Role of alpha-2 adrenoceptors in stress-induced reinstatement of alcohol seeking and alcohol self-administration in rats
ABSTRACT 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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ABSTRACT: 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.05/2014; 4(3):356-67. DOI:10.1002/brb3.222
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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 unselectedWistar 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 theWistar 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 pharmacological blockade of CRF1-R on alcohol drinking.Frontiers in Psychiatry 04/2013; 4:23. DOI:10.3389/fpsyt.2013.00023
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ABSTRACT: Cues associated with alcohol can stimulate subjective states that increase relapse. Alcohol-cue associations may be strengthened by enhancing adrenergic activity with yohimbine or weakened by blocking adrenergic activity with propranolol. Alcohol-cue associations may also be weakened by long cue exposure sessions or strengthened by short cue exposure sessions. A useful treatment approach for alcoholism may combine adrenergic manipulation with cue exposure sessions of a specific duration. The present study sought to determine if cue exposure during long- or short-duration extinction sessions with post-session yohimbine or propranolol would alter alcohol cue-induced responding and self-administration. Rats were trained to respond for alcohol during sessions that included an olfactory cue given at the beginning of the session and a visual/auditory cue complex delivered concurrently with alcohol. Cue-induced responding was assessed before and after the repeated extinction sessions. Repeated alcohol extinction sessions of long duration (45 min) or short duration (5 min) were followed immediately by injections of saline, yohimbine, or propranolol. After the second set of cue-induced responding tests, reacquisition of operant alcohol self-administration was examined. To determine if the experimental procedures were sensitive to memory manipulation through other pharmacological mechanisms, the NMDA receptor antagonist MK-801 was given 20 min prior to long-duration extinction sessions. Both the long- and short-duration extinction sessions decreased cue-induced responding. Neither yohimbine nor propranolol, given post-session, had subsequent effects on cue-induced responding or alcohol self-administration. MK-801 blocked the effect of extinction sessions on cue-induced responding but had no effect on self-administration. The present study shows that manipulation of the NMDA system in combination with alcohol cue exposure therapy during extinction-like sessions may be more effective than manipulation of the adrenergic system in reducing the strength of alcohol-cue associations in this specific model of alcohol relapse.Pharmacology Biochemistry and Behavior 01/2013; DOI:10.1016/j.pbb.2013.11.020 · 2.82 Impact Factor