towards cocaine procurement, male Long‐Evans rats were trained to self‐administer cocaine under a heterogeneous chained schedule of reinforcement (FIFR) in order to dissociate anticipatory (‘drug‐seeking’) from consummatory (‘drug‐taking’) behavior. Completion of a fixed‐interval (10 min) was followed by a period (10 min) of continuously reinforced responding (0.32mg/kg cocaine; FR1) on another lever. Microdialysis conducted during this procedure revealed that extracellular dopamine levels within the NAcC gradually ‘ramp up’ across the fixed‐interval in parallel with lever pressing activity, as drug availability approaches. Similarly, dialysate levels of CRF were specifically and progressively elevated during the fixed‐interval component preceding drug‐access, but were unaffected by drug‐taking. Infusion of CRF into the NAc produced a rapid elevated tonic dopamine levels that was accompanied by enhanced responding during the fixed‐interval component of the procedure, but notably did not affect subsequent cocaine intake. Conversely, pharmacological blockade of CRF‐R2, dampened extracellular dopamine levels in the NAc and suppressed lever pressing behavior during the fixed‐interval. Taken together, these data suggest that in response to appetitive or aversive stimuli, CRF may be a critical mediator of motivated processes that are classically associated with dopamine transmission. To this end, stress‐evoked CRF release in the NAc may represent a candidate mechanism by which stress triggers aberrant cocaine‐seeking.Support or Funding InformationNIDA R01‐DA031734 to KAM