Boctor Sherin Y, Ferguson Sherry A
Department of Interdisciplinary Biomedical Sciences, University of Arkansas for Medical Sciences, Little Rock, AR 72205, United States.
Neurotoxicology. 2009 Jan;30(1):151-4. doi: 10.1016/j.neuro.2008.10.011. Epub 2008 Nov 7.
Glutamate activation of the NMDA receptor is essential for neuronal differentiation, migration, and survival. Treatment with NMDA receptor antagonists, such as ketamine (KET) or phencyclidine (PCP), can trigger apoptosis in neonatal rats. However, L-carnitine (LC) treatment appears to prevent glutamate-induced toxicity in the developing CNS. Previously, we described altered preweaning behaviors (i.e., abnormal home cage, slant board and forelimb hang behaviors) resulting from neonatal PCP and KET treatment. Those adverse effects of KET were somewhat ameliorated by LC [Boctor SY, Wang C, Ferguson SA. Neonatal PCP is more potent than ketamine at modifying preweaning behaviors of Sprague-Dawley rats. Toxicol Sci 2008;106:172-9]. Here, a portion of those subjects were evaluated for prepulse inhibition (PPI) of the acoustic startle response at postnatal day (PND) 25 since previous reports described PCP-induced effects on this response. Rats were subcutaneously treated with: saline; 10 mg/kg PCP (1x/day) on PNDs 7, 9 and 11; 20 mg/kg KET (6 injections every 2h on PND 7); or a similar regimen of ketamine and 250 mg/kg LC on PND 7, with a single injection of 250 mg/kg LC on PNDs 8-11 (KLC). Male and female rats were assessed using a standard PPI paradigm with prepulses of 68, 78 and 82 dB. Body weight was decreased 17-21% and whole brain weight was decreased 10% in PCP-treated rats. Specifically, cerebellar weight was significantly less in PCP-treated rats relative to control. Despite the magnitude of those PCP-induced changes, startle response in normal pulse only trials and percent of PPI in PCP-, KET-, and KLC-treated groups were comparable to controls. Average latency to maximum startle was 2.6 ms less in females than males (p<0.007); there were no other significant sex effects. The lack of neonatal PCP treatment on later PPI is similar to that reported by Rasmussen et al. [Rasmussen BA, O'Neil J, Manaye KF, Perry DC, Tizabi Y. Long-term effects of developmental PCP administration on sensorimotor gating in male and female rats. Psychopharmacology (Berl) 2007; 190: 43-9.], and indicates that neonatal PCP-induced effects on PPI [Wang C, McInnis J, Ross-Sanchez M, Shinnick-Gallagher P, Wiley JL, Johnson KM. Long-term behavioral and neurodegenerative effects of perinatal phencyclidine administration: implications for schizophrenia. Neuroscience 2001; 107: 535-50.] appear difficult to replicate.
NMDA受体的谷氨酸激活对于神经元的分化、迁移和存活至关重要。用NMDA受体拮抗剂如氯胺酮（KET）或苯环己哌啶（PCP）进行治疗可引发新生大鼠的细胞凋亡。然而，左旋肉碱（LC）治疗似乎可预防发育中的中枢神经系统中谷氨酸诱导的毒性。此前，我们描述了新生期PCP和KET治疗导致的断奶前行为改变（即异常的笼内行为、斜板行为和前肢悬挂行为）。LC在一定程度上改善了KET的那些不良影响[Boctor SY, Wang C, Ferguson SA. Neonatal PCP is more potent than ketamine at modifying preweaning behaviors of Sprague-Dawley rats. Toxicol Sci 2008;106:172-9]。在此，由于之前的报告描述了PCP对该反应的影响，对其中一部分受试动物在出生后第25天（PND 25）进行了听觉惊吓反应的前脉冲抑制（PPI）评估。大鼠皮下注射以下药物：生理盐水；在PND 7、9和11时给予10 mg/kg PCP（每天1次）；在PND 7时给予20 mg/kg KET（每2小时注射6次）；或在PND 7时给予类似方案的氯胺酮和250 mg/kg LC，并在PND 8 - 11时单次注射250 mg/kg LC（KLC）。使用标准的PPI范式，对雄性和雌性大鼠进行评估，前脉冲强度为68、78和82 dB。PCP处理的大鼠体重下降了17 - 21%，全脑重量下降了10%。具体而言，与对照组相比，PCP处理的大鼠小脑重量显著减轻。尽管PCP引起了这些变化，但在仅正常脉冲试验中的惊吓反应以及PCP、KET和KLC处理组中的PPI百分比与对照组相当。雌性大鼠达到最大惊吓的平均潜伏期比雄性大鼠短2.6毫秒（p<0.007）；没有其他显著的性别效应。新生期PCP处理对后期PPI缺乏影响与Rasmussen等人的报告相似[Rasmussen BA, O'Neil J, Manaye KF, Perry DC, Tizabi Y. Long-term effects of developmental PCP administration on sensorimotor gating in male and female rats. Psychopharmacology (Berl) 2007; 190: 43-9.]，这表明新生期PCP对PPI的影响[Wang C, McInnis J, Ross-Sanchez M, Shinnick-Gallagher P, Wiley JL, Johnson KM. Long-term behavioral and neurodegenerative effects of perinatal phencyclidine administration: implications for schizophrenia. Neuroscience 2001; 107: 535-50.]似乎难以复制。
