Early life stress‐potentiated cocaine seeking is mediated by upregulation of kappa opioid receptor function
Authors: Karkhanis Anushree N , Albertson Steven E , Weiner Jeff L , Jones Sara R 
Published: November 2023

Cocaine addiction exhibits a complex pathology, which is often exacerbated in individuals exposed to major adverse events during their life. Particularly, exposure to chronic stress during adolescence augments drug‐ and cue‐induced cocaine craving as well as severity of withdrawal symptoms, potentially driving cocaine addiction in humans. Similarly, in rodents, adolescent social isolation (aSI) results in augmented locomotor response to systemic cocaine administration and elevated cocaine seeking compared to rats that are group housed during adolescence (aGH). Stress results in an increase in dynorphin, the endogenous kappa opioid receptor (KOR) agonist. Moreover, aSI results in upregulation of KOR binding sites and function. Additionally, KOR activation time‐dependently modulates vulnerability to cocaine and reward processing. Thus, the goal of this study was to compare the reinforcing efficacy of cocaine in aSI and aGH animals and to investigate the underlying mechanisms involved in driving the potentiated effect of cocaine on locomotor behavior and augmented cocaine seeking in aSI rats. To that effect, following a 6‐week protocol in which rats were either housed in groups (aGH; 4 rats/cage) or individually (aSI; 1 rat/cage), jugular catheters were implanted and after a recovery period of 2 days, rats were given access to levers to self‐administer cocaine using various schedules of reinforcement. Systemic administration of cocaine (15 mg/kg; i.p.) resulted in an augmented locomotor response to cocaine. Self‐administration using a progressive ratio schedule showed an enhanced motivation to self‐administer cocaine in aSI compared to aGH rats (mean final ratio: aGH, 77; aSI, 268; at 2.25 mg/kg/infusion). Threshold analysis, during which the cocaine dose administered for each lever press is systematically reduced in ten minute bins, showed that rats exposed to aSI were willing to “pay a greater price” to maintain their level of cocaine intake compared to aGH (lever presses/mg of cocaine: aGH, 200; aSI, 500). Administration of nor‐binaltorphimine (nBNI; 10 mg/kg; i.p.), a KOR antagonist reduced this enhanced motivation to self‐administer cocaine selectively in aSI rats (lever presses/mg of cocaine post nBNI: aGH, 198; aSI, 210). Interestingly, cocaine consumption in the two groups was not different. This suggests that the reinforcing value of cocaine is greater for rats exposed to early‐life stress than the control group as there is no difference in intake when the cost of self‐administering cocaine is only a single lever‐press. It is likely that rats exposed to chronic early‐life stress self‐administer cocaine for positive reinforcement, thus increasing the risk of developing addictive behaviors. The KOR inhibition‐induced attenuation of cocaine seeking suggests that KORs potentially contribute to the augmented motivation to self‐administer cocaine. Thus, KORs are promising therapeutic targets to treat cocaine addiction especially in individuals exposed to childhood adversities and are therefore predisposed to cocaine addiction.Support or Funding InformationAA023874 (ANK); AA021099 (JLW and SRJ); DA014030, DA011697 (SRJ)