Carr K D, Yamamoto N, Omura M, Cabeza de Vaca S, Krahne L
Department of Pharmacology, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA.
Psychopharmacology (Berl). 2002 Aug;163(1):76-84. doi: 10.1007/s00213-002-1132-0. Epub 2002 Jun 27.
Previous studies indicate that the D(3) dopamine (DA) receptor is preferentially expressed in limbic forebrain DA terminal areas and may mediate functional effects opposite those of the D(1) and D(2) receptor types. However, the locations of the D(3) receptors that regulate behavior, and the range of behavioral functions regulated, are not clear.
The objective of this study was to evaluate behavioral and cellular effects of the preferential D(3) dopamine receptor antagonist, U99194A.
In experiment 1, the rewarding effect of U99194A (5.0, 10.0 and 20.0 mg/kg, SC) was measured in terms of its ability to lower the threshold for lateral hypothalamic self-stimulation (LHSS) in ad libitum fed rats. To amplify a possibly weak reward signal, testing was also conducted in food-restricted rats. The ability of U99194A to alter the threshold-lowering effect of d-amphetamine was also assessed. In experiment 2, effects of U99194A on horizontal and vertical motor activity were compared in ad libitum fed and food-restricted rats. In experiment 3, effects of a behaviorally active dose of U99194A (5.0 mg/kg) on brain c-fos expression were measured and compared to those produced by d-amphetamine (0.5 mg/kg, IP). In experiment 4, the motor and cellular activating effects of U99194A were challenged with the D(1) dopamine receptor antagonist, SCH-23390 (0.1 mg/kg).
U99194A displayed no rewarding efficacy in the LHSS paradigm. U99194A did, however, augment the rewarding effect of d-amphetamine. U99194A also produced a motor activating effect, reversible by SCH-23390, which was greater in food-restricted than ad libitum fed rats. The pattern and intensity of fos-like immunoreactivity (FLI) induced by U99194A was similar to that produced by d-amphetamine and was blocked, in caudate-putamen and nucleus accumbens, by SCH-23390.
These results indicate that U99194A has psychostimulant-like effects on motor activity and striatal c-fos expression that are dependent upon the D(1) DA receptor. However, doses of U99194A that are adequate to stimulate motor activity and c-fos expression in striatal and limbic structures do not possess direct rewarding effects in the LHSS paradigm. Overall, these results seem consistent with the hypothesis that D(3) antagonism enhances D(1)/D(2) mediated signaling with behavioral effects dependent on both the density of D(3) receptors and the prevailing level of DA transmission in particular brain regions.
先前的研究表明，D3多巴胺（DA）受体在前脑边缘DA终末区域优先表达，可能介导与D1和D2受体类型相反的功能效应。然而，调节行为的D3受体的位置以及所调节的行为功能范围尚不清楚。
本研究的目的是评估选择性D3多巴胺受体拮抗剂U99194A的行为和细胞效应。
在实验1中，通过测量U99194A（5.0、10.0和20.0mg/kg，皮下注射）降低自由摄食大鼠下丘脑外侧自我刺激（LHSS）阈值的能力，来检测其奖赏效应。为了放大可能微弱的奖赏信号，也对食物限制大鼠进行了测试。还评估了U99194A改变d-苯丙胺降低阈值效应的能力。在实验2中，比较了U99194A对自由摄食和食物限制大鼠水平和垂直运动活动的影响。在实验3中，测量了行为活性剂量的U99194A（5.0mg/kg）对脑c-fos表达的影响，并与d-苯丙胺（0.5mg/kg，腹腔注射）产生的影响进行比较。在实验4中，用D1多巴胺受体拮抗剂SCH-23390（0.1mg/kg）挑战U99194A的运动和细胞激活作用。
U99194A在LHSS范式中未显示出奖赏效力。然而，U99194A确实增强了d-苯丙胺的奖赏效应。U99194A还产生了运动激活作用，可被SCH-23390逆转，在食物限制大鼠中比自由摄食大鼠中更大。U99194A诱导的fos样免疫反应性（FLI）的模式和强度与d-苯丙胺产生的相似，并在尾状核-壳核和伏隔核中被SCH-23390阻断。
这些结果表明，U99194A对运动活动和纹状体c-fos表达具有类似精神兴奋剂的作用，这取决于D1 DA受体。然而，足以刺激纹状体和边缘结构中运动活动和c-fos表达的U99194A剂量在LHSS范式中不具有直接奖赏作用。总体而言，这些结果似乎与以下假设一致：D3拮抗作用增强D1/D2介导的信号传导，其行为效应取决于D3受体的密度和特定脑区中DA传递的现有水平。
