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.
Chiang
Yao-Chang
YC
Laboratory of Neuropharmacology, Department of Pharmacology, Chang-Gung University, 259 Wen-Hwa 1st Road, Tao-Yuan, Kwei-Shan 333, Taiwan.
Chen
Pei-Chun
PC
Chen
Jin-Chung
JC
D000661:Amphetamine / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal; D001667:Binding, Competitive; D001713:Biphenyl Compounds / Q000494:pharmacology; D000697:Central Nervous System Stimulants / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D018491:Dopamine Agonists / Q000493:pharmacokinetics; D018492:Dopamine Antagonists / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects; D004347:Drug Interactions; D007189:Indans / Q000494:pharmacology; D008297:Male; D009043:Motor Activity / Q000187:drug effects*; D010879:Piperazines / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D012337:RNA, Ribosomal, 18S / Q000187:drug effects; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D017448:Receptors, Dopamine D2 / Q000187:drug effects / Q000378:metabolism*; D050637:Receptors, Dopamine D3; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D013764:Tetrahydronaphthalenes / Q000493:pharmacokinetics; D013997:Time Factors; D014316:Tritium / Q000493:pharmacokinetics
D001713:Biphenyl Compounds; D000697:Central Nervous System Stimulants; D018491:Dopamine Agonists; D018492:Dopamine Antagonists; C493595:Drd3 protein, rat; D007189:Indans; D010879:Piperazines; D012333:RNA, Messenger; D012337:RNA, Ribosomal, 18S; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; D013764:Tetrahydronaphthalenes; C105771:GR 103691; D014316:Tritium; C086335:(5,6-dimethoxyindan-2-yl)dipropylamine; D000661:Amphetamine; C031349:7-hydroxy-2-N,N-dipropylaminotetralin