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

University of Toronto, Toronto, Ontario, Canada
Psychopharmacology (Impact Factor: 3.88). 06/2005; 179(2):366-73. 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.

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    • "Norepinephrine acts presynaptically at α-2 receptors in the LC; thus, duloxetine may reduce NE signaling by decreasing output from this region. In support of this hypothesis, in vivo recordings have revealed that chronic SNRI treatment leads to decreased LC firing in rats (West et al. 2009), and pharmacological activation of α-2 adrenoceptors has been shown to reduce both ethanol self-administration and stress-induced reinstatement of ethanol seeking in rats (Le et al. 2005). Likewise, NE exerts its excitatory effects at postsynaptic α-1 and β-1/2 adrenoreceptors in many brain regions, including those involved in stress and anxiety. "
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    ABSTRACT: Alcohol use disorders have been linked to increased anxiety, and enhanced central noradrenergic signaling may partly explain this relationship. Pharmacological interventions believed to reduce the excitatory effects of norepinephrine have proven effective in attenuating ethanol intake in alcoholics as well as in rodent models of ethanol dependence. However, most preclinical investigations into the effectiveness of these drugs in decreasing ethanol intake have been limited to acute observations, and none have concurrently assessed their anxiolytic effects. The purpose of these studies was to examine the long-term effectiveness of pharmacological interventions presumed to decrease norepinephrine signaling on concomitant ethanol self-administration and anxiety-like behavior in adult rats with relatively high levels of antecedent anxiety-like behavior. Adult male Long-Evans rats self-administered ethanol on an intermittent access schedule for eight to ten weeks prior to being implanted with osmotic minipumps containing either an a1-adrenoreceptor antagonist (prazosin, 1.5 mg/kg/day), a β1/2-adrenoreceptor antagonist (propranolol, 2.5 mg/kg/day), a serotonin/norepinephrine reuptake inhibitor (duloxetine, 1.5 mg/kg/day) or vehicle (10% dimethyl sulfoxide). These drugs were continuously delivered across four weeks, during which animals continued to have intermittent access to ethanol. Anxiety-like behavior was assessed on the elevated plus maze before treatment and again near the end of the drug delivery period. Our results indicate that chronic treatment with a low dose of prazosin or duloxetine significantly decreases ethanol self-administration (P < 0.05). Furthermore, this decrease in drinking is accompanied by significant reductions in the expression of anxiety-like behavior (P < 0.05). These findings suggest that chronic treatment with putative inhibitors of central noradrenergic signaling may attenuate ethanol intake via a reduction in anxiety-like behavior.
    Brain and Behavior 07/2014; 4(4). DOI:10.1002/brb3.230 · 2.24 Impact Factor
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    • "Nor-BNI, U50,488, and antalarmin were obtained from the NIDA Drug Supply Program (Baltimore, MD) and yohimbine was obtained from Sigma-Aldrich (St. Louis, MO). The doses of yohimbine and antalarmin and their pretreatment times were based on our published studies (Le et al. 2005, 2009; Marinelli et al. 2007a) and those for U50,488 and nor-BNI were based on previous reports (Redila and Chavkin 2008; Schank et al. 2012). "
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    ABSTRACT: Introduction Stress is related to heavy alcohol use and relapse in alcoholics. Using the reinstatement model, we have shown that corticotropin-releasing factor (CRF) underlies stress-induced relapse to alcohol seeking in laboratory rodents. Little is known about how other neurotransmitters interact with CRF in these effects. Dynorphin and its receptor (kappa opioid receptor, KOR) are involved in stress responses and in alcohol seeking. KOR and CRF receptors (CRF R) may interact in the production of stress-related behaviors but it is not known whether this interaction is involved in reinstatement of alcohol seeking. Methods Male Long Evans rats were trained to self-administer alcohol (12% w/v). After extinction of responding, we determined the effects of the KOR agonist, U50,488 (2.5, 5 mg/kg) on reinstatement of alcohol seeking, and their sensitivity to the selective KOR antagonist nor-binaltorphimine dihydrochloride (nor-BNI) (10 mg/kg) administered at different times before U50,488. We then examined the effects of nor-BNI on reinstatement induced by the stressor yohimbine (1.25 mg/kg) and on reinstatement induced by exposure to alcohol-associated cues. Finally, we determined whether CRF R1 blockade with antalarmin (10, 20 mg/kg) attenuates alcohol seeking induced by U50,488. Results U50,488 reinstated alcohol seeking. Prior treatment with nor-BNI 2, but not 24 h before administration of U50,488 or yohimbine blocked reinstatement induced by these drugs. Cue-induced reinstatement was blocked by nor-BNI administered 2 h prior to testing. Finally, U50,488-induced reinstatement was blocked by antalarmin. Conclusions These data further support a role for KOR in reinstatement of alcohol seeking under nonstress and stressful conditions and that KOR and CRF R interact in these effects.
    Brain and Behavior 05/2014; 4(3):356-67. DOI:10.1002/brb3.222 · 2.24 Impact Factor
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    • "During extinction the lever presses were no longer associated with alcohol delivery, but house light was still presented to allow for its concomitant extinction. Stress exposure consisted of the challenge with the pharmacological stressor yohimbine at doses previously shown to produce reinstatement to alcohol seeking in unselected Wistar rats (Le et al., 2005; Marinelli et al., 2007; Cippitelli et al., 2010a). Yohimbine (0.0, 0.625, 1.25, and 2.5 mg/kg) was administered 30 min prior to the 30 min reinstatement session that was conducted under identical condition of extinction sessions. "
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    ABSTRACT: Marchigian Sardinian alcohol-preferring (msP) rats exhibit innate preference for alcohol, are highly sensitive to stress and stress-induced alcohol seeking. Genetic analysis showed that over-expression of the corticotropin-releasing factor (CRF) system of msP rats is correlated with the presence of two single nucleotide polymorphisms (SNPs) occurring in the promoter region (position -1836 and -2097) of the CRF1 receptor (CRF1-R) gene. Here we examined whether these point mutations were associated to the innate alcohol preference, stress-induced drinking and seeking. We have recently re-derived the msP rats to obtain two distinct lines carrying the wild type (GG) and the point mutations (AA), respectively. The phenotypic characteristics of these two lines were compared with those of unselected Wistar rats. Both AA and GG rats showed similar patterns of voluntary alcohol intake and preference. Similarly, the pharmacological stressor yohimbine (0.0, 0.625, 1.25 and 2.5 mg/kg) elicited increased operant alcohol self-administration under fixed and progressive ratio reinforcement schedules in all three lines. Following extinction, yohimbine (0.0, 0.625, 1.25 and 2.5 mg/kg) significantly reinstated alcohol seeking in the three groups. However, at the highest dose this effect was no longer evident in AA rats. Treatment with the CRF1-R antagonist antalarmin (0, 5, 10 and 20 mg/kg) significantly reduced alcohol-reinforced lever pressing in the AA line (10 and 20 mg/kg) while a weaker or no effect was observed in the Wistar and the GG group, respectively. Finally, antalarmin significantly reduced yohimbine-induced increase in alcohol drinking in all three groups. In conclusion, these specific SNPs in the CRF1-R gene do not seem to play a primary role in the expression of the msP excessive-drinking phenotype or stress-induced drinking but may be associated with a decreased threshold for stress-induced alcohol seeking and an increased sensitivity to the effects of pharmacolo
    Frontiers in Psychiatry 04/2013; 4:23. DOI:10.3389/fpsyt.2013.00023
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