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The present study was designed to ascertain the effects of repeated exposure to stress and the acute administration of corticosterone (1, 3, 10 mg/kg, intraperitoneally (i.p.)) on the ethanol withdrawal-induced impairment of novel object recognition in mice. Mice were chronically treated with 3% ethanol for 7 d, with or without exposure to restraint stress for 1 h/d. A significant decrease in cognitive function was observed in the ethanol plus no stress group at 48 h after the discontinuation of ethanol treatment. This impaired recognition was recovered in the ethanol plus stress group. Moreover, we investigated the effects of acute pretreatment with corticosterone, which is a corticosteroid-type hormone produced in the cortex of the adrenal glands, on the impaired recognition after the discontinuation of ethanol treatment in mice. The impaired recognition in the 3% ethanol alone-treated group at 48 h after the discontinuation of ethanol treatment was recovered by treatment with the middle dose (3 mg/kg) of corticosterone, but not with the low or high doses (1, 10 mg/kg). These results suggest that chronic stress during the development of ethanol dependence may reduce the impaired recognition after the discontinuation of ethanol treatment. Moreover, acute pretreatment with the middle dose of corticosterone also recovered the impaired recognition after the discontinuation of ethanol treatment in mice. Adequate regulation of the hypothalamic-pituitary-adrenal (HPA) axis by corticosterone may improve the impaired recognition after the discontinuation of ethanol treatment.

Rationale: Both the acute and chronic consumption of ethanol have been reported to modify several molecular events in the central nervous system, and the endogenous μ-opioid receptor system is involved in the reinforcing/rewarding effects of ethanol., Objectives: The present study was designed to clarify the effects of chronic ethanol treatment on cellular processes involving μ-opioid receptor and the development of morphine-induced rewarding effects., Methods: Male C57BL/6J mice were continuously treated with a liquid diet containing 3.0 w/v ethanol. The direct involvement of μ-opioid receptor functions in the activation of G-proteins and changes in protein levels in the lower midbrain of mice after chronic treatment with ethanol were investigated by a [(35)S] GTPγS binding assay and Western blotting, respectively. The rewarding effects of morphine (5 mg/kg) under treatment with ethanol were measured by the conditioned place preference paradigm., Results: The function of μ-opioid receptor was increased by treatment with ethanol in the lower midbrain using [(35)S] GTPγS binding assay. Furthermore, the GRK2 protein level was significantly increased by treatment with ethanol. Chronic treatment with ethanol enhanced the rewarding effects of morphine. On the other hand, this enhancement of the rewarding effects of morphine by ethanol treatment was significantly inhibited by the GRK2 inhibitor β-adrenergic receptor kinase 1 inhibitor., Conclusions: The present study demonstrated that chronic treatment with ethanol enhanced the rewarding effects of morphine by up-regulating functional changes in μ-opioid receptor, mediated by GRK2.

Abstract: The present study was designed to ascertain the influence of repeated exposure to stress on the development of ethanol dependence in mice. Mice were chronically treated with 3% ethanol for 7 days, with or without exposure to restraint stress for 1h/day. A significant loss of body weight was observed in the ethanol plus stress group compared with the other groups. In the ethanol plus stress group, mice exhibited persistent piloerection, which is considered to be a withdrawal sign that reflects emotion, after the discontinuation of ethanol treatment. The ethanol plus stress group also showed a marked increase in the intake of liquid diet, which is considered to be trying to avoid an unpleasant ethanol-withdrawal symptom, during ethanol withdrawal. In the hole-board test, a significant decrease in head-dipping behavior was observed in both the ethanol alone and ethanol plus stress groups at 6h after the discontinuation of ethanol treatment. This abnormal emotion was recovered in the ethanol alone group, but not in the ethanol plus stress group, at 48h after the discontinuation of ethanol treatment. These results suggest that repeated exposure to stress may affect the development of ethanol dependence and prolong the expression of withdrawal-induced emotional abnormality. [Copyright &y& Elsevier]