Kalivas P W, Alesdatter J E
Alcohol and Drug Abuse Program, Washington State University, Pullman.
J Pharmacol Exp Ther. 1993 Oct;267(1):486-95.
Systemic administration of N-methyl-D-aspartate (NMDA) antagonists prevents the development of behavioral sensitization to amphetamine-like psychostimulants. Pretreatment with the noncompetitive NMDA antagonist, MK-801, resulted in a dose-dependent blockade of behavioral sensitization to cocaine. However, pretreatment with the highest dose of MK-801 (0.25 mg/kg i.p.) alone inhibited the behavioral response to a subsequent cocaine challenge 24 hr later. The induction of behavioral sensitization is known to result, at least partly, from an action by psychostimulants in the ventral tegmental area (VTA). To determine whether the dose-dependent inhibition of behavioral sensitization to cocaine by NMDA antagonists resulted from receptor blockade in the VTA, rats were pretreated in the VTA with the MK-801 or the competitive NMDA antagonist, 3-(2-carboxypiperazine-4-yl) propyl-1-phosphonic acid, before systemically administered cocaine (30 mg/kg i.p.). Two to 3 days later rats were challenged with cocaine alone (15 mg/kg i.p.). Pretreatment with either NMDA antagonist into the VTA prevented the manifestation of behavioral sensitization. Intracranial pretreatment with MK-801 was also made into the nucleus accumbens and amygdala which have been implicated in psychostimulant-induced sensitization. Whereas MK-801 was without effect in the nucleus accumbens, when microinjected into the ventral amygdala it prevented the manifestation of behavioral sensitization to a cocaine challenge. The blockade of sensitization by MK-801 in the VTA was produced with a minimum effective dose of 0.01 nmol, whereas the minimum effective dose in the amygdala was 1.0 nmol. These data demonstrate that stimulation of NMDA receptors in the VTA and amygdala is necessary in the development of behavioral sensitization to cocaine.
N-甲基-D-天冬氨酸（NMDA）拮抗剂的全身给药可预防对苯丙胺样精神兴奋剂产生行为敏化。用非竞争性NMDA拮抗剂MK-801进行预处理，可导致对可卡因行为敏化的剂量依赖性阻断。然而，单独用最高剂量的MK-801（0.25毫克/千克腹腔注射）进行预处理，会抑制24小时后对随后可卡因激发的行为反应。已知行为敏化的诱导至少部分是由精神兴奋剂在腹侧被盖区（VTA）的作用引起的。为了确定NMDA拮抗剂对可卡因行为敏化的剂量依赖性抑制是否源于VTA中的受体阻断，在全身给予可卡因（30毫克/千克腹腔注射）之前，先在VTA中用MK-801或竞争性NMDA拮抗剂3-(2-羧基哌嗪-4-基)丙基-1-膦酸对大鼠进行预处理。两到三天后，单独用可卡因（15毫克/千克腹腔注射）对大鼠进行激发。在VTA中用任何一种NMDA拮抗剂进行预处理均可防止行为敏化的表现。还将MK-801颅内预处理至伏隔核和杏仁核，这些脑区与精神兴奋剂诱导的敏化有关。虽然MK-801对伏隔核没有作用，但当微量注射到腹侧杏仁核时，它可防止对可卡因激发的行为敏化的表现。MK-801在VTA中产生敏化阻断的最小有效剂量为0.01纳摩尔，而在杏仁核中的最小有效剂量为1.0纳摩尔。这些数据表明，VTA和杏仁核中NMDA受体的刺激在对可卡因行为敏化的发展中是必要的。
