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Abstract
Drug addiction is a chronic disease characterized by recurring episodes of abstinence and relapse. The precise mechanisms underlying this pattern are yet to be elucidated, but stress is thought to be a major factor in relapse. Recently, we reported that rats under withdrawal and exposed to a mild chronic stressor, prolonged food restriction, show increased heroin seeking compared to sated controls. Previous studies demonstrated a critical role for corticotropin-releasing factor (CRF) and corticosterone, hormones involved in the stress response, in acute food deprivation-induced reinstatement of extinguished drug seeking. However, the role of CRF and corticosterone in chronic 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. Rats were then removed from the training chambers, and subjected to 14 days of unrestricted (sated rats) or a mildly restricted (FDR rats) access to food, which maintained their body weight (BW) at 90% of their baseline weight. On day 14, different groups of rats were administered a selective CRF1 receptor antagonist (R121919; 0.0, 20.0 mg/kg; s.c.), a non-selective CRF receptor antagonist (α-helical CRF; 0.0, 10.0, 25.0 μg/rat; i.c.v.) or a glucocorticoid receptor antagonist (RU486; 0.0, 30.0 mg/kg; i.p.), and underwent a 1 h drug seeking test under extinction conditions. An additional group of rats was tested following adrenalectomy. All FDR rats showed a statistically significant increase in heroin seeking compared to the sated rats. No statistically significant effects for treatment with α-helical CRF, R121919, RU486 or adrenalectomy were observed. These findings suggest that stress may not be a critical factor in the augmentation of heroin seeking in food-restricted rats.
Highlights
Stress is consistently reported by drug users as a factor in subjective craving as well as in the initiation, maintenance, and relapse of drug use (Brewer et al, 1998; Matheny and Weatherman, 1998; Sinha and O’Malley, 1999; Sinha, 2001, 2008)
In contrast to the robust attenuation of acute food deprivation-induced reinstatement of drug seeking following treatment with corticotropin-releasing factor (CRF)-receptor antagonists, treatment with R121919, a selective CRF1-R antagonist, or α-helical CRF, a non-specific CRF-R antagonist, did not result in a statistically significant reduction in heroin seeking in food restricted rats under withdrawal
Neither treatment with RU486, a glucocorticoid receptor antagonist, nor adrenalectomy affected heroin seeking in this model
Summary
Stress is consistently reported by drug users as a factor in subjective craving as well as in the initiation, maintenance, and relapse of drug use (Brewer et al, 1998; Matheny and Weatherman, 1998; Sinha and O’Malley, 1999; Sinha, 2001, 2008). Acute food deprivation (FD: 24– 48 h), can induce reinstatement to drug seeking in rats with a history of heroin or cocaine self-administration (Shalev et al, 2000, 2003). This effect is attenuated by antagonism of the stress neuropeptide corticotropin-releasing factor (CRF) receptor, but not the removal of corticosterone (Shalev et al, 2003, 2006), a pattern of results similar to those obtained by Shaham et al (1997) in a study utilizing footshock as a stressor
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