Dopamine D2 receptor-deficient mice exhibit decreased dopamine transporter function but no changes in dopamine release in dorsal striatum

被引:188
作者
Dickinson, SD
Sabeti, J
Larson, GA
Giardina, K
Rubinstein, M
Kelly, MA
Grandy, DK
Low, MJ
Gerhardt, GA
Zahniser, NR
机构
[1] Univ Colorado, Hlth Sci Ctr, Dept Pharmacol, Denver, CO 80262 USA
[2] Univ Colorado, Hlth Sci Ctr, Dept Psychiat, Denver, CO 80262 USA
[3] Univ Colorado, Hlth Sci Ctr, Program Neurosci, Denver, CO 80262 USA
[4] Oregon Hlth & Sci Univ, Dept Physiol & Pharmacol, Portland, OR 97201 USA
[5] Oregon Hlth & Sci Univ, Vollum Inst Adv Biomed Res, Portland, OR 97201 USA
[6] Univ Buenos Aires, CONICET, Inst Invest Ingn Genet & Biol Mol, Buenos Aires, DF, Argentina
关键词
D-2 dopamine autoreceptor; gene knockout mice; Dopamine uptake; in vivo microdialysis; in vivo electrochemistry; striatum;
D O I
10.1046/j.1471-4159.1999.0720148.x
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Presynaptic D-2 dopamine (DA) autoreceptors, which are well known to modulate DA release, have recently been shown to regulate DA transporter (DAT) activity, To examine the effects of D-2 DA receptor deficiency on DA release and DAT activity in dorsal striatum, we used mice genetically engineered to have two (D-2(+/+)), one (D-2(+/-)), or no (D-2(-/-)) functional copies of the gene coding for the D-2 DA receptor. In vivo microdialysis studies demonstrated that basal and Kf-evoked extracellular DA concentrations were similar in all three genotypes, However, using in vivo electrochemistry, the D-2(-/-) mice were found to have decreased DAT function, i.e., clearance of locally applied DA was decreased by 50% relative to that in D-2(+/+) mice. In D-2(+/+) mice, but not D-2(-/-) mice, local application of the D-2-like receptor antagonist raclopride increased DA signal amplitude, indicating decreased DA clearance. Binding assays with the cocaine analogue [H-3]WIN 35,428 showed no genotypic differences in either density or affinity of DAT binding sites in striatum or substantia nigra, indicating that the differences seen in DAT activity were not a result of decreased DAT expression. These results further strengthen the idea that the D-2 DA receptor subtype modulates activity of the striatal DAT.
引用
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页码:148 / 156
页数:9
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