D(3) dopamine receptors are down-regulated in amphetamine sensitized rats and their putative antagonists modulate the locomotor sensitization to amphetamine

D(3) 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 D(3) dopamine receptors alter during the amphetamine sensitization and test if manipulation of D(3) receptors would affect the development of locomotor sensitization to amphetamine. We have found that D(3) dopamine receptors are down-regulated in the limbic forebrain in chronic amphetamine-treated (5 mg/kg x 7 days) animals. The levels of both D(3) 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 D(3) receptor antagonist (U99194A or GR103691; 20 microg x 7 days; intracerebroventricle) and amphetamine (5 mg/kg x 7 days, i.p.), the locomotor sensitization to amphetamine was significantly inhibited. However, when the putative D(3) 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 D(3) agonist 7-hydroxydipropylaminotetralin partially blocked the inhibitory effect of U99194A on locomotor sensitization. These data prove the participation of D(3) dopamine receptors in the development of amphetamine sensitization and, in addition, suggest a potential application for D(3) antagonists in the prevention of amphetamine addiction.