D₃ dopamine receptors are down-regulated in amphetamine sensitized rats and their putative antagonists modulate the locomotor sensitization to amphetamine

D₃ dopamine receptor agonists inhibit locomotor activity in rodents and modulate the reinforcing effect of psychostimulants; however, their functional role during behavioral sensitization remains unclear. In the present study, we intend to investigate if D₃ dopamine receptors alter during the amphetamine sensitization and test if manipulation of D₃ receptors would affect the development of locomotor sensitization to amphetamine. We have found that D₃ dopamine receptors are down-regulated in the limbic forebrain in chronic amphetamine-treated (5 mg/kg×7 days) animals. The levels of both D₃ receptor protein (B_max value) and mRNA decreased significantly in the behaviorally sensitized rats compared to the saline-treated controls. When animals were co-administered a putative D₃ receptor antagonist (U99194A or GR103691; 20 μg×7 days; intracerebroventricle) and amphetamine (5 mg/kg×7 days, i.p.), the locomotor sensitization to amphetamine was significantly inhibited. However, when the putative D₃ receptor antagonist U99194A was administered during the amphetamine withdrawal period at day 10, it did not affect the development of locomotor sensitization. Furthermore, pretreatment with the preferential D₃ agonist 7-hydroxydipropylaminotetralin partially blocked the inhibitory effect of U99194A on locomotor sensitization. These data prove the participation of D₃ dopamine receptors in the development of amphetamine sensitization and, in addition, suggest a potential application for D₃ antagonists in the prevention of amphetamine addiction.