Department of Psychiatry, School of Medicine, University of California San Diego, United States.
Brain Res. 2012 Feb 9;1437:69-76. doi: 10.1016/j.brainres.2011.12.007. Epub 2011 Dec 13.
In rats, prepulse inhibition (PPI) of acoustic startle is disrupted by systemic administration of dopaminergic agonists, such as the dopamine D3 receptor (D3R)-preferential agonist pramipexole (PPX). PPX has D3R-active (S) and -inactive (R) stereoisomers. Here, we tested the neuroanatomical and stereochemical selectivity of PPX effects on PPI.
(S)-PRA or (R)-PRA (0, 0.47, 1.42, 4.73 μmol/kg) was injected sc 15 min prior to PPI testing in adult male Sprague Dawley rats. In separate rats, (S)-PPX (0, 3, 10 μg/0.5μl/side, ic) was infused into the nucleus accumbens (NAc), caudodorsal striatum (CS), or olfactory tubercle/Islands of Calleja (ICj) 15 min prior to PPI testing. D3R expression in these brain regions was assessed using quantitative rt-PCR. The PPI-disruptive effects of systemic (S)-PPX were also tested after pretreatment with the D3R-selective antagonist, U99194 (10mg/kg).
Systemic administration of PPX stereoisomers demonstrated a dose-dependent effect of (S)-PPX on PPI, while (R)-PPX had no effect on PPI. PPX decreased PPI when infused into the NAc and ICj, but not the CS. Quantitative rt-PCR revealed D3R expression in ICj>NAc>CS. The PPI-disruptive effects of PPX were prevented by U99194.
The PPI-reducing effects of PPX are stereospecific for the D3R-active (S)-isomer, neuroanatomically preferential for the D3R-rich ventral vs. D3R poor caudodorsal striatum, and prevented by pharmacologic D3R blockade. These findings are consistent with the conclusion that PPX disrupts PPI via stimulation of mesolimbic D3Rs.
在大鼠中，全身给予多巴胺能激动剂，如多巴胺 D3 受体（D3R）-优先激动剂普拉克索（PPX），会破坏声起始惊跳的前脉冲抑制（PPI）。PPX 具有 D3R 活性（S）和非活性（R）对映异构体。在这里，我们测试了 PPX 对 PPI 的影响的神经解剖和立体化学选择性。
（S）-普拉克索或（R）-普拉克索（0、0.47、1.42、4.73 μmol/kg）在成年雄性 Sprague Dawley 大鼠进行 PPI 测试前 15 分钟通过皮下注射给药。在单独的大鼠中，（S）-PPX（0、3、10μg/0.5μl/侧，ic）在 PPI 测试前 15 分钟被注入伏隔核（NAc）、尾壳核背侧部（CS）或嗅结节/卡列加岛（ICj）。使用定量 rt-PCR 评估这些脑区中的 D3R 表达。还在预先用 D3R 选择性拮抗剂 U99194（10mg/kg）预处理后测试了系统给予（S）-PPX 的 PPI 破坏作用。
PPX 立体异构体的全身给药显示出（S）-PPX 对 PPI 的剂量依赖性影响，而（R）-PPX 对 PPI 没有影响。当 PPX 注入 NAc 和 ICj 时，会降低 PPI，但在 CS 中则不会。定量 rt-PCR 显示 ICj>D3R 表达>NAc>CS。PPX 的 PPI 破坏作用被 U99194 阻止。
PPX 的 PPI 降低作用是 D3R 活性（S）-异构体的立体特异性的，神经解剖学上优先作用于富含 D3R 的腹侧部，而不是 D3R 贫乏的尾壳核背侧部，并且被药理学 D3R 阻断所阻止。这些发现与结论一致，即 PPX 通过刺激中脑边缘 D3R 来破坏 PPI。
