Cumming Paul, Rosa-Neto Pedro, Watanabe Hideaki, Smith Donald, Bender Dirk, Clarke Paul B S, Gjedde Albert
PET Center, Arhus Kommunehospital, Nørrebrogade 44, Arhus, Denmark.
Neuroimage. 2003 Jul;19(3):1127-36. doi: 10.1016/s1053-8119(03)00079-x.
Positive reinforcing properties of nicotine and the psychostimulants have been attributed to elevated dopamine release in the basal ganglia. It is well known that the specific binding of [(11)C]raclopride to dopamine D(2,3) receptors in living striatum is reduced by cocaine and amphetamines, revealing increased competition between endogenous dopamine and [(11)C]raclopride for dopamine D(2,3) receptors. However, the sensitivity of [(11)C]raclopride binding to nicotine-induced dopamine release is less well documented. In order to provide the basis for mapping effects of nicotine, we first optimized reference tissue methods for quantifying [(11)C]raclopride binding sites in striatum of living pigs (n = 16). In the same animals, the rate of cerebral blood flow (CBF) was mapped using [(15)O]water. Neither a low dose of nicotine (50 mu kg(-1), iv) nor a high dose of nicotine (500 microg kg(-1), iv) altered CBF in the pig brain, an important condition for calculating the binding of radioligands when using a reference tissue to estimate the free ligand concentration. The methods of Logan and of Lammertsma were compared using the cerebellum or the occipital cortex as reference tissues for calculating the binding potential (pB) of [(11)C]raclolpride in brain. Irrespective of the method used, the mean undrugged baseline pB in striatum (ca. 2.0) was significantly asymmetric, with highest binding in the left caudate and right putamen. Test-retest estimates of pB were stable. Subtraction of Logan pB maps revealed that the low dose of nicotine reduced the pB of [(11)C]raclopride by 10% in a cluster of voxels in the left anteroventral striatum, but this effect did not persist after correction for multiple comparisons. The high dose of nicotine (n = 9) acutely reduced pB by 10% bilaterally in the ventral striatum; 3 h after the high nicotine dose, the reductions had shifted dorsally and caudally into the caudate and putamen. Evidently, nicotine challenge enhances the competition between endogenous dopamine for [(11)C]raclopride binding sites with a complex temporal and spacial pattern in pig brain, initially presenting in the left ventral striatum.
尼古丁和精神兴奋剂的正性强化特性被认为与基底神经节中多巴胺释放增加有关。众所周知，可卡因和苯丙胺会降低[(11)C]雷氯必利在活体纹状体中与多巴胺D(2,3)受体的特异性结合，这表明内源性多巴胺与[(11)C]雷氯必利对多巴胺D(2,3)受体的竞争增加。然而，[(11)C]雷氯必利结合对尼古丁诱导的多巴胺释放的敏感性的文献记载较少。为了为绘制尼古丁的作用提供依据，我们首先优化了参考组织方法，以定量活体猪（n = 16）纹状体中[(11)C]雷氯必利的结合位点。在同一动物中，使用[(15)O]水绘制脑血流量（CBF）图。低剂量尼古丁（50μg kg(-1)，静脉注射）和高剂量尼古丁（500μg kg(-1)，静脉注射）均未改变猪脑的CBF，这是在使用参考组织估计游离配体浓度时计算放射性配体结合的一个重要条件。使用小脑或枕叶皮质作为参考组织，比较了Logan法和Lammertsma法计算[(11)C]雷氯必利在脑中的结合潜能（pB）。无论使用何种方法，纹状体中未用药的平均基线pB（约2.0）均明显不对称，左尾状核和右壳核的结合最高。pB的重测估计值稳定。Logan pB图相减显示，低剂量尼古丁使左前腹侧纹状体一组体素中[(11)C]雷氯必利的pB降低了10%，但在进行多重比较校正后，这种效应并未持续。高剂量尼古丁（n = 9）使腹侧纹状体双侧的pB急性降低10%；高尼古丁剂量后3小时，降低区域已背侧和尾侧转移至尾状核和壳核。显然，尼古丁激发增强了内源性多巴胺与[(11)C]雷氯必利结合位点之间的竞争，在猪脑中呈现出复杂的时间和空间模式，最初出现在左腹侧纹状体。
