The dopamine D3 receptor antagonist nafadotride inhibits development of locomotor sensitization to amphetamine.
Behavioral sensitization is a well-studied model of behavioral plasticity mediated at least in part by dopaminergic systems believed to play an important role in several psychiatric conditions. In the rodent, locomotion is regulated by the opposing balance of D3 and D2 receptors, with D2 activation increasing and D3 stimulation inhibiting locomotion. However, receptor occupancy of D3 dopamine receptors is far greater than D2 or D1 occupancy at typical post-stimulant dopamine concentrations. We therefore hypothesized that tolerance of D3 receptor inhibition of locomotion contributes to the development of sensitization. To test this hypothesis, we examined the effect of the D3 receptor antagonist nafadotride on sensitization. As predicted, nafadotride inhibits augmentation of the locomotion response to repetitive amphetamine. This finding is consistent with the proposed model of adaptive down-regulation of D3 dopamine receptor function contributing to the development of behavioral sensitization.
Richtand
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NM
Cincinnati Veterans Affairs Medical Center, Department of Psychiatry, V-116A, 3200 Vine Street, Cincinnati, OH 45220, USA. neil.richtand@uc.edu
Logue
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Welge
J A
JA
Perdiue
J
J
Tubbs
L J
LJ
Spitzer
R H
RH
Sethuraman
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Geracioti
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TD
D000661:Amphetamine / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D018491:Dopamine Agonists / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000494:pharmacology*; D065127:Dopamine D2 Receptor Antagonists; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D008124:Locomotion / Q000187:drug effects*; D008297:Male; D009281:Naphthalenes / Q000494:pharmacology*; D011759:Pyrrolidines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D050637:Receptors, Dopamine D3; D013764:Tetrahydronaphthalenes / Q000494:pharmacology
D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D065127:Dopamine D2 Receptor Antagonists; D018765:Dopamine Uptake Inhibitors; C493595:Drd3 protein, rat; D009281:Naphthalenes; D011759:Pyrrolidines; D050637:Receptors, Dopamine D3; D013764:Tetrahydronaphthalenes; D000661:Amphetamine; C097285:nafadotride; C031349:7-hydroxy-2-N,N-dipropylaminotetralin