School of Medicine and Galway Neuroscience Centre, National University of Ireland, Galway, Ireland; Centro Universitário Unievangélica, Anápolis - GO CEP, 75083-515, Brazil.
School of Medicine and Galway Neuroscience Centre, National University of Ireland, Galway, Ireland.
Prog Neuropsychopharmacol Biol Psychiatry. 2019 Mar 8;89:303-309. doi: 10.1016/j.pnpbp.2018.10.003. Epub 2018 Oct 5.
Methamphetamine, an amphetamine derivative, is a powerful psychomotor stimulant and commonly used drug of abuse. This study examined the effect of binge-like methamphetamine (MA) dosing (4 × 4 mg/kg, s.c., 2 h apart) on regional dopamine and dopaminergic metabolite levels in rat brain at a range of early time points after final dose (2-48 h). Body temperature was elevated when measured 2 h after the last dose. MA increased dopamine levels in the frontal cortex 2 and 24 h after the last dose. The dopamine level was also increased in the amygdala at 24 h. No change was observed in the striatum at any time point, but levels of the dopamine metabolite DOPAC were markedly reduced at 24 and 48 h. Tyrosine hydroxylase expression is induced downstream of dopamine activity, and it is the rate limiting enzyme in dopamine synthesis. The effect of MA binge-like dosing on the volume of tyrosine hydroxylase containing cell bodies and the area fraction of tyrosine hydroxylase containing fibres was also assessed. MA increased the area fraction of tyrosine hydroxylase fibres in the frontal cortex and reduced the volume of tyrosine hydroxylase containing cell bodies 2 h after last dose in the ventral tegmental area and the substantia nigra. An increase in cell body volume in the substantia nigra was observed 48 h after treatment. These findings collectively highlight the importance of the dopaminergic system in methamphetamine induced effects, identify the frontal cortex, amygdala and striatum as key regions that undergo early changes in response to binge-like methamphetamine dosing and provide evidence of time-dependent effects on the cell bodies and fibres of tyrosine hydroxylase expressing neurons.
甲基苯丙胺，一种苯丙胺衍生物，是一种强效的精神刺激药物，也是常见的滥用药物。本研究在最后一次剂量后 2-48 小时的一系列早期时间点，检测了 binge-like 甲基苯丙胺（MA）给药（4×4mg/kg，sc，间隔 2 小时）对大鼠脑内区域多巴胺和多巴胺代谢物水平的影响。最后一次给药后 2 小时测量时，体温升高。MA 在最后一次给药后 2 和 24 小时增加了前额叶皮层的多巴胺水平。在 24 小时时，杏仁核中的多巴胺水平也增加了。在任何时间点，纹状体都没有观察到变化，但多巴胺代谢物 DOPAC 的水平在 24 和 48 小时时明显降低。酪氨酸羟化酶的表达是多巴胺活性的下游诱导，它是多巴胺合成的限速酶。还评估了 binge-like MA 给药对含酪氨酸羟化酶细胞体的体积和含酪氨酸羟化酶纤维的面积分数的影响。MA 在最后一次给药后 2 小时增加了前额叶皮层中酪氨酸羟化酶纤维的面积分数，并减少了腹侧被盖区和黑质中含酪氨酸羟化酶细胞体的体积。在治疗后 48 小时观察到黑质细胞体体积增加。这些发现共同强调了多巴胺能系统在甲基苯丙胺诱导的作用中的重要性，确定了前额叶皮层、杏仁核和纹状体是对 binge-like MA 给药早期变化的关键区域，并提供了关于细胞体和酪氨酸羟化酶表达神经元纤维的时间依赖性影响的证据。
