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Behavioral sensitization has been proposed to play an important role in addiction. Elucidation of the neural processes mediating sensitization may therefore lead to the development of new pharmacotherapeutic treatments. A large number of studies have examined sensitization to psychostimulants and morphine. In contrast, despite the prevalence of alcoholism, the neural processes underlying sensitization to ethanol have not been identified. The aim of the present study was to examine the role of different components of the dopamine system in sensitization to the locomotor stimulant effects of ethanol in DBA/2J mice. Sensitization was induced by administering ethanol [2 g/kg intraperitoneally (ip)] before locomotor activity trials. Control groups received saline (12.5 ml/kg ip) before each activity trial. The ability of the dopamine uptake inhibitors GBR 12909 (3.33-10.0 mg/kg) and bupropion (20 and 30 mg/kg) to cross-sensitize to ethanol was then examined. In addition, the effects of SKF 82958 (0.1-1.0 mg/kg), a dopamine D(1) (D(1)) receptor agonist, quinpirole (0.05 and 0.1 mg/kg), a dopamine D(2)/D(3) (D(2)/D(3)) receptor agonist, and a combination of SKF 82958 and quinpirole were examined. Cross-sensitization was observed between the dopamine uptake inhibitor GBR 12909 and ethanol. In contrast, the less selective uptake inhibitor bupropion did not exhibit cross-sensitization. Similarly, stimulation of D(1) and D(2)/D(3) receptors did not cause cross-sensitization even when the agonists were administered together. Taken together, these data suggest that sensitization to ethanol is associated with changes in the dopaminergic system.

Rationale: Behavioral sensitization has been accorded a central role in contemporary theories of drug addiction. Accordingly, a substantial effort has been made to determine the processes mediating sensitization to psychostimulants. However, few studies have examined the mechanisms underlying sensitization to ethanol., Objectives: Experiments were conducted to assess the role of N-methyl-D-aspartate (NMDA) and non-NMDA glutamate receptors in expression of sensitization to ethanol's locomotor stimulant effects., Methods: Sensitization was induced in DBA/2 J mice by administering ethanol (2 g/kg) intraperitoneally (i.p.) before four activity trials. Control groups were given saline (12.5 ml/kg i.p.) before each activity trial. Subsequently, the effects of two NMDA receptor antagonists, MK-801 and ifenprodil, and two non-NMDA glutamate receptor antagonists, DNQX and GYKI 52466, were assessed on expression of the sensitized locomotor response., Results: MK-801 reduced the stimulant effects of ethanol and completely prevented expression of sensitization at doses exceeding 0.075 mg/kg. In contrast, although ifenprodil also reduced the stimulant effects of ethanol, the antagonist did not alter expression of sensitization. Non-NMDA glutamate antagonists were more consistent in their effects on sensitization. DNQX reduced the magnitude of the sensitized response at a low dose that did not alter the stimulant effects of ethanol. The more selective AMPA antagonist GYKI 52466 reduced the stimulant effects of ethanol and completely blocked expression of sensitization., Conclusions: The results provide initial evidence to suggest that both NMDA and non-NMDA glutamate receptors play a role in expression of sensitization to ethanol. Additional research will be required to elucidate the mechanisms underlying differences in the efficacy of glutamate antagonists.