Khanna J M, Kalant H, Shah G, Chau A
Department of Pharmacology, University of Toronto, Canada.
Pharmacol Biochem Behav. 1993 Aug;45(4):983-6. doi: 10.1016/0091-3057(93)90152-j.
We recently reported that the noncompetitive NMDA antagonists, (+)MK-801 and ketamine, block the development of rapid tolerance to ethanol. In the present article, we show that D-cycloserine (CS), an agonist at the glycine site of the NMDA receptor that enhances learning and memory, also enhances the development of rapid tolerance to ethanol. Rats were pretreated on day 1 with saline or CS, followed 30 min later by ethanol (2.3 g/kg, IP) or saline. At the end of motor impairment testing on the tilt-plane apparatus, a second injection of CS (3 mg/kg, IP, each time) or saline was given, followed 30 min later by ethanol or saline. Ethanol pretreatment alone (at this dose) did not result in rapid tolerance to ethanol on day 2. However, the group pretreated with CS and ethanol on day 1 showed significant tolerance on day 2 compared to other groups. Pretreatment with CS on day 1 did not affect the motor impairment response to the first exposure to ethanol whether this was on day 1 or day 2. In another experiment, administration of (+)MK-801 (0.25 mg/kg, IP) prior to CS abolished the rapid tolerance enhancement by CS. These findings are further evidence that the NMDA system, which requires activation by the glycine receptor, plays a major role in the development of at least some forms of ethanol tolerance.
我们最近报道，非竞争性N-甲基-D-天冬氨酸（NMDA）拮抗剂（+）MK-801和氯胺酮可阻断对乙醇快速耐受性的形成。在本文中，我们表明，D-环丝氨酸（CS）作为NMDA受体甘氨酸位点的激动剂，可增强学习和记忆，也能增强对乙醇快速耐受性的形成。在第1天，大鼠预先接受生理盐水或CS处理，30分钟后再给予乙醇（2.3克/千克，腹腔注射）或生理盐水。在倾斜平面装置上进行运动障碍测试结束时，再次注射CS（3毫克/千克，腹腔注射，每次）或生理盐水，30分钟后再给予乙醇或生理盐水。单独的乙醇预处理（此剂量）在第2天并未导致对乙醇的快速耐受性。然而，与其他组相比，在第1天用CS和乙醇预处理的组在第2天表现出显著的耐受性。第1天用CS预处理不影响对首次接触乙醇的运动障碍反应，无论首次接触是在第1天还是第2天。在另一项实验中，在CS之前给予（+）MK-801（0.25毫克/千克，腹腔注射）可消除CS对快速耐受性的增强作用。这些发现进一步证明，需要甘氨酸受体激活的NMDA系统在至少某些形式的乙醇耐受性形成中起主要作用。
