Thacker Stephanie K, Perna Marla K, Ward Jeffery J, Schaefer Tori L, Williams Michael T, Kostrzewa Richard M, Brown Russell W
Department of Psychology, East Tennessee State University, Johnson City, TN 37614, USA.
Eur J Neurosci. 2006 Oct;24(7):2075-83. doi: 10.1111/j.1460-9568.2006.05048.x.
Male and female Sprague-Dawley rats were administered quinpirole (1 mg/kg, i.p.) or saline once daily from postnatal day (P)1 to P21. This drug treatment has been shown to produce long-term priming of the D2 receptor. Beginning on P62, rats were administered the atypical antipsychotic olanzapine (2.5 mg/kg) or saline twice daily (i.p.) for 28 days. One day after olanzapine treatment ceased, rats were tested on the place and match-to-place versions of the Morris water maze (MWM) for seven consecutive days. Dopamine D2 receptor priming was verified through a yawning behavioural test, a D2 receptor-mediated event, before olanzapine was administered as well as after olanzapine treatment and behavioural testing were complete. Results showed that neonatal quinpirole treatment induced D2 priming that was eliminated by olanzapine treatment. On the MWM place version, D2-primed rats demonstrated a significant impairment that was eliminated by olanzapine treatment, but olanzapine treatment to animals neonatally treated with saline produced a significant deficit on the place version of the MWM. There were no significant deficits on the match-to-place version. Brain tissue analyses revealed that neonatal quinpirole treatment produced a significant decrease in hippocampal NGF, BDNF and ChAT that was eliminated by olanzapine treatment. Neonatal quinpirole treatment produced a significant decrease in BDNF and ChAT in the frontal cortex that was unaffected by olanzapine treatment. These results show that olanzapine eliminates D2 receptor priming and cognitive impairment and also alleviates decreases in neurotrophins and acetylcholinergic markers produced by D2 priming in the hippocampus.
从出生后第1天（P1）至P21，每天给雄性和雌性Sprague-Dawley大鼠腹腔注射喹吡罗（1毫克/千克）或生理盐水一次。已证明这种药物治疗可产生D2受体的长期致敏作用。从P62开始，每天给大鼠腹腔注射两次非典型抗精神病药物奥氮平（2.5毫克/千克）或生理盐水，持续28天。奥氮平治疗停止一天后，连续七天对大鼠进行位置版和位置匹配版的莫里斯水迷宫（MWM）测试。在给予奥氮平之前以及奥氮平治疗和行为测试完成后，通过打哈欠行为测试（一种D2受体介导的事件）验证多巴胺D2受体致敏作用。结果表明，新生期喹吡罗治疗诱导的D2致敏作用被奥氮平治疗消除。在MWM位置版测试中，D2致敏大鼠表现出明显的损伤，该损伤被奥氮平治疗消除，但对新生期用生理盐水治疗的动物给予奥氮平治疗后，在MWM位置版测试中产生了明显的缺陷。在位置匹配版测试中没有明显缺陷。脑组织分析显示，新生期喹吡罗治疗使海马中的神经生长因子（NGF）、脑源性神经营养因子（BDNF）和胆碱乙酰转移酶（ChAT）显著降低，而奥氮平治疗可消除这种降低。新生期喹吡罗治疗使额叶皮质中的BDNF和ChAT显著降低，而奥氮平治疗对此无影响。这些结果表明，奥氮平消除了D2受体致敏作用和认知障碍，还减轻了海马中由D2致敏作用导致的神经营养因子和乙酰胆碱能标志物的降低。
