Abstract：Objective To observe the long-term changes in anxiety-like behavior and tyrosine hydroxylase (TH) expression in the substantia nigra (SN) after hypoxic-ischemic brain damage (HIBD) in a neonatal rat model and to further explore the relationship between dopamine (DA) level and long-term anxiety-like behavior using the DA receptor (DAR) antagonist. Methods Seven-day-old (P7) neonatal Sprague-Dawley (SD) rats were randomized into normal control, sham-operated, HIBD and HIBD+DAR antagonist groups. HIBD model was prepared by ligating the right common carotid artery and 8% hypoxia exposure. The rats in the sham-operated group were sham-operated and were not subjected to right common carotid artery ligation and hypoxia exposure. The DAR antagonist was injected intraperitoneally before and after inducing HIBD. The same amount of normal saline was given to the other three groups as a control. Anxiety-like behavior was evaluated by elevated plus maze test, and TH expression in the SN was measured by immunohistochemistry on P14, P21, and P28. Results On P21 and P28, the time spent in the open arms and the percentage of open arms entries in the HIBD group were significantly increased compared with those in the normal control, sham-operated and HIBD+DAR antagonist groups (P<0.05); in addition, the HIBD+DAR antagonist group showed a significantly longer time spent in the open arms than the normal control group (P<0.05). On P14, P21, and P28, TH expression in the HIBD and HIBD+DAR antagonist groups was significantly lower than that in the normal control and sham-operated groups, and TH level in the HIBD group was significantly lower than that in the HIBD+DAR antagonist group (P<0.05). Conclusions DAR antagonist allows the restoration of anxiety-like behavior and alleviates the damage to dopaminergic neurons in SD rats after HIBD.
TAO Hui-Kang,TANG Qin,DAI Jin-Jin et al. Impact of dopamine receptor modulation on reduced anxiety-like behavior in neonatal rats after hypoxic-ischemic brain damage[J]. CJCP, 2014, 16(10): 1045-1050.
Volpe JJ. Neonatal encephalopathy: an inadequate term forhypoxic–ischemic encephalopathy[J]. Ann Neurol, 2012, 72(2):156-166.
[2]
Odd DE, Whitelaw A, Gunnell D, et al. The association betweenbirth condition and neuropsychological functioning andeducational attainment at school age: a cohort study[J]. Arch DisChild, 2011, 96(1): 30-37.
Hei MY, Luo YL, Zhang XC. Hypoxic-ischemic injurydecreases anxiety-like behaviour in rats associated with loss oftyrosin hydroxyalse immunoreactive neurons of the substantianigra[J]. Braz J Med Biol Res, 2012, 41(1): 13-19.
[5]
Busceti CL, Bucci D, Molinaro G, et al. Lack or inhibition ofdopaminergic stimulation induces a development increase ofstriatal tyrosine hydroxylase-positive interneurons[J]. PLoSOne, 2012, 7(9): e44025.
[6]
Golden JP, DeMaro JA, Knoten A, et al. Dopamine-dependentcompensation maintains motor behavior in mice withdevelopmental ablation of dopaminergic neurons[J]. J Neurosci,2013, 33(43): 17095-17107.
Vannucci RC, Connor JR, Mauger DT, et al. Rat model ofperinatal hypoxic-ischemic brain damage[J]. J Neurosci Res,1999, 55(2): 158-163.
[9]
Fan LW, Lin S, Pang Y, et al. Hypoxia-ischemia inducedneurological dysfunction and brain injury in the neonatal rat[J].Behav Brain Res, 2005, 165(1): 80-90.
[10]
Pagida MA, Konstantinidou AE, Tsekoura E, et al.Vulnerability of the mesencephalic dopaminergic neuronsof the human neonate to prolonged perinatal hypoxia: animmunohistochemical study of tyrosine hydroxylase expressionin autopsy material[J]. J Neuropathol Exp Neurol, 2013, 72(4):337-350.
[11]
Aumann TD, Egan K, Lim J, et al. Neuronal activity regulatesexpression of tyrosine hydroxylase in adult mouse substantianigra pars compacta neurons[J]. J Neurochem, 2011, 116(4):646-658.
[12]
Chun LS, Free RB, Doyle TB, et al. D1-D2 dopamine receptorsynergy promotes calcium signaling via multiple mechanisms[J].Mol Parmacol, 2013, 84(2): 190-200.
Hou I, Suzuki C, Kanegawa N, et al. β-Lactotensin derivedfrom bovine β-lactoglobulin exhibits anxiolytic-like activityas an agonist for neurotensin NTS2 receptor via activation ofdopamine D1 receptor in mice[J]. J Nurochem, 2011, 119(4):785-790.
[15]
de la Perez Mora M, Jacobsen KX, Crespo-Ramirez M, et al.Wiring and volume transmission in rat amygdala. Implicationsfor fear and anxiety[J]. Neurochem Res, 2008, 33(8): 1618-1633.
