Footshock stress reinstates cocaine seeking in rats after extended post-stress delays

Centre for the Neurobiology of Stress, Department of Life Science, University of Toronto at Scarborough, Toronto, ON, Canada.
Psychopharmacology (Impact Factor: 3.88). 12/2007; 195(1):61-70. DOI: 10.1007/s00213-007-0846-4
Source: PubMed


Exposure to footshock stress reinstates drug seeking in rats when tests for reinstatement are conducted immediately after termination of the stressor. It is not known, however, whether footshock is effective in inducing reinstatement if a post-stress delay is imposed before testing for reinstatement.
The objectives of the study were to determine for how long footshock remains effective in inducing the reinstatement of cocaine seeking if testing is delayed after termination of the stressor and to determine whether the context in which a post-stress delay is carried out influences the magnitude of reinstatement.
Rats self-administered cocaine (1.0 mg/kg per infusion) for 8-10 days. After extinction, tests for reinstatement by intermittent footshock (20 min; 0.8 mA) were conducted after post-stress delays of up to 60 min. Although footshock was always administered in the self-administration (SA) chamber, delays were given either in the SA chamber or home cage (HC).
Footshock induced reinstatement after post-stress delays of up to 40 min. No differences in responding during tests for reinstatement were observed between animals in the SA chamber and under HC conditions.
Within a limited time window, footshock is effective in reinstating cocaine seeking, when testing is delayed after termination of the stressor. Together with previous work from this laboratory, the findings are consistent with the idea that stress can induce the reinstatement of drug seeking by conditioning excitation to the context in which it is administered and that this conditioned excitation can overcome the inhibitory processes maintaining extinction responding, even after a post-stress delay.

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    • "Anxiety and negative affect also facilitate the initiation and maintenance of tobacco smoking (Anda et al., 1999; Morissette et al., 2007), and acute footshock stress reinstates nicotine (NIC) seeking after extinction of the drugreinforced behavior (Buczek et al., 1999). Further, stress is also able to facilitate the initial acquisition, maintenance and relapse of many other abused drugs such as ethanol, cocaine and opioids (Piazza and Le Moal (1998); Le et al., 1998; Sinha, 2001; Brown and Erb, 2007; Cleck and Blendy, 2008). "
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    ABSTRACT: Background: Stress affects the responsiveness to nicotine (NIC), by increasing drug use, facilitating relapse and reinstating NIC self administration even after prolonged abstinence. In turn, high corticosterone (CORT) blood levels induced by stress may alter the neurobiological properties of NIC by acting on the dopamine (DA) mesolimbic system. Methods: In this study, we evaluated the effect of exposure to acute restraint stress on NIC-induced stimulation of the mesolimbic DA system of the rat, by studying extracellular DA levels in the nucleus accumbens shell (NAccs) with microdialysis. Results: NIC intravenous administration (130 μg/kg) increased DA levels in the NAccs in control rats but not in subjects exposed to stress; this latter phenomenon was prevented by blockade of CORT effects with the inhibitor of corticosterone synthesis metirapone (100 mg/kg) or the glucorticoid receptor antagonist mifepristone (150 μmol/kg). Conclusions: These observations show that exposure to acute stress inhibits the stimulatory response of the mesolimbic DA system to NIC and suggest that this effect is mediated by circulating CORT acting on its receptors. These results may bear relevance in explaining the role played by stressful stimuli in NIC-seeking and taking behavior.
    Drug and alcohol dependence 07/2012; 127(1-3). DOI:10.1016/j.drugalcdep.2012.06.006 · 3.42 Impact Factor
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    • "While a number of studies have utilized intermittent footshock (Brown and Erb 2007; Buffalari and See 2009) and yohimbine (Bongiovanni and See 2008; Feltenstein and See 2006; Kupferschmidt et al. 2009) as a means to study stress-induced reinstatement of drugseeking in rodents, only one recent study has examined stress-induced reinstatement in females (Anker and Carroll 2010). Relative to males, female rats (cycle phase not determined) showed greater yohimbine-induced reinstatement, an effect consistent with clinical data suggesting that women are more susceptible than men to relapse to cocaine abuse following exposure to a stressor (Hyman et al. 2008; McKay et al. 1996). "
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    ABSTRACT: Previous studies have shown that female rats exhibit enhanced cocaine-seeking across several phases of the addiction cycle when compared to males. Drug-seeking in females is also estrous cycle dependent and inversely associated with plasma progesterone. Although sex and estrous cycle-dependent differences have been reported in the reinstatement of cocaine-seeking triggered by cocaine injections or drug-paired cues, it is not yet known what role the estrous cycle may have on stress-induced reinstatement, either alone or in combination with drug-paired cues. Here, we examined male and female rats for reinstatement of extinguished cocaine-seeking produced by cocaine-paired cues or the stress-activating drug, yohimbine. Male and female Sprague-Dawley rats self-administered intravenous cocaine (0.5 mg/kg/infusion) paired with a light + tone stimulus for 10-14 days. Lever responding was then allowed to extinguish, with subsequent reinstatement testing occurring 30 min following an injection of yohimbine (1.25 or 2.5 mg/kg, intraperitoneal) or vehicle either in the presence or absence of the conditioned stimulus. While males and females showed similar cue- and yohimbine-induced reinstatement (3-4 times over "No Cue"-vehicle responding), combining these stimuli resulted in a robust enhancement in cocaine-seeking in both groups, with a greater increase in females (10-12 vs. 14-15 times over "No Cue"-vehicle responding for the males and females, respectively). When examined as a function of the estrous cycle, females in proestrus demonstrated higher levels of responding during yohimbine + cues reinstatement. This cycle-dependent enhanced sensitivity to stress enhancement of cocaine-paired cues may generalize to greater relapse susceptibility under stressful conditions.
    Psychopharmacology 02/2011; 216(1):53-62. DOI:10.1007/s00213-011-2187-6 · 3.88 Impact Factor
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    • "While many of the reinstatement studies have been conducted with ip priming injections of cocaine, other events such as drug-associated exteroceptive cues or stress-evoking stimuli have been used in animal models of relapse. Stress has emerged as a major factor that predicts cocaine craving (Sinha et al., 2003) and relapse to cocaine abuse (Sinha, 2008; Stewart, 2000) in humans as well as the reinstatement of cocaine seeking in rats (Brown and Erb, 2007; Boutrel et al., 2005; Feltenstein and See, 2006; Shalev et al., 2003). "
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    ABSTRACT: This review summarizes findings from human and animal research investigating the influence of progesterone and its metabolites allopreganolone and pregnanolone (progestins) on the effects of cocaine and other drugs of abuse. Since a majority of these studies have used cocaine, this will be the primary focus; however, the influence of progestins on other drugs of abuse will also be discussed. Collectively, findings from these studies support a role for progestins in (1) attenuating the subjective and physiological effects of cocaine in humans, (2) blocking the reinforcing and other behavioral effects of cocaine in animal models of drug abuse, and (3) influencing behavioral responses to other drugs of abuse such as alcohol and nicotine in animals. Administration of several drugs of abuse in both human and nonhuman animals significantly increased progestin levels, and this is explained in terms of progestins acting as homeostatic regulators that decrease and normalize heightened stress and reward responses which lead to increased drug craving and relapse. The findings discussed here highlight the complexity of progestin-drug interactions, and they suggest a possible use for these agents in understanding the etiology of and developing treatments for drug abuse.
    Neuroscience & Biobehavioral Reviews 11/2010; 35(2):315-33. DOI:10.1016/j.neubiorev.2010.04.003 · 8.80 Impact Factor
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