Luthman J, Fredriksson A, Lewander T, Jonsson G, Archer T
Department of Histology and Neurobiology, Karolinska Institute, Stockholm, Sweden.
Psychopharmacology (Berl). 1989;99(4):550-7. doi: 10.1007/BF00589907.
Neonatal intracisternal administration of 6-hydroxydopamine (6-OHDA, 50 micrograms on day 1 after birth) caused a marked hyperactivity when the rats were tested as adults. These rats also showed severe DA depletions in striatum and nucleus accumbens. Pretreatment with the noradrenaline (NA) uptake inhibitor desipramine provided protection against NA depletion in frontal cortex and nucleus accumbens. Pretreatment with DA uptake inhibitors, amfolenic acid or GBR 12909, before 6-OHDA, provided full protection against DA depletion but produced marked NA depletion in frontal cortex. These rats did not demonstrate any degree of hyperactivity. Low doses of d-amphetamine (0.25 mg/kg SC) or methylphenidate (1 mg/kg SC) reversed the hyperactivity in DA-depleted rats but increased motor activity in vehicle-treated and NA-depleted rats. Higher doses of d-amphetamine (1 mg/kg) or methylphenidate (4 mg/kg) produced potentiated levels of locomotion but attenuated levels of rearing in DA-depleted animals. The results further suggest the utility of the neonatal DA lesion in rats as a potential animal model for derivation of therapeutic agents that may be efficacious in the treatment of the hyperkinetic syndrome.
新生大鼠出生后第1天脑池内注射6-羟基多巴胺（6-OHDA，50微克），成年后进行测试时会出现明显的多动症状。这些大鼠的纹状体和伏隔核中多巴胺（DA）也严重耗竭。用去甲肾上腺素（NA）摄取抑制剂地昔帕明预处理可防止额叶皮质和伏隔核中的NA耗竭。在注射6-OHDA之前，用DA摄取抑制剂、氨苯蝶啶或GBR 12909预处理可完全防止DA耗竭，但会导致额叶皮质中NA明显耗竭。这些大鼠未表现出任何程度的多动。低剂量的右旋苯丙胺（0.25毫克/千克，皮下注射）或哌甲酯（1毫克/千克，皮下注射）可逆转DA耗竭大鼠的多动，但会增加溶剂处理和NA耗竭大鼠的运动活性。高剂量的右旋苯丙胺（1毫克/千克）或哌甲酯（4毫克/千克）可使DA耗竭动物的运动水平增强，但竖毛水平减弱。结果进一步表明，新生大鼠DA损伤作为一种潜在的动物模型，可用于研发可能有效治疗多动综合征的治疗药物。
