Is it stress? The role of the CRF system and HPA axis, and the identification of brain sites involved in chronic food restriction-induced augmentation of heroin seeking

Drug addiction is a chronic disease characterized by recurring episodes of abstinence and relapse. The mechanisms that underlie this pattern are yet to be elucidated. Recently, we reported that abstinent rats with a history of chronic food restriction show increased heroin seeking compared to sated controls. It is thought that food restriction may cause sensitization of drug seeking due to its stress-like properties, suggesting a critical role for corticotropin-releasing factor (CRF) and corticosterone, hormones involved in the stress response. Blocking corticosterone reduces food restriction-induced sensitization of locomotor activity in response to cocaine, while acute food-deprivation induced reinstatement of extinguished drug seeking is attenuated by CRF antagonism but not removal of corticosterone. The role of CRF and corticosterone in food restriction-induced augmentation of drug seeking remains unknown. Here, male Long-Evans rats were trained to self-administer heroin for 10 days in operant conditioning chambers. Following self-administration rats were subjected to 14 days of unrestricted (sated group) or a mildly restricted (FDR group) access to food, which maintained their body weight at ~75% of the sated rats’ body weight. On day 14, rats were administered a selective CRF1 receptor antagonist (R121919; 0.0, 20.0 mg/kg; IP), non-selective CRF receptor antagonist (α-helical CRF; 0.0, 10.0, 25.0 μg/μl; ICV) or a glucocorticoid receptor antagonist (RU486; 0.0, 30.0 mg/kg; IP), and underwent a 1 h drug seeking test under extinction conditions. Rats in the FDR group showed a statistically significant increase in heroin seeking compared to the sated group. No statistically significant effects for treatment with R121919, α-helical CRF or RU486 were observed. These findings suggest that stress may not be a critical factor in our paradigm. In an exploratory study to identify brain sites involved in this effect rats were sacrificed post-test and the expression of the immediate early gene, c-fos, an indicator of neuronal activity, was measured using immunohistochemistry. Interestingly, a statistically significant decrease in Fos immunoreactivity in the nucleus accumbens shell was observed for the FDR compared to sated rats. Although stress may not be a critical factor in our effect, prolonged exposure to food restriction does cause alterations in reward-related brain sites. The identification of specific neuron types affected in these regions should drive future studies