Differential susceptibility to ethanol and amphetamine sensitization in dopamine D3 receptor-deficient mice

Dopamine D3 receptors (D3Rs) have been implicated in behavioral sensitization to various drugs of abuse, but their role in ethanol (EtOH) sensitization has not been directly examined. We used D3R knockout (D3 KO) mice to examine whether the D3R plays a permissive role in EtOH and amphetamine (AMPH) sensitization. We also investigated whether EtOH sensitization is accompanied by alterations in D3R mRNA expression or binding. After comparing EtOH sensitization in C57Bl/6 mice and DBA/2 mice, D3 KO, wild type (WT), and for comparison, D1 and D2 KOs received five biweekly injections of EtOH (2.2 g/kg, i.p.) or saline. Another group of D3 KOs and WT controls received six times AMPH (1.5 mg/kg, i.p.). D3R mRNA and binding were measured in EtOH-sensitized DBA/2 mice with in situ hybridization and [I-125]-7-OH-PIPAT autoradiography, respectively. C57Bl/6 mice expressed EtOH sensitization albeit to a lesser extent than DBA/2 mice. Compared to WT mice, D3 KOs were resistant to EtOH sensitization. The behavioral profile of D3 KOs was more similar to D1 KOs than D2 KOs, which also failed to develop EtOH sensitization. However, D3 KOs developed AMPH sensitization normally. EtOH sensitization was not accompanied by changes in either D3R mRNA or D3R binding in the islands of Calleja, nucleus accumbens, dorsal striatum, or cerebellum. These results suggest a necessary role for the D3R in EtOH but not AMPH sensitization, possibly through postreceptor intracellular mechanisms. Results also suggest that different neurochemical mechanisms underlie sensitization to different drugs of abuse.