Pharmacological manipulation of glucocorticoid receptors differentially affects cocaine self-administration in environmentally enriched and isolated rats

• Rats were raised in environmental enrichment (EC) or isolation (IC).
• EC rats decreased low-dose cocaine self-administration after pretreatment with RU486.
• EC and IC rats significantly differed in responding when pretreated with CORT.
• Glucocorticoid receptor protein did not differ between EC and IC in any area tested.

Social isolation rearing (isolated condition, IC) is used as a model of early life stress in rodents. Rats raised in this condition are often compared to rats raised in an environmentally enriched condition (EC). However, EC rats are repeatedly exposed to forced novelty, another classic stressor in rodents. These studies explored the relationship between cocaine self-administration and glucocorticoid receptor (GR) activation and measured total levels of GR protein in reward-related brain regions (medial prefrontal cortex, orbitofrontal cortex, nucleus accumbens, amygdala) in rats chronically exposed to these conditions. For Experiment 1, rats were housed in EC or IC and were then trained to self-administer cocaine. Rats raised in these housing conditions were tested for their cocaine responding after pretreatment with the GR antagonist, RU486, or the GR agonist, corticosterone (CORT). For Experiment 2, levels of GR from EC and IC rats were measured in brain regions implicated in drug abuse using Western blot analysis. Pretreatment with RU486 (20 mg/kg) decreased responding for a low unit dose of cocaine (0.03 mg/kg/infusion) in EC rats only. IC rats were unaffected by RU486 pretreatment, but earned significantly more cocaine than EC rats after pretreatment with CORT (10 mg/kg). No difference in GR expression was found between EC and IC rats in any brain area examined. These results, along with previous literature, suggest that enrichment enhances responsivity of the HPA axis related to cocaine reinforcement, but this effect is unlikely due simply to differential baseline GR expression in areas implicated in drug abuse.