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 (Bmax 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.
All Science Journal Classification (ASJC) codes
- Molecular Biology
- Clinical Neurology
- Developmental Biology