Is it stress? The role of stress related systems in chronic food restriction-induced augmentation of heroin seeking in the rat

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.

Repeated restraint stress exposure during early withdrawal accelerates incubation of cue‐induced cocaine craving

“…In addition, it is unknown whether the facilitating effects of chronic stress exposure on incubated craving are observed for drugs other than heroin (D’Cunha et al 2013; Sedki et al 2013, 2015) and cocaine (current results). Since the incubation model is relevant to understanding persistent vulnerability to relapse (i.e., Reichel & Bevins, 2009; Pickens et al 2011) and incubation has been shown to occur in human users of several drugs including cocaine (Bedi et al 2011; Wang et al 2013; Li et al 2014; Parvaz et al 2016), further characterizing these effects will help to identify more effective strategies with which to treat craving and relapse in recovering addicts.…”

“…The Shalev laboratory has studied the effects of chronic stress in rats that undergo extended-access heroin self-administration followed by forced abstinence (without extinction training). Their results show that chronic mild food restriction stress (weight maintained at 90% of baseline weight) in male rats during the first two weeks of withdrawal (WD2-WD15) from heroin self-administration produces a robust increase in cue-induced heroin seeking on WD15 compared to non-food restricted controls (D’Cunha et al 2013; Sedki et al 2013). This is due to chronic food restriction, as a shorter (3–5 day) food restriction period did not enhance heroin seeking (D’Cunha et al , 2013).…”

“…This is due to chronic food restriction, as a shorter (3–5 day) food restriction period did not enhance heroin seeking (D’Cunha et al , 2013). However, blocking corticotropin-releasing factor (CRF) receptors and lowering corticosterone levels via adrenalectomy did not prevent the enhanced heroin seeking observed in the food restricted rats (Sedki et al 2013). While these findings do not rule out a role for stress hormones in the enhanced heroin seeking observed following chronic food restriction (i.e., via their downstream signaling cascades), they do suggest that, after two weeks of food restriction, stress hormones no longer directly mediate this effect.…”

“…Many studies have investigated the ability of an acute stressor to reinstate previously extinguished cocaine seeking (for review see Shaham et al 2000 and Mantsch et al 2016). However, none have investigated the effects of repeated stress exposure on the incubation of cue-induced cocaine seeking, although a few studies have used this strategy to study chronic stress-induced changes in heroin seeking (D’Cunha et al 2013; Sedki et al 2013, 2015). The goal of our study was to explore this interaction by assessing the effects of chronic stress exposure during withdrawal on incubated cocaine craving in order to identify time-dependent changes in relapse vulnerability to both cues and stress.…”

Neuroendocrine mechanisms that connect feeding behavior and stress

“…This review shows that ghrelin universally enhances sensitivity to psychostimulants and that ghrelin receptor antagonism may be an important therapeutic target to help quit smoking and curb addictive behaviors. Ghrelin may also be implicated in the narcotic drug seeking following stress, given that, as shown by Sedki et al (2013), blocking CRF receptors or adrenalectomy do not attenuate the effects of food restriction on heroin seeking behavior.…”