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Noradrenaline and alpha-2 receptors are implicated in the neuroadaptive changes in alcohol dependence leading to increased alcohol seeking. Preclinical methods often used to induce dependence, such as alcohol vapor, require long exposure periods. Another method, gavage with alcohol, induces dependence in a shorter time frame (4-6 d), but its effects on relapse are less well understood. We examined the role of alpha-2 receptors in alcohol self-administration (ASA) and relapse in male and female rats made alcohol dependent by gavage. The influence of these variables on the inhibitory effects of the alpha-2 agonist guanfacine on ASA, and on reinstatement induced by the alpha-2 antagonist yohimbine were determined. We also extended this analysis to relapse induced by the kappa opioid receptor agonist U50,488. Male and female Sprague Dawley rats, trained to self-administer alcohol were treated with intragastric vehicle or alcohol (12 g/kg/d for 5 d). In Exp. 1 we examined the effects of alcohol gavage on reinstatement induced by yohimbine (0.625-1.25 mg/kg) and U50,488 (1.25-2.5 mg/kg). In Exp. 2 we determined the effects of a longer period of alcohol gavage on guanfacine (0.25-0.75 mg/kg)-induced reductions in ASA and on yohimbine (0.625-2.5 mg/kg)-induced reinstatement. Our key findings are that alcohol dependence induced by gavage produces sex-specific effects on reinstatement. Non-dependent females had greater reinstatement than males, but dependence reduced reinstatement in females. In males, dependence modestly enhanced yohimbine-induced reinstatement, while U50-induced reinstatement was absent irrespective of dependence condition. Alcohol dependence did not modify the inhibitory effects of guanfacine on ASA in males or females. |
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