Mickley G A, Schaldach M A, Snyder K J, Balogh S A, Len T, Neimanis K, Goulis P, Hug J, Sauchak K, Remmers-Roeber D R, Walker C, Yamamoto B K
Department of Psychology, Carnegie Hall, Baldwin-Wallace College, Berea, OH 44017-2088, USA.
Physiol Behav. 1998 Jun 1;64(3):381-90. doi: 10.1016/s0031-9384(98)00097-3.
These experiments explored the effects of glutamate, N-methyl-D-aspartate (NMDA) receptor blockade on the formation, retention, and expression of conditioned taste aversion (CTA) in young rats. Previous data from our laboratory suggested that ketamine administration potentiates a CTA in E18 rat fetuses. The current studies investigated this phenomenon in neonates. High-pressure liquid chromatography (HPLC) methods were used to determine the amount of ketamine that must be injected intraperitoneally (i.p.) to achieve brain ketamine levels in neonates comparable to those found in the fetuses from our previous experiments. Then, on their day of birth, Sprague-Dawley rat pups received injections of either 0.1, 10, or 70 mg/kg of ketamine HCI, i.p. or a Sal control injection. One-half hour later, pups were injected orally with either Saccharin (Sac; 10 microL of 0.3%) or water followed by an injection of either lithium chloride (LiCl; 81 mg/kg) or Sal (i.p.). The CTA was evaluated in two different tests. Two weeks after conditioning, the dam was anesthetized and the frequency with which pups attached to Sac-painted nipples versus nipples painted with water was measured (i.e., the nipple taste test, NTT). Controls for state-dependent learning were run in which 10 mg/kg of ketamine or saline (Sal) was administered before both taste aversion conditioning and the NTT. After weaning, the CTA was also evaluated by measuring the amount of Sac (0.3%) or water consumed during a two-bottle test. Neonates that received Sal control injections before the Sac + LiCl pairing acquired CTAs and avoided Sac-painted nipples. However, the pups injected with ketamine on the conditioning day only (P0) did not avoid Sac-painted nipples (as compared to controls). Pups that had ketamine both at the time of CTA training and testing, or just before the NTT, also failed to avoid Sac-painted nipples. Ketamine's acute effects apparently influenced the outcome of the NTT of state-dependent control subjects. Rat pups that received the highest doses of ketamine (10 or 70 mg/kg) and tasted Sac on P0 later failed to show a neophobia for Sac-painted nipples. Whereas, rat pups that received the high dose of ketamine and water on P0, later exhibited a neophobic response. These data suggest that ketamine did not impair the animal's ability to taste Sac. These data reflecting a ketamine-induced blockade of neonatal CTAs may be contrasted with our previous findings in which ketamine potentiated fetal CTAs. However, they are in consonance with data from adult rats suggesting that ketamine can cause an amnesia for CTAs. NMDA receptor blockade may shape memory formation in a manner that is dependent on the stage of brain development.
这些实验探究了谷氨酸、N-甲基-D-天冬氨酸（NMDA）受体阻断对幼鼠条件性味觉厌恶（CTA）形成、保留和表达的影响。我们实验室之前的数据表明，给予氯胺酮可增强E18大鼠胎儿的CTA。当前的研究在新生大鼠中探究了这一现象。采用高压液相色谱（HPLC）方法来确定必须腹腔注射（i.p.）多少氯胺酮才能使新生大鼠脑内氯胺酮水平与我们之前实验中胎儿的水平相当。然后，在出生当天，将Sprague-Dawley大鼠幼崽腹腔注射0.1、10或70 mg/kg的盐酸氯胺酮，或注射生理盐水作为对照。半小时后，给幼崽口服糖精（Sac；10 μL的0.3%溶液）或水，随后腹腔注射氯化锂（LiCl；81 mg/kg）或生理盐水。通过两种不同的测试来评估CTA。条件反射建立两周后，将母鼠麻醉，测量幼崽附着在涂有Sac的乳头与涂有水的乳头的频率（即乳头味觉测试，NTT）。进行状态依存性学习的对照实验，在味觉厌恶条件反射和NTT之前均给予10 mg/kg的氯胺酮或生理盐水（Sal）。断奶后，还通过测量两瓶测试中消耗的Sac（0.3%）或水的量来评估CTA。在Sac + LiCl配对前接受生理盐水对照注射的新生大鼠获得了CTA并避开了涂有Sac的乳头。然而，仅在条件反射当天（P0）注射氯胺酮的幼崽并未避开涂有Sac的乳头（与对照组相比）。在CTA训练和测试时或仅在NTT之前注射氯胺酮的幼崽也未能避开涂有Sac的乳头。氯胺酮 的急性效应显然影响了状态依存性对照实验对象的NTT结果。在P0接受最高剂量氯胺酮（10或70 mg/kg）并品尝Sac的大鼠幼崽后来对涂有Sac的乳头未表现出新恐惧症。而在P0接受高剂量氯胺酮和水的大鼠幼崽后来表现出了新恐惧症反应。这些数据表明氯胺酮并未损害动物品尝Sac的能力。这些反映氯胺酮诱导新生大鼠CTA阻断的数据可能与我们之前氯胺酮增强胎儿CTA的发现形成对比。然而，它们与成年大鼠的数据一致，表明氯胺酮可导致CTA失忆。NMDA受体阻断可能以一种依赖于脑发育阶段的方式塑造记忆形成。
