Le AD, Harding S, Juzytsch W, Funk D, Shaham Y. Role of alpha-2 adrenoceptors in stress-induced reinstatement of alcohol seeking and alcohol self-administration in rats. Psychopharmacology (Berl) 179: 366-373

ArticleinPsychopharmacology 179(2):366-73 · June 2005with10 Reads
DOI: 10.1007/s00213-004-2036-y · Source: PubMed
Alpha-2 adrenoceptors are known to be involved in stress-induced reinstatement of heroin and cocaine seeking in laboratory animals. Here, we studied the involvement of these receptors in stress-induced reinstatement of alcohol seeking by using an agonist (lofexidine) and an antagonist (yohimbine) of these receptors, which inhibit and activate, respectively, noradrenaline transmission. We also tested the effect of lofexidine and yohimbine on alcohol self-administration. Lofexidine is used clinically for treating opiate withdrawal symptoms and yohimbine induces stress-like responses in humans and non-humans. Rats were trained to self-administer alcohol (12% w/v, 1 h/day) and after extinction of the alcohol-reinforced behavior, they were tested for the effect of lofexidine (0, 0.05 and 0.1 mg/kg, IP) on reinstatement of alcohol seeking induced by intermittent footshock stress (10 min, 0.8 mA) or for the effect of yohimbine (0, 1.25 and 2.5 mg/kg, IP) on reinstatement of alcohol seeking. Other rats were trained to self-administer alcohol, and after stable responding, the effects of lofexidine and yohimbine on alcohol self-administration were determined. Pretreatment with lofexidine (0.05 mg/kg and 0.1 mg/kg) attenuated stress-induced reinstatement of alcohol seeking and also decreased alcohol self-administration. In contrast, yohimbine pretreatment potently reinstated alcohol seeking after extinction and also induced a profound increase in alcohol self-administration. Results indicate that activation of alpha-2 adrencoceptors is involved in both stress-induced reinstatement of alcohol seeking and alcohol self-administration. To the degree that the present results are relevant to human alcoholism, alpha-2 adrencoceptor agonists should be considered in the treatment of alcohol dependence.
    • "Subsequent studies on stress-induced reinstatement explored two main research questions: the generality of intermittent footshock-induced reinstatement to other stressors and the neurobiological mechanisms of stress-induced reinstatement (Mantsch et al., 2015; Shaham et al., 2000a). Regarding the generality question, in the self-administration model, effective stressors include acute 1-day food deprivation (Highfield et al., 2002; Shalev et al., 2000), delayed (1 day) cold swim stress (Conrad et al., 2010), and the pharmacological stressors corticotropin-releasing factor (CRF) (Erb et al., 1998; Le et al., 2000; Shaham et al., 1997a), kappa-opioid receptor agonists (Valdez et al., 2007), and the prototype alpha-2 adrenoceptor antagonist, yohimbine (Le et al., 2005; Lee et al., 2004; Shepard et al., 2004). However, the validity of using yohimbine as a stressor in reinstatement was recently questioned (Chen et al., 2014). "
    [Show abstract] [Hide abstract] ABSTRACT: High rates of relapse to drug use during abstinence is a defining feature of drug addiction. In abstinent drug users, drug relapse is often precipitated by acute exposure to the self-administered drug, drug-associated cues, stress, as well as by short-term and protracted withdrawal symptoms. In this review, we discuss different animal models that have been used to study behavioral and neuropharmacological mechanisms of these relapse-related phenomena. In the first part, we discuss relapse models in which abstinence is achieved through extinction training, including the established reinstatement model, as well as the reacquisition and resurgence models. In the second part, we discuss recent animal models in which drug relapse is assessed after either forced abstinence (e.g., the incubation of drug craving model) or voluntary (self-imposed) abstinence achieved either by introducing adverse consequences to ongoing drug self-administration (e.g., punishment) or by an alternative nondrug reward using a discrete choice (drug vs. palatable food) procedure. We conclude by briefly discussing the potential implications of the recent developments of animal models of drug relapse after voluntary abstinence to the development of medications for relapse prevention.
    Chapter · Dec 2016
    • "In rats, administration of propranolol, a beta-adrenergic receptor antagonist, reduced operant responding for alcohol (Gilpin and Koob, 2010). Moreover, increasing NE transmission via inactivation of presynaptic alpha-2 adrenergic autoreceptors potentiates reinstatement of EtOH self-administration, while activating this receptor attenuates EtOH drinking (Le et al., 2005). Furthermore, prazosin, an alpha-1 adrenergic receptor (a1AR) antagonist, reduces EtOH drinking in alcohol-dependent (Walker et al., 2008) and alcohol-preferring rats (Verplaetse et al., 2012), and reduces stress-induced reinstatement of alcohol seeking in rats (Le et al., 2011 ). "
    [Show abstract] [Hide abstract] ABSTRACT: Background Early-life stress is associated with increased vulnerability to alcohol addiction. However, the neural substrates linking chronic childhood/adolescent stress and increased risk of alcohol addiction are not well understood. In the nucleus accumbens (NAc), dopamine (DA) and norepinephrine (NE) signaling can be profoundly influenced by stress, anxiety, and drugs of abuse, including ethanol (EtOH). Here, we employed a rodent model of early-life stress that results in enduring increases in behavioral risk factors of alcoholism to gain a better understanding of how chronic adolescent stress may impact the EtOH sensitivity of DA and NE release in the NAc.Methods Male Long–Evans rats were either group housed (GH; 4 rats/cage) or socially isolated (SI; 1 rat/cage) for 6 weeks beginning on postnatal day 28. SI and GH rats were tested in adulthood for anxiety-like behaviors (elevated plus maze), and the effects of EtOH (1 and 2 g/kg; intraperitoneally.) on NAc DA and NE were assessed by microdialysis.ResultsSI animals showed increased anxiety-like behavior compared to GH animals. Although SI had no effect on baseline levels of DA or NE, baseline DA levels were positively correlated with anxiety measures. In addition, while no significant differences were observed with 1 g/kg EtOH, the 2 g/kg dose induced significantly greater DA release in SI animals. Moreover, EtOH (2 g/kg) only elevated NAc NE levels in SI rats.Conclusions These results suggest that chronic early-life stress sensitizes accumbal DA and NE release in response to an acute EtOH challenge. A greater EtOH sensitivity of DA and NE release dynamics in the NAc may contribute to increases in behavioral risk factors of alcoholism, like greater EtOH self-administration, that are observed in SI rats.
    Full-text · Article · Nov 2014
    • "However, with the increasing use of yohimbine in reinstatement studies, evidence emerges for notable behavioral and neurobiological differences between the effects of intermittent footshock and yohimbine on reward seeking. Unlike footshock (Ahmed & Koob 1997; Mantsch & Goeders 1999), yohimbine potently reinstates food seeking and also increases alcohol and food selfadministration (Le et al. 2005; Marinelli et al. 2007; Cifani et al. 2012; Ayanwuyi et al. 2013; Noori, Helinski & Spanagel 2014). Unlike intermittent footshock, yohimbine does not induce stress-related 22 kHz ultrasonic distress vocalizations (Mahler et al. 2013). "
    [Show abstract] [Hide abstract] ABSTRACT: Yohimbine is an alpha-2 adrenoceptor antagonist that has been used in numerous studies as a pharmacological stressor in rodents, monkeys and humans. Recently, yohimbine has become the most common stress manipulation in studies on reinstatement of drug and food seeking. However, the wide range of conditions under which yohimbine promotes reward seeking is significantly greater than that of stressors like intermittent footshock. Here, we addressed two fundamental questions regarding yohimbine's effect on reinstatement of reward seeking: (1) whether the drug's effect on operant responding is dependent on previous reward history or cue contingency, and (2) whether yohimbine is aversive or rewarding under conditions typically used in reinstatement studies. We also used in vivo microdialysis to determine yohimbine's effect on dopamine levels in nucleus accumbens (NAc) and medial prefrontal cortex (mPFC). We found that the magnitude of yohimbine-induced (0.5, 1.0, 2.0 mg/kg) operant responding during the reinstatement tests was critically dependent on the contingency between lever pressing and discrete tone-light cue delivery but not the previous history with food reward during training. We also found that yohimbine (2 mg/kg) did not cause conditioned place aversion. Finally, we found that yohimbine modestly increased dopamine levels in mPFC but not NAc. Results suggest that yohimbine's effects on operant responding in reinstatement studies are likely independent of the history of contingent self-administration of food or drug rewards and may not be related to the commonly assumed stress-like effects of yohimbine.
    Full-text · Article · Jul 2014
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