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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

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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

Sedki, Firas (2012) 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. Masters thesis, Concordia University.

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Abstract

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.

Divisions:Concordia University > Faculty of Arts and Science > Psychology
Item Type:Thesis (Masters)
Authors:Sedki, Firas
Institution:Concordia University
Degree Name:M.A.
Program:Psychology
Date:22 August 2012
Thesis Supervisor(s):Shalev, Uri
Keywords:Heroin, Self-administration, Chronic food restriction, Chronic stress, CRF, Corticosterone, c-fos, Nucleus accumbens
ID Code:974823
Deposited By:FIRAS SEDKI
Deposited On:30 Oct 2012 11:20
Last Modified:30 Oct 2012 11:20

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