Role of alpha-2 adrenoceptors in stress-induced reinstatement of alcohol seeking and alcohol self-administration in rats.
OBJECTIVE
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Lê
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AD
Department of Neuroscience, Center for Addiction and Mental Health, 33 Russell Street, Toronto, ON, Canada, M5S 2S1. anh_le@camh.net
Harding
S
S
Juzytsch
W
W
Funk
D
D
Shaham
Y
Y
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000437:Alcoholism / Q000523:psychology*; D000818:Animals; D003000:Clonidine / Q000031:analogs & derivatives / Q000494:pharmacology; D003216:Conditioning, Operant / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004597:Electroshock; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D018341:Receptors, Adrenergic, alpha-2 / Q000187:drug effects / Q000502:physiology*; D012054:Reinforcement, Psychology; D012646:Self Administration; D013315:Stress, Psychological / Q000523:psychology*; D015016:Yohimbine / Q000494:pharmacology
D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D018341:Receptors, Adrenergic, alpha-2; D015016:Yohimbine; D003000:Clonidine; C025655:lofexidine