Nowak Przemyslaw, Jochem Jerzy, Zwirska-Korczala Krystyna, Josko Jadwiga, Noras Lukasz, Kostrzewa Richard M, Brus Ryszard
Department of Pharmacology, Medical University of Silesia, 41-808 Zabrze, Poland.
Neurotox Res. 2008 Apr;13(2):79-83. doi: 10.1007/BF03033559.
To determine whether noradrenergic nerves might have a modulatory role on the sensitivity or reactivity of histaminergic receptor systems in brain, behavioral effects of the respective histamine H1, H2 and H3 antagonists S(+)chlorpheniramine, cimetidine and thioperimide in control adult rats were compared to the effects in adult rats that had been lesioned as neonates with the noradrenergic neurotoxin DSP-4. On the 1st and 3rd days after birth rat pups were treated with either saline or DSP-4 (50 mg/kg sc), then returned to their home cages with the dam. At 8 weeks when rats were tested, S(+)chlorpheniramine (10 mg/kg ip) was found to increase locomotor activity in intact and DSP-4 lesioned rats, while cimetidine (5 mg/kg, ip) and thioperimide (5 mg/kg, ip) increased activity several-fold solely in the DSP-4 group. Exploratory activity, nociceptive activity, and irritability were little altered by the histamine antagonists, although oral activity was increased by thioperimide in intact and lesioned rats, and by cimetidine or S(+)chlorpheniramine in DSP-4 rats. High performance liquid chromatography with electrochemical detection was used to determine that DSP-4 produced a 90% reduction in frontal cortex, hippocampus and hypothalamus, with a 90% elevation of NE in cerebellum--reflecting reactive sprouting of noradrenergic fibers consequent to lesion of noradrenergic tracts projecting to proximal brain regions. These findings indicate that perinatal noradrenergic fiber lesioning in rat brain is associated with an altered behavioral spectrum by histamine H1, H2 and H3 receptor antagonists, thereby implicating histaminergic systems as modulators of noradrenergic systems in brain.
为了确定去甲肾上腺素能神经是否可能对脑内组胺能受体系统的敏感性或反应性具有调节作用，将组胺H1、H2和H3拮抗剂S(+)氯苯那敏、西咪替丁和硫代哌咪对成年对照大鼠的行为效应，与新生期用去甲肾上腺素能神经毒素DSP-4损伤的成年大鼠的效应进行了比较。出生后第1天和第3天，给幼鼠腹腔注射生理盐水或DSP-4（50mg/kg，皮下注射），然后让它们与母鼠一起回到笼中。在8周龄对大鼠进行测试时，发现S(+)氯苯那敏（10mg/kg，腹腔注射）可增加完整大鼠和DSP-4损伤大鼠的运动活性，而西咪替丁（5mg/kg，腹腔注射）和硫代哌咪（5mg/kg，腹腔注射）仅在DSP-4组使活性增加了几倍。组胺拮抗剂对探索活性、伤害感受活性和易怒性影响很小，尽管硫代哌咪可增加完整大鼠和损伤大鼠的口腔活性，西咪替丁或S(+)氯苯那敏可增加DSP-4大鼠的口腔活性。采用高效液相色谱-电化学检测法确定，DSP-4使额叶皮质、海马和下丘脑的去甲肾上腺素减少了90%，而小脑的去甲肾上腺素增加了90%，这反映了投射到近端脑区的去甲肾上腺素能神经束损伤后去甲肾上腺素能纤维的反应性发芽。这些发现表明，大鼠脑内围产期去甲肾上腺素能纤维损伤与组胺H1、H2和H3受体拮抗剂改变的行为谱相关，从而提示组胺能系统是脑内去甲肾上腺素能系统的调节因子。
