Nucleus accumbens dopamine D1 receptors regulate the expression of ethanol-induced behavioural sensitization

Repeated ethanol administration may induce behavioural sensitization, defined as a progressive potentiation of locomotor stimulant effects. This process is associated with neuroadaptations in the mesolimbic pathway and the nucleus accumbens. The aim of the present study was to analyse dopamine D-1 receptor (D1R) participation in locomotor response to an agonist and an antagonist of the D1R in mice with different levels of sensitization to ethanol. In three separate experiments, mice received administrations of 2.2 g/kg ethanol or saline every other day for 10 d. According to their locomotor response on the last day, ethanol-treated animals were classified into two groups : sensitized or non-sensitized. After the treatment, mice were challenged with 4 or 8 mg/kg SKF-38393 (i.p.), a D1R agonist (expt 1); or with 0.01 or 0.1 mg/kg SCH-23390 (i.p.), a D1R antagonist, followed by 2.2 g/kg ethanol (i.p.) administration (expt 2). In expt 3, mice were challenged with intra-accumbens (intra-NAc) SKF-38393 (1 mu g/side, in 0.2 mu l), and with intra-NAc SCH-23390 (3 mu g/side, in 0.2 mu l) followed by 2.2 g/kg ethanol (i.p.). Although the i.p. administration of SKF-38393 did not affect the locomotion of mice, the intra-NAc administration of SKF-38393 significantly increased the locomotor activity in sensitized mice, suggesting that sensitized mice present functionally hyperresponsive D(1)Rs in the NAc. Both i.p. and intra-NAc administration of SCH-23390 blocked the expression of ethanol sensitization, suggesting that the activation of NAc D(1)Rs seems to be essential for the expression of ethanol sensitization.