Le Masurier Marisa, Cowen Philip J, Sharp Trevor
University Department of Pharmacology, Mansfield Road, Oxford, OX1 3QT, UK.
Psychopharmacology (Berl). 2004 Feb;171(4):435-40. doi: 10.1007/s00213-003-1607-7. Epub 2003 Sep 30.
Acute depletion of brain tyrosine using a tyrosine-free amino acid mixture offers a nutritional approach to reduce central catecholamine function. Recent preclinical data suggest that tyrosine-free amino acid mixtures may have region-specific effects through targeting dopamine neurones.
Here we used fos immunocytochemistry to examine the neuroanatomical sites of action of a tyrosine-free amino acid mixture administered either alone or combined with amphetamine.
Rats (male, Sprague Dawley, 240-260 g) were administered (IP) either a tyrosine-free amino acid mixture (1 g/kg), or the same mixture supplemented with tyrosine and phenylalanine (1 g/kg). Mixtures were injected twice (1 h apart) followed 1 h later by amphetamine (2 mg/kg SC). Two hours later, cardiac perfusion was performed and brains were processed for fos immunocytochemistry. Fos positive cells were counted using computer imaging software.
The tyrosine-free amino acid mixture alone did not alter fos expression in ten regions of the rat forebrain compared to saline controls. However, the mixture reduced the increase in fos expression evoked by amphetamine. This effect was region-specific and was greatest in caudate putamen, nucleus accumbens, bed nucleus stria terminalis and lateral habenula, and lacking in other areas including cingulate and insular cortices, lateral septum and central amygdaloid nucleus. Moreover, in most regions the effect of the tyrosine-free mixture was less after tyrosine and phenylalanine supplementation.
In summary, a tyrosine-free amino acid mixture reduced amphetamine-induced fos expression but this effect was region-specific and included dopamine-rich regions. These data further support the idea that tyrosine depletion strategies have potential as treatments for mania and other hyperdopaminergic states.
使用不含酪氨酸的氨基酸混合物急性消耗脑内酪氨酸，提供了一种降低中枢儿茶酚胺功能的营养方法。最近的临床前数据表明，不含酪氨酸的氨基酸混合物可能通过靶向多巴胺神经元产生区域特异性作用。
在此，我们使用Fos免疫细胞化学方法来研究单独给药或与苯丙胺联合给药的不含酪氨酸的氨基酸混合物的神经解剖学作用部位。
给大鼠（雄性，Sprague Dawley，体重240 - 260克）腹腔注射不含酪氨酸的氨基酸混合物（1克/千克），或补充酪氨酸和苯丙氨酸的相同混合物（1克/千克）。混合物分两次注射（间隔1小时），1小时后皮下注射苯丙胺（2毫克/千克）。两小时后，进行心脏灌注，然后对大脑进行Fos免疫细胞化学处理。使用计算机成像软件对Fos阳性细胞进行计数。
与生理盐水对照组相比，单独使用不含酪氨酸的氨基酸混合物并未改变大鼠前脑十个区域的Fos表达。然而，该混合物减少了苯丙胺引起的Fos表达增加。这种作用具有区域特异性，在尾状壳核、伏隔核、终纹床核和外侧缰核中最为明显，而在其他区域如扣带回和岛叶皮质、外侧隔核和中央杏仁核中则不存在。此外，在大多数区域，补充酪氨酸和苯丙氨酸后，不含酪氨酸混合物的作用减弱。
总之，不含酪氨酸的氨基酸混合物减少了苯丙胺诱导的Fos表达，但这种作用具有区域特异性，且包括富含多巴胺的区域。这些数据进一步支持了酪氨酸消耗策略有可能作为治疗躁狂症和其他多巴胺能亢进状态的观点。
