Sensitization to ethanol's stimulant effect is associated with region-specific increases in brain D2 receptor binding

Rationale: Stimulation of locomotor activity by low doses of ethanol (EtOH) and the potentiation of this response after repeated administration (sensi tization) have been related to EtOH's rewarding and addictive properties an d to altered dopaminergic activity in brain. In mice, behavioral sensitizat ion to EtOH occurs only in a subset of treated animals, and this provides a n opportunity for distinguishing general drug effects from sensitization-sp ecific brain effects. Objectives: In view of evidence suggesting a role for dopamine D2 receptors in EtOH preference and abuse liability, the present study addressed the hypothesis that D2 binding would be altered in specific brain regions in mice showing differential sensitization responses to chro nic EtOH administration. Methods: Male albino Swiss mice received 2.4 g/kg EtOH i.p. daily for 21 days and were then separated into sensitized or non- sensitized subgroups on the basis of weekly locomotor activity tests. Resul ts: Autoradiographic analyses of [H-3]raclopride binding to D2 sites reveal ed significant increases in the anterior caudate-putamen of mice in the EtO H-sensitized group when compared with either saline controls (+40%, P<0.000 09) or to mice in the EtOH non-sensitized group (+32%; P<0.0003). Smaller i ncreases were seen in the ventrolateral caudate-putamen of sensitized anima ls (+18% vs control, P<0.02; and 12% vs non-sensitized mice, P<0.07). No di fferences were found in other brain regions, including the nucleus accumben s, olfactory bulb and substantia nigra. Conclusions: The observed increases in D2-receptor binding in circumscribed targets of nigrostriatal projectio ns may reflect either a pre-existing condition in sensitization-prone anima ls or a selective vulnerability of D2 receptors to chronic EtOH in these an imals. In either case, it may be a marker for differential susceptibility t o EtOH sensitization.