Bowyer J F, Gough B, Slikker W, Lipe G W, Newport G D, Holson R R
Division of Neurotoxicology, National Center for Toxicological Research, Jefferson, AR 72079.
Pharmacol Biochem Behav. 1993 Jan;44(1):87-98. doi: 10.1016/0091-3057(93)90284-z.
Extracellular levels of dopamine (DA) and metabolites as well as serotonin [5-hydroxytryptamine (5-HT)] and 5-hydroxyindoleacetic acid (5-HIAA) were determined in the caudate putamen (CPU) of either 6- or 12-month-old female rats using microdialysis and high-performance liquid chromatography with electrochemical detection (HPLC-ED) before, during, and after four consecutive injections (given at 2-h intervals) of methamphetamine (METH). In 6-month-old rats administered 4 x 5 mg/kg METH at an environmental temperature (ET) of 23 degrees C, peak extracellular DA levels (between 50 and 150 rho g/10 microliters) were attained 30-45 min after each dose of METH while dihydroxyphenylacetic acid (DOPAC) decreased steadily after the first doses of METH until it reached a plateau at 50% of control (550-700 pg/10 microliters) levels. Increases in 5-HT levels during METH administrations paralleled DA increases while 5-HIAA decreases paralleled DOPAC decreases. The total CPU DA and 5-HT content of these rats was about 65% of control at 3 days post-METH. Reducing the ET to 4 degrees C during dosing decreased the peak and average DA levels attained during the 4 x 5 mg/kg METH administration to about 50% of that observed at a 23 degrees C ET. Increasing the dose to 4 x 10 mg/kg METH (4 degrees C ET) increased peak and average CPU DA levels to 200% that observed during 4 x 5 mg/kg METH at a 23 degrees C ET. However, no significant decreases in total CPU DA content of any rats dosed with METH at a 4 degrees C ET were observed 3 days post-METH. In 12-month-old rats dosed with 4 x 5 mg/kg METH (23 degrees C ET), the peak and average extracellular DA levels were only 30-60% that of 6-month-old rats. However, the CPU DA content of older rats was significantly decreased both 3 (30% control) and 14 (60% control) days post-METH. In summary, METH toxicity may not be predicted solely by the extracellular levels of DA attained during METH administration; age and ET also greatly influence METH neurotoxicity.
使用微透析和高效液相色谱-电化学检测法（HPLC-ED），在连续四次注射（每隔2小时注射一次）甲基苯丙胺（METH）之前、期间和之后，测定6月龄或12月龄雌性大鼠尾状壳核（CPU）中多巴胺（DA）及其代谢物以及血清素[5-羟色胺（5-HT）]和5-羟吲哚乙酸（5-HIAA）的细胞外水平。在环境温度（ET）为23摄氏度的条件下，给6月龄大鼠注射4×5mg/kg的METH，每次注射METH后30-45分钟达到细胞外DA水平峰值（50至150μg/10微升之间），而二羟基苯乙酸（DOPAC）在首次注射METH后稳步下降，直至降至对照水平（550-700pg/10微升）的50%并达到平台期。METH给药期间5-HT水平的升高与DA升高平行，而5-HIAA的降低与DOPAC降低平行。这些大鼠在METH给药后3天，CPU中DA和5-HT的总含量约为对照的65%。给药期间将ET降至4摄氏度，会使4×5mg/kg METH给药期间达到的DA峰值和平均水平降至在23摄氏度ET下观察到的水平的约50%。将剂量增加到4×10mg/kg METH（4摄氏度ET），会使CPU中DA峰值和平均水平增加到在23摄氏度ET下4×5mg/kg METH给药期间观察到水平的200%。然而，在4摄氏度ET下用METH给药的任何大鼠，在METH给药后3天未观察到CPU中DA总含量有显著下降。在23摄氏度ET下给12月龄大鼠注射4×5mg/kg METH，细胞外DA水平峰值和平均值仅为6月龄大鼠的30-60%。然而，老年大鼠在METH给药后3天（对照的30%）和14天（对照的60%），CPU中DA含量显著下降。总之，METH毒性可能不能仅通过METH给药期间达到的DA细胞外水平来预测；年龄和ET也会极大地影响METH神经毒性。
