Bardgett Mark E, Humphrey William M, Csernansky John G
Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA.
Neuropsychopharmacology. 2002 Dec;27(6):930-8. doi: 10.1016/S0893-133X(02)00376-7.
Previous studies have shown that excitotoxic hippocampal lesions in rats attenuate the ability of different doses of haloperidol, but not of clozapine, to suppress locomotor activity. The purpose of the present study was to determine if kainic acid-induced hippocampal damage reduces the degree of locomotor suppression produced by two relatively newer antipsychotic drugs, risperidone and olanzapine. Young adult male rats received bilateral intracerebroventricular infusions of the excitotoxin, kainic acid (KA), or vehicle and were tested for locomotor responses to drug treatment 30 days later. Infusions of KA produced neuronal loss in the CA3 region of the dorsal hippocampus in every rat. As reported previously, KA lesions reduced the ability of haloperidol (0.35 mg/kg) to completely suppress the locomotor activity elicited by amphetamine (1.5 mg/kg) relative to the effect of haloperidol in non-lesioned controls. Lesioned animals treated with a moderate dose of risperidone (1.4 mg/kg) also exhibited significantly more locomotor activity after amphetamine treatment in comparison to control animals. A trend toward greater activity was also observed in the lesioned group relative to the control group after olanzapine (3.0 mg/kg) injection (p =.09, 2-tailed). The locomotor effects of lower and higher doses of risperidone and olanzapine were not altered by kainic acid lesions. These data suggest that the locomotor-suppressive effects of moderate doses of risperidone and, perhaps, olanzapine involve hippocampal neurons, but that higher doses of each drug can suppress activity in a hippocampal-independent manner.
先前的研究表明，大鼠体内由兴奋性毒素引起的海马损伤会削弱不同剂量氟哌啶醇（而非氯氮平）抑制运动活动的能力。本研究的目的是确定海藻酸诱导的海马损伤是否会降低两种相对较新的抗精神病药物利培酮和奥氮平所产生的运动抑制程度。成年雄性幼鼠接受双侧脑室内注射兴奋性毒素海藻酸（KA）或赋形剂，并于30天后测试其对药物治疗的运动反应。每只大鼠注射KA后，其背侧海马CA3区均出现神经元损失。如先前报道，与未损伤对照组中氟哌啶醇的作用相比，KA损伤降低了氟哌啶醇（0.35毫克/千克）完全抑制苯丙胺（1.5毫克/千克）引发的运动活动的能力。与对照动物相比，接受中等剂量利培酮（1.4毫克/千克）治疗的损伤动物在苯丙胺治疗后也表现出明显更多的运动活动。注射奥氮平（3.0毫克/千克）后，损伤组相对于对照组也观察到活动增加的趋势（p = 0.09，双侧）。较低和较高剂量的利培酮和奥氮平的运动效应未因海藻酸损伤而改变。这些数据表明，中等剂量的利培酮以及可能的奥氮平的运动抑制作用涉及海马神经元，但每种药物的较高剂量可以以不依赖海马的方式抑制活动。
